Cellulitis, Osteomyelitis and Sepsis

• Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick PM, Masson EA, McCollum PT: The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial. Eur J Vasc Endovasc Surg. 25:513-8, 2003. OBJECTIVE: ischaemic lower-extremity ulcers in the diabetic population are a source of major concern because of the associated high risk of limb-threatening complications. The aim of this study was to evaluate the role of hyperbaric oxygen in the management of these ulcers. METHOD: eighteen diabetic patients with ischaemic, non-healing lower-extremity ulcers were recruited in a double-blind study. Patients were randomly assigned either to receive 100% oxygen (treatment group) or air (control group), at 2.4 atmospheres of absolute pressure for 90 min daily (total of 30 treatments). RESULTS: healing with complete epithelialisation was achieved in five out of eight ulcers in the treatment group compared to one out of eight ulcers in the control group. The median decrease of the wound areas in the treatment group was 100% and in the control group was 52% (p=0.027). Cost-effectiveness analysis has shown that despite the extra cost involved in using hyperbaric oxygen, there was a potential saving in the total cost of treatment for each patient during the study. CONCLUSION: hyperbaric oxygen enhanced the healing of ischaemic, non-healing diabetic leg ulcers and may be used as a valuable adjunct to conventional therapy when reconstructive surgery is not possible. Comments: The patients were judged to have ischemic disease if their ankle-brachial index was under 0.8 or great toe-brachial index under 0.7 (if calf vessels incompressible). The study was small involving 18 patients, nine in the treated and 9 in the control groups. Both control and the treatment group received hyperbaric treatments, the difference being that the treatment group was given 100% oxygen in the chamber. The ulcers were generally Wagner grade II and, while larger and deeper in the treatment group, they had been there longer in the control group (9 months, 3-60) than in the treatment group (6 months, 3-60 months). While the patients undoubtedly had arteriosclerosis, the importance of the arteriosclerosis and the propriety of adding "ischaemia" to the title might be questioned as the transcutaneous partial pressures of oxygen (TcPO2) were normal in both groups (treatment 46+/-15 and control 43+/-19).

• Ahmed S, Meghji S, Williams RJ et al: Staphylococcus aureus fibronectin binding proteins are essential for internalization by osteoblasts but do not account for differences in intracellular levels of bacteria. Infect Immun 69:2872-7, 2001. Staphylococcus aureus is a major pathogen of bone that has been shown to be internalized by osteoblasts via a receptor-mediated pathway. Here we report that there are strain-dependent differences in the uptake of S. aureus by osteoblasts. An S. aureus septic arthritis isolate, LS-1, was internalized some 10-fold more than the laboratory strain 8325-4. Disruption of the genes for the fibronectin binding proteins in these two strains of S. aureus blocked their ability to be internalized by osteoblasts, thereby demonstrating the essentiality of these genes in this process. However, there were no differences in the capacity of these two strains to bind to fibronectin or osteoblasts. Analysis of the kinetics of internalization of the two strains by osteoblasts revealed that strain 8325-4 was internalized only over a short period of time (2 h) and to low numbers, while LS-1 was taken up by osteoblasts in large numbers for over 3 h. These differences in the kinetics of uptake explain the fact that the two strains of S. aureus are internalized by osteoblasts to different extents and suggest that in addition to the fibronectin binding proteins there are other, as yet undetermined virulence factors that play a role in the internalization process. Comments: This article is one of several included here pointing out that bacteria may hide within the cell where the concentration of antibiotics may not approach that in the extracellular fluid. As a result, cure with the administration of systemic antibiotics may be difficult. The injection of local antibiotics in and around the bone obviously increases the gradient of the concentration of antibiotics across the cell wall.

• Apelqvist J et al: Wound classification is more important than site of ulceration in the outcome of diabetic foot ulcers. Diabetic Medicine 6:526-520, 1989. 314 consecutive patients classified according to Wagner as having superficial (through the full thickness of the dermis, N=150), deep (N=50), osteomyelitis &/or abscess (N=46), minor gangrene (N=39), or major gangrene (N=29). Healing for at least 6 months: 88% and 78% for superficial and deep, 57% for abscess and osteomyelitis, 2 of 68 with gangrene... lowest healing rate (5%) in patients with multiple ulcers who had the worst blood flow.

• Arbeit RD, Maki D et al: The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 38: 1673-81, 2004. Daptomycin is the first available agent from a new class of antibiotics, the cyclic lipopeptides, that has activity against a broad range of gram-positive pathogens, including organisms that are resistant to methicillin, vancomycin, and other currently available agents. Daptomycin (4 mg/kg intravenously [iv] every 24 h for 7-14 days) was compared with conventional antibiotics (penicillinase-resistant penicillins [4-12 g iv per day] or vancomycin [1 g iv every 12 h]) in 2 randomized, international trials involving 1092 patients with complicated skin and skin-structure infections. Among 902 clinically evaluable patients, clinical success rates were 83.4% and 84.2% for the daptomycin- and comparator-treated groups, respectively (95% confidence interval, -4.0 to 5.6). Among patients successfully treated with iv daptomycin, 63% required only 4-7 days of therapy, compared with 33% of comparator-treated patients (P<.0001). The frequency and distribution of adverse events were similar among both treatment groups. Overall, the safety and efficacy of daptomycin were comparable with conventional therapy. Comments: Daptomycin is a welcome new antibiotic with a distinct mechanism of action: disrupting multiple aspects of bacterial cell membrane function. Presumably binding to the membrane, it causes rapid depolarisation, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which in turn results in bacterial cell death. The bactericidal activity of daptomycin is concentration-dependent. There is in vitro evidence of synergy with ß-lactam antibiotics. It is inactivated by pulmonary surfactants and, hence, is not indicated for the treatment of pneumonia. In skin and soft tissue infections, 4 mg/kg daptomycin is given intravenously once daily.

• Balsells M, Viadé J, Millán M et al: Prevalence of osteomyelitis in non-healing diabetic foot ulcers: usefulness of radiologic and scintigraphic findings. Diabetes Res Clin Pract 38:123-7,1997. The study was conducted in order to assess the prevalence of osteomyelitis and the predictive value of radiographic (xR) and combined Tc 99-bone and leukocyte scanning (CS) findings in diabetic foot ulcers that met criteria for hospital admission (FUH). Out of 150 episodes of ulceration managed in an outpatient basis, 33 (in 28 NIDDM patients) requiring admission were evaluated. In all cases plain xR and CS were carried out. Seventeen episodes (51.5%) had a good outcome (healed or improving, at the time of the last follow up). Osteomyelitis was found in 21 episodes and 14 (66.6%) of them required an amputation. In 13 cases where xR showed characteristic radiologic changes of osteomyelitis (11 of them had a positive CS) 11 (84.6%) underwent an amputation. However, when osteomyelitis was diagnosed only by a positive CS, only 3/8 (37.5%) required a toe amputation. Severe peripheral vasculopathy was present in 44% of cases who required amputation and only in 17.6% of those who did not. We conclude that in FU underlying osteomyelitis is frequent and associated to a higher amputation rate than when no bone infection is identified (66.6 vs 17%), even when corrected for vascular status (OR 11, CI 95% 1.65-74.2), with a worse outcome when xR changes are already present.

• Bamberger DM, Daus GP and Gerding DN: Osteomyelitis in the feet of diabetic patients; Long-term results, prognostic factors and the role of antimicrobial and surgical therapy. Am J Med 83:653-660, 1987. Of 51 patients, 15 patients had a BK amputation and 9 a toe amputation. The absence of necrosis and/or gangrene, the presence of swelling and the use of antimicrobial therapy active against the isolated pathogens for at least 4 weeks intravenously or combined orally-intravenously for ten weeks predicted a good outcome.

• Calhoun JH, Cantrell J, et al: Treatment of diabetic foot infections: Wagner classification, therapy, and outcome. Foot & Ankle 9:101-108, 1988. 850 foot infections in 355 patients. Patients treated with the Wagner algorithms did better than those not so treated. Healing in various grades protocol (nonprotocol): 0-89% (1/1 failed); 1- 86% (53%) ; 2- 73% (12%); 3 - 79% (12%); 4 - 88% (20%); 5 - 97% (?). Overall: 355 patients, 710 legs, 805 operations, 32 vascular procedures, 9 AK amputations, 121 BK amputations, 8 Syme amputations, 24 ankle disarticulations, 21 metatarsal amputations, 72 ray resections, 158 toe amputations, 47 incision and drainage, 42 skin grafts and 273 debridements.

• Croll SD, Nicholas GG, Osborne MA, Wasser TE, Jones S: Role of magnetic resonance imaging in the diagnosis of osteomyelitis in diabetic foot infections. J Vasc Surg 24(2):266-70, 1996. PURPOSE: The role of magnetic resonance imaging (MRI) in the diagnosis of osteomyelitis in foot infections in diabetics was investigated. The accuracy, sensitivity, and specificity of MRI, plain radiography, and nuclear scanning were determined for diagnosing osteomyelitis, and a cost comparison was made. METHODS: Twenty-seven patients with diabetic foot infections were studied prospectively. All patients underwent MRI and plain radiography. Twenty-two patients had technetium bone scans, and 19 patients had Indium scans. Nineteen patients had all four tests performed. Patients with obvious gangrene or a fetid foot were excluded. RESULTS: The diagnosis of osteomyelitis was established by pathologic specimen (n = 18), bone culture (n = 3), or successful response to medical management (n = 6). Osteomyelitis was confirmed in nine of the pathologic specimens. The diagnostic sensitivity, specificity, and accuracy for MRI was 88%, 100%, and 95%, respectively, for plain radiography it was 22%, 94%, and 70%, respectively, for technetium bone scanning it was 50%, 50%, and 50%, respectively, and for Indium leukocyte scanning it was 33%, 69%, and 58%, respectively. The data were analyzed statistically with the two-tailed Fisher's exact test. MRI was the only test that was statistically significant (p < 0.01). CONCLUSIONS: MRI appeared to be the single best test for the diagnosis of osteomyelitis associated with diabetic foot infections. It had a better diagnostic accuracy than conventional modalities and appeared to be more cost-effective than the frequently used Indium scan.

• D'Agostino DP, Colomb DG, Dean JB: Effects of hyperbaric gases on membrane nanostructure and function in neurons. J Appl Physiol 2009. This mini-review summarizes current ideas of how hyperbaric gases (>1-10 ATA) affect neuronal mechanisms of excitability through molecular interaction with membrane components. The dynamic nature of the lipid bilayer, its resident proteins, and the underlying cytoskeleton, makes each respective nanostructure a potential target for modulation by hyperbaric gases. Depending on the composition of the gas mixture, the relative concentrations of O2 and inert gas, and total barometric pressure, the net effect of a particular gas on the cell membrane will be determined by the gas' i) lipid solubility, ii) ability to oxidize lipids and proteins (O2), and iii) capacity, in the compressed state, to generate localized shear and strain forces between various nanostructures. A change in the properties of any one membrane component is anticipated to change conductance of membrane-spanning ion channels and thus neuronal function. Key words: anesthesia, barosensitivity, oxidative stress, nitrogen narcosis.

• Delcourt A, Huglo D et al: Comparison between Leukoscan (Sulesomab) and Gallium-67 for the diagnosis of osteomyelitis in the diabetic foot. Diabetes Metab.31:125-33, 2005. OBJECTIVES: The diagnosis of osteomyelitis in patients with diabetic foot is difficult both clinically and radiologically. An early diagnosis is crucial to optimize therapeutic strategy. Among the diagnostic methods currently used, scintigraphy with ex-vivo labelled white blood cells is the gold standard, but cannot be performed in all centers; therefore 67Gallium citrate (67Ga) imaging in combination with a bone scintigraphy is still widely used. METHOD: The results of imaging 24 diabetic patients with 31 suspected osteomyelitic lesions using the antigranulocyte Fab' fragment (Sulesomab or LeukoScan or immunoscintigraphy) were prospectively compared with results from the bone scan coupled with 67Ga. The diagnosis of osteomyelitis was confirmed by either biopsy or follow-up, radiological imaging and clinical outcome. RESULTS AND CONCLUSION: Sulesomab correctly identified 12 of 18 osteomyelitic lesions while 67Ga was able to detect only 8 of 18. Therefore the sensitivity is 67% for Sulesomab and 44% for 67Ga. Among the 13 non-osteomyelitic lesions imaging with Sulesomab was able to rule out infection in 11 cases and 67Ga in 10 cases. The specificity is therefore 85% for Sulesomab and 77% for 67Ga. Image interpretation for Sulesomab in this group of patients is occasionally suboptimal when imaging is performed at 3 hours post injection. High vascular background in the early images may obscure infection especially in small bones. Practically, scintigraphy with Sulesomab is fast and simple due to ease of labeling, no ex-vivo handling of blood, low radiation and provides rapid diagnosis. The diagnosis of osteomyelitis obtained by the antibody fragment scintigraphy influences the management (guided biopsy) and therapy. In several patients, imaging with Sulesomab was able to rule out osteomyelitis, helping to avoid useless antibiotic therapy and its associated side effects.

• Dillon RS: Saving on soaks. Letter to the editor in New Eng Journal of Medicine 311:540, 1984. Volume of expensive soak solutions markedly reduced by placing foot in a plastic bag and putting bagged foot then in basin of water. Soak solution then poured into bag giving a thin layer of soak solution around foot. Allows local use of expensive antibiotics.

• Dillon RS: Successful treatment of osteomyelitis and soft tissue infections in ischemic diabetic legs by local antibiotic injections and the end-diastolic pneumatic compression boot. Ann Surg 204(6):643-9, 1986. Abstract: Thirty-four legs at risk of amputation due to peripheral arterial insufficiency associated with ischemic necrosis, soft tissue infections, osteomyelitis, and variable degrees of peripheral neuropathy were reported in 28 diabetic patients. Amputation had been considered in 27 legs for which standard therapies had failed for the current illness and in two legs in which standard therapy had failed for previous illnesses. Local therapy was the initial form of therapy for five legs in which standard therapy appeared likely to fail. Infection was controlled in all patients with the use of local antibiotics and compression boot therapy. Early leg amputation was avoided in all but one patient. Late leg amputation occurred in two patients who were lost to follow-up care. Osteomyelitis, ischemic necrosis, and advanced soft tissue infection were shown not to be clear-cut indications for amputation in the ischemic diabetic foot. Comments: It should be appreciated that significant ischemia was present in every patient. All had abnormal Doppler waveforms. Twenty legs had ABI's less than 0.5 in one tibial artery, 11 had ABI's below 0.5 in both tibial arteries, 12 had ABI's over 0.5 but faint to absent Doppler sounds and 6 had pseudohypertension. Review the entire article.
  

• Dillon RS: Treatment of osteomyelitis in diabetic foot with systemic and locally-injected antibiotics and the end-diastolic pneumatic compression boot - Case studies. Vasc Surg (Westerminister Press) 24: 682-695, 1990. Abstract:The treatment of 35 patients for 43 episodes of osteomyelitis in the distal lower extremity is summarized and the long-term courses of three patients are illustrated in detail. Systemic antibiotics were used both to help control infection in the foot and to prevent septic emboli. The systemic antibiotics were given by the oral route alone (16 episodes), by the parenteral route alone (4 episodes), or by both oral and parenteral routes (22 episodes). Local foot treatments included injections of antibiotics into the infected areas of the foot, multielectrolyte-antibiotic foot soaks, and the end-diastolic pneumatic compression boot. X-ray evidence of osteomyelitis was found one to four weeks after it was clinically suspected and was associated with an improvement in the clinical status of the foot. Osteomyelitis was not considered an indication for amputation. The osteomyelitis lesions healed and foot structure and function were maintained. Comments: Lost in the editorial process of this manuscript was the fact that these were not selected for this report because of their successful treatment; they were consecutive referrals who were found to have osteomyelitis. Patients with severe ischemia and infection likely present with gangrene. Patients with x-ray changes of osteomyelitis must have sufficient blood flow to allow the serial dissolution and remodeling processes characteristic of osteomyelitis. These patients, hence, do have some blood flow and with the techniques described may almost all be cured. It is to be appreciated, however, that most all these patients had significant ischemia: 26 feet had no palpable pulses, 4 had one palpable pulse while 12 feet had both the dorsalis pedis and posterior tibial palpable. The mean of the ABI in the dorsalis pedis and posterior tibial was under 0.6 in 13 feet and under 0.4 in 6 feet. Sterilization of the drainage, healing of the associated ulcers and normalization of the sed rate point to a success regardless what the x-ray may be showing. Allowed some time (weeks to months), the involved bone may be conserved without surgery. How do other centers fare with such cases? See Armstrong et al for the Texas Wound Classification System in our Epidemiology library; close to 100% of our patients would have had amputations in their institution. How is our success interpreted by some reviewers? Those in the Georgia Medicare system, for example, call us investigational, but they also ignore the success reported at the Mayo Clinic and reports like that of Niezgoda below. View original article in Vascular Surgery and/or View 60 cases of osteomyelitis successfully treated by these techniques

• Dillon RS: Management of soft-tissue infections in elderly persons with diabetes. Geriatric Medicine Today 6:21-35, 1987. Rationale of boot therapy and local antibiotic usage presented. Immune problems in elderly diabetic also discussed.

• Dorigo B, Cameli AM, Trapani M, Raspanti D, Torri M and Mosconi G: Efficacy of femoral intra-arterial administration of Teicoplanin in gram-positive diabetic foot infections. Angiology 46:1115-1122, 1995. Twenty-five hospitalized diabetic patients with foot ulcers alone or together with metatarsophalangeal osteomyelitis reported. Forty-four percent of the patients had abnormal arterial Doppler studies. With the use of a severity grading system like that of Wagner, the patients included 12 "class 2", 10 "class 3" and 3 "class 4" patients. Staphylococcus aureus was present alone in 16 patients and associated with Pseudomonas aeruginosa in 2 patients, with Candida albicans in two and with coagulase-negative staphylococcus in one. In 4 patients other gram-positive cocci were isolated. All of the isolated strains were resistant to the antibiotics tested. Teicoplanin, 200 mg, was administered once a day by femoral intra-arterial injection for an average period of 14.72±7.16 days (range 10 to 36 days). Six patients were treated with additional antibiotic intramuscularly or intravenously because of a mixed infection. Gram-positive infection was eliminated in all patients. Healing occurred in 72% and improvement in 28% of the patients. The authors chose Teicoplanin as opposed to Vancomycin because of the potential for ototoxicity and renal toxicity of the latter. They chose the intra-arterial route in an attempt to improve tissue antibiotic concentrations and shorten the duration of treatment.Comments: This article is included because of its novel approach in the administration of the antibiotic. One might ask if they had an indwelling arterial line or used a daily arterial stick. In recent years the Vancomycin preparation available in the United States has been relatively free from renal and ear toxicity raising the possibility that impurities in previous preparations were related to the toxicity problem. We have approached these same patients with local injections of antibiotics. No question about it: if you put the antibiotic there, you know it is there.

• Duckworth C, Fisher JF, Carter SA Newman CL, Cogburn C, Nesbit RR and Wray CH: Tissue penetration of clindamycin in diabetic foot infections. J Antimicrobial Chem 31:581-584, 1993. Among 4 diabetics having debridements or amputations for foot infections, in 9 of 11 tissue samples the clindamycion levels exceeded the MICs reported for many commonly involved pathogens.

• Ellington JK, Harris M, Webb L et al: Intracellular Staphylococcus aureus. A mechanism for the indolence of osteomyelitis. J Bone Joint Surg Br 85:918-21, 2003. Staphylococcus aureus is the bacterial pathogen which is responsible for approximately 80% of all cases of human osteomyelitis. It can invade and remain within osteoblasts. The fate of intracellular Staph. aureus after the death of the osteoblast has not been documented. We exposed human osteoblasts to Staph. aureus. After infection, the osteoblasts were either lysed with Triton X-100 or trypsinised. The bacteria released from both the trypsinised and lysed osteoblasts were cultured and counted. Colonies of the recovered bacteria were then introduced to additional cultures of human osteoblasts. The number of intracellular Staph. aureus recovered from the two techniques was equivalent. Staph. aureus recovered from time zero and 24 hours after infection, followed by lysis/trypsinisation, were capable of invading a second culture of human osteoblasts. Our findings indicate that dead or dying osteoblasts are capable of releasing viable Staph. aureus and that Staph. aureus released from dying or dead osteoblasts is capable of reinfecting human osteoblasts in culture.

• El-Maghraby TA, Moustafa HM, Pauwels EK: Nuclear medicine methods for evaluation of skeletal infection among other diagnostic modalities. Q J Nucl Med Mol Imaging 50:167-92, 2006. Skeletal infection continues to be a common and difficult condition in clinical practice and early accurate diagnosis is very challenging. Clinical and laboratory features of skeletal infections are not always present, may be confusing, and are nonspecific for bone infection in its early stages, therefore, several imaging modalities are used for early detection of osteomyelitis. Plain films should always be the first step in the imaging assessment of osteomyelitis, however, the sensitivity for X-ray radiography has been reported to range from 43% to 75%, and the specificity from 75% to 83%. Over years, scintigraphic procedures have become an essential part of the diagnostic procedure for osteomyelitis. The standard approach for bone scintigraphy with tech (99m)Tc labeled methylene diphosphonate to assess for osteomyelitis is to perform a three-phase procedure. The positive uptake on all three phases is highly sensitive for osteomyelitis (sensitivity 73% to 100%). (67)Ga citrate gained more attention for the more specific diagnosis of osteomyelitis due to its known capacity to localize in cases of active infection and pus. The reported specificity for (67)Ga scintigraphy in osteomyelitis is around 67-70% and the specificity is much higher (92%) when (67)Ga single photon emission tomography was obtained. Labeled white blood cell (WBC) imaging has become the procedure of choice to diagnose most cases of skeletal infections except for those of the spine. Labeling of leucocytes can be done either by (111)In or (99m)Tc labeled hexamethylpropylene amineoxime. The sensitivity and specificity for labeled WBCs are in the high range of 80% to 90%. [(18)F]fluorodeoxyglucose positron emission tomography (PET) has been found to accumulate non-specifically at sites of infection and inflammation. Investigational studies showed that PET is particularly valuable in the evaluation of chronic osteomyelitis and infected prostheses. Other imaging modalities include sonography, computed tomography (CT) and magnetic resonance imaging (MRI). The sensitivity and specificity of CT for the diagnosis of osteomyelitis has not been established clearly and are in the range of 65% to 75%. The sensitivity of MRI for osteomyelitis has been generally reported as being between 82% and 100%, and specificity between 75% and 96%. Cases of osteomyelitis commonly referred to diagnostic imaging departments include chronic osteomyelitis, diabetic foot infections, vertebral osteomyelitis, joint prostheses and patients with suspected reinfection. These specific entities need special attention and careful selection of the correct tracer or combination of imaging modalities that is best suited for the proper therapeutic management protocols.

• Faglia E, Favales F, Aldeghi A, Calia P, Quarantiello A, Oriani G, Michael M, Campagnoli P and Marabito A: Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcers, A randomized study. Diabetes Care 19: 1338-1343, 1996. Authors' results: Of the treated group (mean session = 38.8±8), three subjects (8.6%) underwent major amputation: two below the knee and one above the knee. In the nontreated group, 11 subjects (11%) underwent major amputations: 7 below the knee and 4 above the knee. The difference is statistically significant (P= 0.016). The relative risk for the treated group was 0.26 (95% CI 0.08-0.84). The transcutaneous oxygen tension measured on the dorsum of the foot significantly increased in subjects treated with hyperbaric oxygen therapy: 14.0±11.8 mmHg in treated group, 5.0±5.4mmHg in nontreated group (P=0.0002). Multivariate analysis of major amputation on all the considered variables confirmed the protective role of s-HBOT (odds ratio 0.084, P=0.033, 95% CI 0.008-0.821) and indicated as negative prognostic determinants low ankle-brachial index values (odds ration 1.1715, P=0.013, 95% CI 1.121-2.626) and high Wagner grade (odds ratio 11.199, P=0.022, 95% CI 1.406-89.146). Comments: On the surface, this is a persuasive paper. The patients are well randomized and an important end-point is compared, major amputations. Closer examination of their case material would be helpful, however. Neither their treated or control group had major amputations (MA) in the Wagner I class of patients. Their treated group had one MA in the Wagner III class and the untreated group none. The rest of the amputations in both groups were in the Wagner IV class (gangrene of toe or forefoot). What does one do with a gangrenous toe? In the treated group, 16 toes were amputated among 22 class IV patients and in the control group 8 toes were amputated among 20 class IV patients. If the amputations of the toes are added to the major amputations, there is no difference between the groups. If both groups had equal numbers of gangrenous toes, the control group fared better (unless their surgeon removed a foot for a gangrenous toe). More likely, the control group had fewer gangrenous toes and a larger number of patients with gangrene of the forefoot and the latter may be more likely to come to a MA. The statistics in this paper dazzle those of us who find CHI squares challenging. One is reminded of the UGDP Phenformin Study in which phenformin appeared to promote death. However, if one notes who dies (the older patients) and then compares the control and the phenformin groups, one finds the phenformin group had more very old and very young people than the control group.. while both groups had the same average age. In this study, we have already seen that one of the major factors the authors report has poor prognostic significance (Wagner IV) class, may be misleading. We are told that both groups had the same degree of ischemia as determined by similar ABI's. However, 30.3% of the control group presented with claudication compared to 11.4% of the treated group. If the reader suspects I am skeptical of the value of hyperbaric treatments for all patients, he is right. The University of Pennsylvania has had a large hyperbaric chamber for over 50 years. It has been available for the treatment of diabetic feet but has not found great use. For more on hyperbaric treatments, see the articles of Gabb and Robin and of Kindwall below. Gawlik et al describe the reaction of the German reimbursement committees to the data available in 2001.

• Fejfarova V, Jirkovska A, Skibova J, Petkov V: Pathogen resistance and other risk factors in the frequency of lower limb amputations in patients with the diabetic foot syndrome. Vnitr Lek 48(4):302-6, 2002. Patients with diabetes mellitus undergo more amputations due to peripheral vascular disease, neuropathy and especially to infection requiring long-lasting antibiotic therapy than non diabetic patients. The aim of our study was to assess the association between the presence of resistant pathogens presented in diabetic ulcers and the frequency of lower limb amputations. METHODS: 191 diabetic patients consecutively treated for the diabetic foot in our foot clinic were included into two years retrospective study. Peripheral ischemia, the presence of osteomyelitis and the incidence of all Gram positive and negative resistant pathogens (defined as resistance to all oral antibiotics) especially of resistant Staphylococcus species presenting in diabetic foot ulcers were determined. RESULTS: 50/191 (26%) patients underwent amputation, of whom 44/50 (88%) had minor and 6/50 (12%) had major amputations. 53/181 (29%) patients with diabetic foot ulcers had resistant pathogens in their defects. Amputated patients had significantly more resistant microorganisms than patients without amputations--24/42 (57%) vs. 29/139 (21%); p < 0.001. Resistant Staphylococcus species were found in 21% (38/181) of all patients. Patients with amputations had significantly more resistant Staphylococcus species in comparison with patients without amputations--18/42 (43%) vs. 20/139 (14%); p < 0.001. Significantly higher incidence of peripheral vascular disease--79% (38/48) vs. 60% (81/136); p < 0.05 and osteomyelitis--69% (33/48) vs. 13% (18/140); p < 0.001--were found in patients with amputations in comparison with patients without amputations. CONCLUSION: The presence of pathogens resistant to all oral antibiotics and especially of resistant Staphylococcus species was significantly higher in diabetic patients with lower limb amputations in comparison with patients without amputations.

• Fife CE, Buyukcakir C, Otto GH, Sheffield PJ, Warriner RA, Love TL, Mader J: The predictive value of transcutaneous oxygen tension measurement in diabetic lower extremity ulcers treated with hyperbaric oxygen therapy: a retrospective analysis of 1,144 patients. Wound Repair Regen. 10:198-207, 2002. The objective of this retrospective analysis was to determine the reliability of transcutaneous oxygen tension measurement (TcPO2) in predicting outcomes of diabetics who underwent hyperbaric oxygen therapy for lower extremity wounds. Six hyperbaric facilities provided TcPO2 data under several possible conditions: breathing air, breathing oxygen at sea level, and breathing oxygen in the chamber. Overall, 75.6% of the patients improved after hyperbaric oxygen therapy. Baseline sea-level air TcPO2 identified the degree of tissue hypoxia but had little statistical relationship with outcome prediction because some patients healed after hyperbaric oxygen therapy despite very low prehyperbaric TcPO2 values. Breathing oxygen at sea level was unreliable for predicting failure, but 68% reliable for predicting success after hyperbaric oxygen therapy. TcPO2 measured in chamber provides the best single discriminator between success and failure of hyperbaric oxygen therapy using a cutoff score of 200 mmHg. The reliability of in-chamber TcPO2 as an isolated measure was 74% with a positive predictive value of 58%. Better results can be obtained by combining information about sea-level air and in-chamber oxygen. A sea-level air TcPO2 < 15 mmHg combined with an in-chamber TcPO2 < 400 mmHg predicts failure of hyperbaric oxygen therapy with a reliability of 75.8% and a positive predictive value of 73.3%.Comments: See comments under Kalani below.

• Fischer BH: Treatment of ulcers on legs with hyperbaric oxygen. J Dermatologic Surg 1:55-58, 1975. (From New York Univ Med Ctr) 30 patients with lesions present 15 days to six years. Most patients had failed other forms of Rx. 28 patients healed and other 2 improved. Pressure chamber had pure O2 under pressure of 22mm Hg (1.03 atmospheres)... avoided higher pressures lest capillary flow impeded. O2 flow at 4L/min with continuous humidification. Each O2 Rx lasted 2-3 hours and performed twice daily. Saline dressings applied during off O2 hours. After 2nd or 3rd day of O2 Rx, demarcation line seen between necrotic and viable tissue allowing debridements as necessary. Pure O2 under ambient pressure said to have little effect on skin lesions. Pressurized O2 failed to heal lesions associated with severe ischemia. Mechanism of benefit for pressurized O2: reduction of edema, rise in tissue PO2, O2-stimulation of granulation tissue, suppression of bacterial proliferation by rise in redox potentia. Comments: This is an old method that has fallen by the wayside. When an O2 catheter is placed on the leg within the Circulator Boot bags, O2 is essentially given at 55mm Hg in the long boot and 75mm Hg in the Miniboot without impeding blood flow. The possible benefits of topical O2 therapy can be added to Circulator Boot Rx. Fischer's technique is really topical O2 application under slight pressure. See Kindwall below for true hyperbaric Rx. For more on topical oxygen therapy as used with the Circulator Boot, see our introduction (Topical O2 vs CB therapy).

• Gabb G and Robin ED: Hyperbaric oxygen, a therapy in search of diseases. Chest 92: 1074-1082, 1987. Summary: The application of HBO to the therapy of various human diseases developed over a 300 year period. Like most of medicine, the basis of these applications was and continues to be pragmatic in nature, and involves uncritical and untested judgments. The possibility of risks has been understated and possible benefits overstated. Individual physicians offering HBO and organized groups, such as the Undersea Medical Society, advocating its use may be highly motivated, well meaning, and sincerely convinced that HBO is an important therapeutic approach. It may be that buried among the host of indications, will be some disorders for which HBO is uniquely and highly effective. If so, the present nonsystem for evaluating responses to HBO will require modification, so that these potentially valuable additions to therapeutics are not lost. Because of its almost global application to a wide variety of diseases, HBO therapy lends itself easily to medical adventurism (therapy in search of a disease) and economic exploitation. If there is some patient benefit to come from the experience of the last 300 years, changes in approach, initiated by baromedical devotees or by medicine generally, or resulting from pressures outside of medicine, will be required. Comments: This is a hard-nosed review of hyperbaric medicine listing its multiple unproven indications for treatment, a surprising number of risks, and a charge that the growth of the treatment has been more due to its coverage by third party payers than any clinical efficacy.

• Gadepalli R, Dhawan B et al: A clinico-microbiological study of diabetic foot ulcers in an Indian Tertiary Care Hospital. Diabetes Care. 29:1727-32, 2006. OBJECTIVE: To determine the microbiological profile and antibiotic susceptibility patterns of organisms isolated from diabetic foot ulcers. Also, to assess potential risk factors for infection of ulcers with multidrug-resistant organisms (MDROs) and the outcome of these infections. RESEARCH DESIGN AND METHODS: Pus samples for bacterial culture were collected from 80 patients admitted with diabetic foot infections. All patients had ulcers with Wagner's grade 3-5. Fifty patients (62.5%) had coexisting osteomyelitis. Gram-negative bacilli were tested for extended spectrum beta-lactamase (ESBL) production by double disc diffusion method. Staphylococcal isolates were tested for susceptibility to oxacillin by screen agar method, disc diffusion, and mec A-based PCR. Potential risk factors for MDRO-positive samples were explored. RESULTS: Gram-negative aerobes were most frequently isolated (51.4%), followed by gram-positive aerobes and anaerobes (33.3 and 15.3%, respectively). Seventy-two percent of patients were positive for MDROs. ESBL production and methicillin resistance was noted in 44.7 and 56.0% of bacterial isolates, respectively. MDRO-positive status was associated with presence of neuropathy (P = 0.03), osteomyelitis (P = 0.01), and ulcer size >4 cm(2) (P < 0.001) but not with patient characteristics, ulcer type and duration, or duration of hospital stay. MDRO-infected patients had poor glycemic control (P = 0.01) and had to be surgically treated more often (P < 0.01). CONCLUSIONS: Infection with MDROs is common in diabetic foot ulcers and is associated with inadequate glycemic control and increased requirement for surgical treatment. There is a need for continuous surveillance of resistant bacteria to provide the basis for empirical therapy and reduce the risk of complications.

• Gawlik C, Schmacke N, Gibis B, Sander G, Rheinberger P: [Reimbursement and importance of hyperbaric oxygenation for diabetic foot ulcers in German publically funded ambulatory health care] [Article in German]. Z Arztl Fortbild Qualitatssich. 95:715-8, 2001. The Standing Committee of Statutory Health Insurance Physicians and Sickness Funds is the legal body that makes decisions on reimbursement for health care services in the German ambulatory health care sector. In 1994, the Committee declined the reimbursement of hyperbaric oxygen therapy (HBO). In 1999, a new deliberation of the efficacy, appropriateness and cost-effectiveness of HBO was initiated as the proponents of this technology claimed that the efficacy of HBO had since been proven in clinical trials. The deliberation was announced and published in the journal of the German Medical Association (Deutsches Arzteblatt) and the federal register (Bundesanzeiger). All institutions, groups, and interested individuals were given the opportunity to provide a written statement. The statements and, in particular, the scientific literature cited in those statements, were critically appraised by the Committee. In addition, the Committee conducted a thorough review of the literature, guidelines and status of the therapy in other health care systems. More than 40 potential indications for the use of HBO were reviewed by the committee. One indication was for diabetic foot ulcers. Most clinical trials related to this field represented only retrospective case series, which, in view of the established therapies, cannot be used as a sound basis for the acceptance of HBO as a new technology for the therapy of diabetic foot ulcers. Some studies were planned as randomized controlled trials but had serious methodological flaws in conduct and analysis. The main problems were the low numbers of patients included and serious inbalances of important and well known prognostic factors between the treatment groups. Systematic reviews that were published in the international literature after the decision of the Committee drew similar conclusions in view of the methodological flaws in the clinical trial data. In summary, the Committee decided once again to decline coverage of HBO in German ambulatory health care.

• Garrett S, Johnson L, Drisko CH et al.: Two multi-center studies evaluating locally delivered doxycycline hyclate, placebo control, oral hygiene, and scaling and root planing in the treatment of periodontitis. J Periodontol. 70:490-503, 1999. BACKGROUND: The clinical efficacy and safety of doxycycline hyclate (8.5% w/w) delivered subgingivally in a biodegradable polymer (DH) was compared to placebo control (VC), oral hygiene (OH), and scaling and root planing (SRP) in 2 multi-center studies. METHODS: Each study entered 411 patients who demonstrated moderate to severe periodontitis. Patients had 2 or more quadrants each with a minimum of 4 qualifying pockets > or =5 mm that bled on probing. At least 2 of the pockets were > or =7 mm. Treatment with DH, VC, OH, or SRP was provided at baseline and again at month 4. Clinical parameters were recorded monthly. RESULTS: DH and SRP resulted in nearly identical clinical changes over time in both studies. Mean 9 month clinical attachment level gain (ALG) was 0.8 mm for the DH group and 0.7 mm for the SRP group in Study 1, and 0.8 mm (DH) and 0.9 mm (SRP) in Study 2. Mean probing depth (PD) reduction was 1.1 mm for the DH group and 0.9 mm for the SRP group in Study 1 and 1.3 mm for both groups in Study 2. Frequency distributions showed an ALG > or =2 mm in 29% of DH sites versus 27% of SRP sites in Study 1 and 31% of DH sites versus 34% of SRP sites in Study 2. PD reductions > or =2 mm were seen in 32% of DH sites versus 31% of SRP sites in Study 1 and 41% of DH sites versus 43% of SRP sites in Study 2. Comparisons between DH, VC, and OH treatment groups showed DH treatment to be statistically superior to VC and OH. Safety data demonstrated a benign safety profile with use of the DH product. CONCLUSIONS: Results of this trial demonstrate that treatment of periodontitis with subgingivally delivered doxycycline in a biodegradable polymer is equally effective as scaling and root planing and superior in effect to placebo control and oral hygiene in reducing the clinical signs of adult periodontitis over a 9-month period. This represents positive changes resulting from the use of subgingivally applied doxycycline as scaling and root planing was not limited regarding time of the procedure or use of local anesthesia. Comments: 25 authors listed in the original article before their "et al."

• Gilbert DN, Dworkin RJ, Raber SR, and Leggett JE.:Outpatient parenteral antimicrobial-drug therapy. N Engl J Med 337: 829-838, 1997. The authors report enthusiastically on the use of outpatient intravenous antibiotic infusions. They tell of a series of 538 patients with clinical improvement in 99% and cure in 92%... and need for hospitalization in but 8%. Significant cost savings are described. Potential complications are many: sterile phlebitis in 2-10%, large vein thrombosis soon after or many months after catheter placement, pulmonary emboli, superior vena cava syndrome, air embolism (potentially fatal), catheter fragment embolization, catheter tip migration to the right atrium or the jugular vein, catheter erosion through a vein or the right atrium (producing pericardial tamponade), intracatheter clots, fluid leaks through small holes in the catheter causing fluid extravasation or contiguous mass formation, rare idiosyncratic hypersensitivity reactions to the catheter substance, and exit-site infections, tunnel infections and catheter-related bloodstream infections. A rare form of infective endocarditis may occur when a malpositioned catheter traumatizes the tricuspid valve resulting in platelet-fibrin thrombi that become infected. The authors point out that infusions should not be prescribed if there is an equally effective and safe oral antibiotic regimen. Cost savings were illustrated using the DRG model in which a hospital received a given lump payment regardless how long the patient is in the hospital; the hospital profits by sending the patient home even if it provides the antibiotics for nothing. See article by Maki et al below. The real costs of the procedure include the costs of the antibiotics, the infusion equipment, the visiting nurse and any complications. The visiting nurse commonly is reimbursed more than the physician who provides both antibiotic local injections and boot therapy in his office! The HMO that does not embrace the latter is really losing an opportunity to safe money.

• Grady JF, Winters CL: The Boyd amputation as a treatment for osteomyelitis of the foot. J Am Podiatr Med Assoc 90(5):234-9,2000. The Boyd amputation is a surgical technique used to treat osteomyelitis of the foot. This amputation is a technically more difficult procedure to perform than the Syme amputation, but it offers certain advantages. The Boyd amputation provides a more solid stump because it preserves the function of the plantar heel pad. Also, because a portion of the calcaneus is left and fused to the tibia, the weightbearing surface is more solid than in the case of a Syme amputation. The authors recommend a Boyd amputation as an alternative to a Syme or a below-the-knee amputation to treat patients with osteomyelitis of the forefoot and midfoot.

• Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW: Probing to bone in infected pedal ulcers. A clinical sign of underlying osteomyelitis in diabetic patients. JAMA 273:721-3, 1995. OBJECTIVE--To assess a bedside technique for diagnosing osteomyelitis. DESIGN--We prospectively assessed infected pedal ulcers for detectable bone by probing with a sterile, blunt, stainless steel probe. We then examined the relationship between detection of bone and the presence or absence of osteomyelitis that was defined histopathologically and/or clinically. SETTING--A tertiary care center. PATIENTS--Seventy-five hospitalized diabetic patients with a total of 76 infected foot ulcers were studied. RESULTS--Osteomyelitis was diagnosed in 50 instances (66%) and was excluded in 26 instances. Bone was detected by probing in 33 of 50 ulcers with contiguous osteomyelitis; in contrast, bone was probed in only four of 26 ulcers without contiguous osteomyelitis (P < .001). Bone detected on probing was visible in only three instances. Palpating bone on probing the pedal ulcer had a sensitivity of 66% for osteomyelitis, a specificity of 85%, a positive predictive value of 89%, and a negative predictive value of 56%. CONCLUSIONS--Palpation of bone in the depths of infected pedal ulcers in patients with diabetes is strongly correlated with the presence of underlying osteomyelitis. If bone is palpated on probing, specialized roentgenographic and radionuclide tests to diagnose osteomyelitis are unnecessary. Probing for bone should be included in the initial assessment of all diabetic patients with infected pedal ulcers.

• Hamill RJ, Vann JM, Proctor RA: Phagocytosis of Staphylococcus aureus by cultured bovine aortic endothelial cells: model for postadherence events in endovascular infections. Infect Immun 54:833-6, 1986. We examined the interaction of Staphylococcus aureus with cultured bovine aortic endothelial cells as a model for the initial events in the pathogenesis of endovascular infections. Confluent monolayers of cultured endothelial cells were incubated with S. aureus. Cell-associated bacteria were measured by washing away nonadherent organisms, disrupting the monolayers, and performing quantitative cultures. Phagocytosis was differentiated from adherence by treating the cells with lysostaphin; approximately 60% of cell-associated bacteria was found to be intracellular. Phagocytosis could be blocked by using cytochalasin B, which interferes with microfilament function. Addition of fibronectin resulted in a 63% increase in adherence of S. aureus to the endothelial cells but did not increase ingestion. Transmission electron microscopy demonstrated a sequence of events similar to that which occurs during ingestion by professional phagocytes, including: adherence of bacteria to the endothelial cell; formation and elongation of surface extensions of the endothelial cell to surround the adherent bacteria; and complete enclosure within apparent phagosomes. Phagocytosis of bacteria by endothelial cells, followed by intracellular persistence, may be an important postadherence event in the pathogenesis and pathophysiology of endovascular infections.

• Harding,Edwards R: Bacteria and wound healing. Curr Opin Infect Dis 17:91-6.2004. PURPOSE OF REVIEW: Wound healing is a complex process with many potential factors that can delay healing. There is increasing interest in the effects of bacteria on the processes of wound healing. All chronic wounds are colonized by bacteria, with low levels of bacteria being beneficial to the wound healing process. Wound infection is detrimental to wound healing, but the diagnosis and management of wound infection is controversial, and varies between clinicians. RECENT FINDINGS: There is increasing recognition of the concept of critical colonization or local infection, when wound healing may be delayed in the absence of the typical clinical features of infection. The progression from wound colonization to infection depends not only on the bacterial count or the species present, but also on the host immune response, the number of different species present, the virulence of the organisms and synergistic interactions between the different species. There is increasing evidence that bacteria within chronic wounds live within biofilm communities, in which the bacteria are protected from host defences and develop resistance to antibiotic treatment. SUMMARY: An appreciation of the factors affecting the progression from colonization to infection can help clinicians with the interpretation of clinical findings and microbiological investigations in patients with chronic wounds. An understanding of the physiology and interactions within multi-species biofilms may aid the development of more effective methods of treating infected and poorly healing wounds. The emergence of consensus guidelines has helped to optimize clinical management.

• Herrmann M, Vaudaux PE, Pittet D et al: Fibronectin, fibrinogen, and laminin act as mediators of adherence of clinical staphylococcal isolates to foreign material. J Infect Dis 158: 693-701, 1988. Bacterial adherence to polymer surfaces is a required early step in intravenous (iv) device infection. We collected eight strains of Staphylococcus aureus and 19 of coagulase-negative staphylococci from patients with proven iv device bacteremia and studied the role of plasma or connective-tissue proteins in promoting bacterial adherence to polymethylmethacrylate (PMMA) coverslips. Although only a negligible percentage of organisms adhered to albumin-coated PMMA, surface-bound fibronectin significantly promoted adherence of all isolates. Fibrinogen markedly promoted adherence of all S. aureus strains but of only four coagulase-negative strains. Thus, coagulase-negative staphylococci revealed a marked heterogeneity in adherence to fibrinogen-coated surfaces, a result suggesting the existence of heretofore unknown receptors for fibrinogen. Laminin promoted adherence of staphylococci to a much lower extent. Although strain specific, adherence of clinical staphylococcal isolates to foreign surfaces is significantly increased by fibronectin, fibrinogen, and laminin, an observation suggesting the possible contribution of these proteins to the pathogenesis of iv device infection.

• Isenberg JS, Costigan WM and Thordarson DB:Subtotal calcanectomy of osteomyelitis of the os calcis: A reasonable alternative to free tissue transfer.Ann Plast Surg 35:660-663, 1995.From authors' summary: Subtotal calcanectomy, traditionally a technique of the orthopedic surgeon, can in selected cases eradicate infection and achieve wound closure and limb preservation. A review was undertaken of one hospital's experience with this procedure over a 4-year period. Five patients with osteomyelitis of the os calcis were identified who were successfully managed with subtotal calcanectomy. Comments: Many patients are referred with decubitus heel ulcers that have become infected and involve the os calcis superficially. We have treated these with local antibiotic injections followed by Mini-Boot therapy with the foot immersed in Sea Soaks containing antibiotics. As shown in case history 97, occasionally infection involves much of the os calcis. In such cases, we scrape away the soft and necrotic elements at each boot session and continue with our local treatments. We have been gratified to find that over time the cavities may fill in and the ulcers close.

• Kalani M, Jorneskog G, Naderi N, Lind F, Brismar K: Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up. J Diabetes Complications. 16:153-8, 2002. BACKGROUND: The cause of diabetic foot ulcers is multifactorial, e.g., neuropathy and angiopathy, leading to functional disturbances in the macrocirculation and skin microcirculation. Adequate tissue oxygen tension is an essential factor in infection control and wound healing. Hyperbaric oxygen (HBO) therapy, daily sessions of oxygen breathing at 2.5-bar increased pressure in a hyperbaric chamber, has beneficial actions on wound healing including antimicrobial action, prevention of edema and stimulation of fibroblasts. The aim of the present study was to investigate the long-term effect of HBO in treatment of diabetic foot ulcers. METHODS: Thirty-eight diabetic patients (30 males) with chronic foot ulcers were investigated in a prospective study. The mean age was 60+/-13 years and the mean diabetes duration 27+/-14 years. All patients were evaluated with measurements of transcutaneous oxygen tension (tcPO(2)), peripheral blood pressure, and HbA(1c). All patients had a basal tcPO(2) value lower than 40 mmHg, which increased to >/=100 mmHg, or at least three times the basic value, during inhalation of pure oxygen. Seventeen patients underwent 40-60 sessions of HBO therapy, while 21 patients were treated conventionally. The follow-up time was 3 years. RESULTS: 76% of the patients treated with HBO (Group A) had healed with intact skin at a follow-up time of 3 years. The corresponding value for patients treated conventionally (Group B) was 48%. Seven patients (33%) in Group B compared to two patients (12%) in Group A went to amputation. Peripheral blood pressure, HbA(1c), diabetes duration, and basal values of tcPO(2) were similar in both groups. CONCLUSIONS: Adjunctive HBO therapy can be valuable for treating selected cases of hypoxic diabetic foot ulcers. It seems to accelerate the rate of healing, reduce the need for amputation, and increase the number of wounds that are completely healed on long-term follow-up. Additional studies are needed to further define the role of HBO, as part of a multidisciplinary program, to preserve a functional extremity, and reduce the short- and long-term costs of amputation and disability. Comments: TcPO2 values of 40, of course are normal, while values under 20 are not compatible with healing (see our vascular testing library). The rise in TcPO2 with breathing pure oxygen meant that the foot blood flow was adequate to bring some of the hyperoxygenated blood to the foot electrodes. The treated patients reported to the clinic 40-60 times for hyperbaric treatments when their lesions were likely inspected and local treatments administered. We are not told what attention the "conventional" patients received. Reports on Circulator Boot patients must also be viewed with similar reservations. Those patients failing daily care in the hospital or nursing home by a wound care nurse prior to Circulator Boot therapy received, indeed, aggressive "conventional care". Those who were sent home to receive a visiting nurse a few times a week received less than maximal "conventional care".

• Kaleta JL. Fleischli JW, Reilly CH:The Diagnosis of Osteomyelitis in Diabetes Using Erythrocyte Sedimentation Rate, A Pilot Study. J Am Podiat Med Assoc 91:441-450, 2001. Abstract: Osteomyelitis secondary to diabetic foot infections can lead to proximal amputation if not diagnosed in a timely and accurate manner. The authors have found no studies to date that correlate a specific erythrocyte sedimentation rate with osteomyelitis. A retrospective chart review of 29 diabetic patients admitted to the hospital with diagnoses of osteomyelitis or cellulitis of the foot during a 1-year period was performed. Of the various lab values and demographic factors compared, erythrocyte sedimentation rate was the only measure that differed significantly between the two groups. A receiver operating characteristic curve was used to obtain the optimal cutoff value of 70 mm/h, a level above which osteomyelitis was present with the highest sensitivity (89.5%) and highest specificity (100%), along with a positive predictive value of 100% and a negative predictive value of 83%. This study shows that in combination with clinical suspicion in diabetic foot infections, the erythrocyte sedimentation rate is highly predictive of osteomyelitis, and that the value of 70 mm/h is the optimal cutoff to predict accurately the presence or absence of bone infection. Comments: We have also found the sed rate to be very helpful in both the initial diagnosis and follow-up of patients with osteomyelitis. A return to normal almost always signifies cure of the infection. A word of warning, however, an elevated sed rate does not justify a consultaton with a rheumatologist. The latter may suggest that an arteritis is present and insist that steroids be administered. The latter is always a bad idea in diabetics with osteomyelitis.

• Kaplan B and Gibson LB: Topical metronidazole for arterial insufficiency ulcers.JAOA 95:201-203, 1995. Topical metronidazole was approved by the FDA in 1988 for treatment of acne rosacea. It has also been tried to treat infected foot ulcers associated with diabetes, varicose veins, irradiation damage, dental conditions and decubitus ulcers. Here the authors report some benefit in a patient with an ischemic ulcer. Metronidazole is generally active against most obligately anaerobic bacteria and many protozoa. It is inactive against most aerobic or facultatively anaerobic bacteria, fungi or viruses.

• Kessler L, Bilbault P, Ortega F, Grasso C, Passemard R, Stephan D, Pinget M, Schneider F: Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study. Diabetes Care 26:2378-82, 2003.OBJECTIVE: To study the effect of systemic hyperbaric oxygenation (HBO) therapy on the healing course of nonischemic chronic diabetic foot ulcers. RESEARCH DESIGN AND METHODS: From 1999 to 2000, 28 patients (average age 60.2 +/- 9.7 years, diabetes duration 18.2 +/- 6.6 years), of whom 87% had type 2 diabetes, demonstrating chronic Wagner grades I-III foot ulcers without clinical symptoms of arteriopathy, were studied. They were randomized to undergo HBO because their ulcers did not improve over 3 months of full standard treatment. All the patients demonstrated signs of neuropathy. HBO was applied twice a day, 5 days a week for 2 weeks; each session lasted 90 min at 2.5 ATA (absolute temperature air). The main parameter studied was the size of the foot ulcer measured on tracing graphs with a computer. It was evaluated before HBO and at day 15 and 30 after the baseline. RESULTS: HBO was well tolerated in all but one patient (barotraumatic otitis). The transcutaneous oxygen pressure (TcPO(2)) measured on the dorsum of the feet of the patients was 45.6 +/- 18.1 mmHg (room air). During HBO, the TcPO(2) measured around the ulcer increased significantly from 21.9 +/- 12.1 to 454.2 +/- 128.1 mmHg (P < 0.001). At day 15 (i.e., after completion of HBO), the size of ulcers decreased significantly in the HBO group (41.8 +/- 25.5 vs. 21.7 +/- 16.9% in the control group [P = 0.037]). Such a difference could no longer be observed at day 30 (48.1 +/- 30.3 vs. 41.7 +/- 27.3%). Four weeks later, complete healing was observed in two patients having undergone HBO and none in the control group. CONCLUSIONS: In addition to standard multidisciplinary management, HBO doubles the mean healing rate of nonischemic chronic foot ulcers in selected diabetic patients. The time dependence of the effect of HBO warrants further investigations.Comments: Small studies are always hard to randomize without some imbalances occurring between the treated and control groups. While no specific risk factor separated the groups, the control group here was on average 7.5 years older, had had their diabetes 4 years longer, had renal impairment in 10.4 % more patients, had coronary disease in 16.2% more patients and required antibiotic therapy in 12% more patients. Neither group by design had vascular disease and had similar normal TcPO2 levels on average on the dorsum of the feet; the standard deviation of the TcPO2 was 18.1 in the treated group and 24.2 in the control group likely signifying the control group had one or two patients with TcPO2 values well below those in the treated group. The treated group closed their ulcers faster during their two week hospitalization but the benefit was lost during their outpatient followup. One wonders how the study would have turned out if the patients had been able to remain in the hospital (the HBO continuing in the treated group) until all were cured.

• Kessler L, Piemont Y et al:: Comparison of microbiological results of needle puncture vs. superficial swab in infected diabetic foot ulcer with osteomyelitis. Diabet Med. 23: 99-102, 2006. AIM: To study prospectively two methods for the bacteriological diagnosis of osteomyelitis related to diabetic foot ulcer: needle puncture performed across normal skin surrounding the foot ulcer and superficial swabbing of the ulcer. PATIENTS AND METHODS: Diabetic patients with a foot ulcer complicated by bone or joint infection, as detected by X-ray imaging, were included in the study. Ulcer swabbing and needle puncture were performed in each patient. To reach the tissue nearest the bone surface, needle puncture was guided by X-ray imaging and the drop of fluid obtained by aspiration was used for both aerobic and anaerobic bacterial culture. RESULTS: Twenty-one diabetic patients were included. The mean number of microorganisms isolated by needle puncture was significantly lower compared with that obtained by superficial swabbing: 1.09 vs. 2.04 (P < 0.02). Three bacterial species were isolated by needle puncture only in one patient while three or more bacterial isolates were obtained by superficial swabbing in six patients. No bacterial isolate was detected in five patients by needle puncture and in two patients by superficial swabbing. Staphylococcus aureus accounted for 70% of cases (seven patients) when a single bacterial species was obtained by needle puncture. After needle puncture, no wound complication or infection was observed. CONCLUSION: Culture of samples obtained by needle puncture revealed one or two bacterial isolates in two-thirds of diabetic patients with osteomyelitis following foot ulcer. Given the lack of complications, this invasive diagnostic technique should be considered for deep direct sampling in diabetic patients with osteomyelitis related to foot ulcer when surgical debridement is contraindicated or delayed. Needle aspiration can be done on presentation with minimal equipment and fanfare. It has few if any harmful sequelae. Unlike bone biopsies, it does not extend the lesion. When a significant sample size has entered the syringe, the needle can be left in place and separated from the syringe. Antibiotics may then be injected through the syringe and therapy commenced.

• Kindwall, EP: Uses of hyperbaric oxygen therapy in the 1990's. Cleveland Clinic J Med 59: 517-528, 1992. Summary: Hyperbaric oxygen (HO) can produce a variety of effects in addition to reducing air and gas embolism.. It increases the killing ability of leukocytes and is lethal to certain anaerobic bacteria. It inhibits toxin formation by certain anerobes, increases the flexibility of red cells, reduces tissue edema, preserves intracellular ATP, maintains tissue oxygentation in the absence of hemoglobin. In addition, it stimulates fibroblast growth, increases collagen formation, promotes rapid growth of capillaries, and terminates lipid peroxidation. These actions of HO are useful in treating anaerobic infections that result in gas gangrene, as well as severe aerobic infections such as necrotizing fasciitis, malignant external otitis, and chronic refractory osteomyelitis. HO can help preserve ischemic tissues and facilitates the rapid spread and arborization of new capillaries. It promotes healing in certain problem wounds. Adjunctive HO treatment is a new approach to the management of radionecrosis. HO treatment reduces morbidity and mortality resulting from carbon monoxide poisoning. Protocols for HO therapy are at present mostly empirical; much additional research is needed to better define therapeutic indications. Constant O2 Rx at 2 ATA produces pulmonary O2 toxicity in about 6 hours. O2 at 3 ATA will produce a grand mal seizure in 3 hours... Generally 2 chamber types: large walk-in chamber filled with compressed air and in which patient breathes O2 by mask and 2nd, a monoplace chamber which is filled with 100% O2. In the case of ischemic diabetic ulcers Kindwall concludes, "IF THE ANKLE-TO BRACHIAL BLOOD PRESSURE RATIO (ISCHEMIC INDEX) IS LESS THAN 0.45, OR IF THE DOPPLER ANKLE PRESSURE IS LESS THAN 75MM HG, THERE IS LITTLE CHANCE OF HEALING EVEN WITH HBO. " See Knighton in Vascular Test Ref.

• Kumar V: Radiolabeled white blood cells and direct targeting of micro-organisms for infection imaging. Q J Nucl Med Mol Imaging.49:325-38, 2005. Infection imaging is complicated due to multitude of factors interfering with the design of radiopharmaceuticals. More than 3 decades ago, labeled leukocytes have been introduced for infection imaging and new radiopharmaceuticals have been emerging on regular basis. However, labeled leukocytes by in vivo and in vitro methods are very effective for diagnosing various lesions such as osteomyelitis, cellulitis, diabetic foot, Crohn's disease, inflammatory bowel disease and in distinguishing prosthetic infection from loosening of prosthesis. But in vitro labeling method using (111)In-oxine, (99m)Tc-HMPAO or (99m)Tc-stannous colloid have the inherent limitation of personnel safety risks of infection and cross contamination. To overcome these problems, attempts have been made to directly target leukocytes by in vivo labeling techniques. There are several receptors present on the leukocytes and the granulocytes, which can be targeted with suitable ligands. These will include anti-NCA90-Fab, murine MoAb IgG(1) that is cross-reactive to antigen 95 on neutrophils, anti-CD15 antigen and DPC-11870 that targets the leukotriene B4 receptors of granulocytes. In a new approach, (99m)Tc-labeled ciprofloxacin has been developed to directly target ''live bacteria'' to detect infection by in vivo method. This approach showed considerable promise in the preliminary studies but clinical trials showed limitations. Analogs of a natural mammalian antimicrobial agents, such as Ubiquicidin were successful in animal studies and have now entered clinical trials. (99m)Tc-labeled fluconazole (a fungal antibiotic) and labeled Chitinase ((123)I-ChiB_E144Q), have been developed to detect fungal infection. The ability to distinguish between fungal and bacterial infection is considered important, as patients undergoing chemotherapy are prone to fungal infection. Undoubtedly, the new trends and new radiopharmaceuticals developed for infection and inflammation imaging have contributed towards a better understanding of the underlying processes.Comments: The possibility of fungal infection should be considered when what appears to be appropriate antibiotic therapy is failing. Here a scanning technique is in the offing to help determine the presence of fungus. Of course, needle aspiration and repeat culture would be cheaper.

• Ledermann HP, Morrison WB: Differential diagnosis of pedal osteomyelitis and diabetic neuroarthropathy: MR Imaging. Semin Musculoskelet Radiol. 9:272-83, 2005. Almost all diabetic foot infections originate from a foot ulcer. Decreased pain perception and structural deformities such as previous partial foot amputation, Charcot joints, and toe deformity in combination with chronic ischemia lead to a propensity for skin breakdown and subsequent infection. Magnetic resonance (MR) imaging is increasingly performed to evaluate for potential bone infection, but diagnosis of osteomyelitis can be complicated because signal changes from acute Charcot arthropathy, fractures, and postoperative residues may be mistaken for infection. Signal alterations of bone infection may be atypical in sclerosing osteomyelitis and gangrene. Differentiation between osteomyelitis and acute or subacute neuroarthropathy requires careful analysis of the location of bone signal alterations, their distribution, and pattern because qualitative changes are often identical. Presence of secondary signs such as adjacent ulcer, cellulitis, and sinus tract is indicative of osteomyelitis. Differentiation of noninfected neuroarthropathy from infected neuroarthropathy based on MR examinations is difficult. Presence of a sinus tract, disappearance of subchondral cysts, diffuse bone marrow abnormality, and bone erosions are in favor of infection. Comments: Obviously the MRI is an expensive test that does not easily determine the presence of osteomyelitis. Clinical signs (reddening, drainage, an ulcer, probing to bone) and simple tests (sedimentation rate, x-ray of the foot, and needle aspiration of the suspected area on the x-ray) will properly direct the clinician in almost all instances.

• Lew DP and Waldvogel FA: Current Concepts: Osteomyelitis. N Engl J Med 336:999-1007, 1997. Perhaps 5% of this review addresses the ischemic or diabetic foot. In the discussion on pathogenesis, one learns that Staphylococcus aureus may have receptors ("adhesins") for components of bone matrix and cartilage. The fibronectin-binding adhesin may allow the S aureus to bind to surgically implanted devices. Again, the S. aureus can be internalized by cultured osteoblasts and survive intracellularly possibly explaining the persistence of some infections. Phenotypic resistance to antibiotics associated with adherence to the bone may provide another explanation. In discussing clinical features, the authors point out that clinical signs persisting for more than ten days correlate roughly with the development of necrotic bone and chronic osteomyelitis. They note that surgical sampling or needle biopsy provides indispensable information. While various new imaging methods are available, they note that conventional radiography is still necessary at both presentation and follow-up. In the case of the diabetic foot, they quote the Joslin group in claiming that if one can gently advance a sterile surgical probe to reach bone, the diagnosis of osteomyelitis is clearly established. For successful treatment, they suggest that parenteral antibiotics must be administered at least four and usually six weeks to achieve acceptable cure rates. They dismiss the local use of antibiotics, noting that the diffusion of antibiotic given in this way is limited in time and area and that such methods have not undergone controlled study. For the patient with ischemia and/or diabetes, they note that the treatment depends on the oxygen tension of the tissue at the infected site, the potential for revascularization, the extent of local infection and the preference of the patient. Comments: Those of us interested in the diabetic foot are likely to be disappointed in this article. Certainly the large number of diabetic infections deserve more attention. The importance of glycemic control is worth mentioning. It is to be appreciated that a bone biopsy does provide immediate reliable culture information... but at a cost of introducing further trauma to both skin and bone. It is likely rare that serial cultures of draining fistula do not include the important pathogenic bacteria. Local oxygen tension may fall to very low values due to oxygen consumption by cells and bacteria in cellulitic tissue and may not reflect poor arterial flow; such measurements are best combined with Doppler laser or PPG studies for an accurate interpretation of the data. Finally, being advocates of the local injections of antibiotics disseminated with the use of Circulator Boot therapy, we claim a reduced cost, increased safety and increased effectiveness versus their recommended therapy. In patients with very low transcutaneous oxygen levels and obvious pulsatile PPG blood flow, we consider the local administration of antibiotics a necessity and expect to almost immediately improve the oxygenation of the tissue. We invite the authors to visit this website and to review Dr. Dillon's publications referenced elsewhere in this library.

• Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, LeFrock JL, Lew DP, Mader JT, Norden C : Diagnosis and treatment of diabetic foot infections. Plast Reconstr Surg.117(7 Suppl):212S-238S, 2006. EXECUTIVE SUMMARY: 1. Foot infections in patients with diabetes cause substantial morbidity and frequent visits to health care professionals and may lead to amputation of a lower extremity. 2. Diabetic foot infections require attention to local (foot) and systemic (metabolic) issues and coordinated management, preferably by a multidisciplinary foot-care team (A-II). The team managing these infections should include, or have ready access to, an infectious diseases specialist or a medical microbiologist (B-II). 3. The major predisposing factor to these infections is foot ulceration, which is usually related to peripheral neuropathy. Peripheral vascular disease and various immunological disturbances play a secondary role. 4. Aerobic Gram-positive cocci (especially Staphylococcus aureus) are the predominant pathogens in diabetic foot infections. Patients who have chronic wounds or who have recently received antibiotic therapy may also be infected with Gram-negative rods, and those with foot ischemia or gangrene may have obligate anaerobic pathogens. 5. Wound infections must be diagnosed clinically on the basis of local (and occasionally systemic) signs and symptoms of inflammation. Laboratory (including microbiological) investigations are of limited use for diagnosing infection, except in cases of osteomyelitis (B-II). 6. Send appropriately obtained specimens for culture before starting empirical antibiotic therapy in all cases of infection, except perhaps those that are mild and previously untreated (B-III). Tissue specimens obtained by biopsy, ulcer curettage, or aspiration are preferable to wound swab specimens (A-I). 7. Imaging studies may help diagnose or better define deep, soft-tissue purulent collections and are usually needed to detect pathological findings in bone. Plain radiography may be adequate in many cases, but MRI (in preference to isotope scanning) is more sensitive and specific, especially for detection of soft-tissue lesions (A-I). 8. Infections should be categorized by their severity on the basis of readily assessable clinical and laboratory features (B-II). Most important among these are the specific tissues involved, the adequacy of arterial perfusion, and the presence of systemic toxicity or metabolic instability. Categorization helps determine the degree of risk to the patient and the limb and, thus, the urgency and venue of management. 9. Available evidence does not support treating clinically uninfected ulcers with antibiotic therapy (D-III). Antibiotic therapy is necessary for virtually all infected wounds, but it is often insufficient without appropriate wound care. 10. Select an empirical antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s) (B-II). Therapy aimed solely at aerobic Gram-positive cocci may be sufficient for mild-to-moderate infections in patients who have not recently received antibiotic therapy (A-II). Broad-spectrum empirical therapy is not routinely required but is indicated for severe infections, pending culture results and antibiotic susceptibility data (B-III). Take into consideration any recent antibiotic therapy and local antibiotic susceptibility data, especially the prevalence of methicillin-resistant S. aureus (MRSA) or other resistant organisms. Definitive therapy should be based on both the culture results and susceptibility data and the clinical response to the empirical regimen (C-III). 11. There is only limited evidence with which to make informed choices among the various topical, oral, and parenteral antibiotic agents. Virtually all severe and some moderate infections require parenteral therapy, at least initially (C-III). Highly bioavailable oral antibiotics can be used in most mild and in many moderate infections, including some cases of osteomyelitis (A-II). Topical therapy may be used for some mild superficial infections (B-I). 12. Continue antibiotic therapy until there is evidence that the infection has resolved but not necessarily until a wound has healed. Suggestions for the duration of antibiotic therapy are as follows: for mild infections, 12 weeks usually suffices, but some require an additional 12 weeks; for moderate and severe infections, usually 24 weeks is sufficient, depending on the structures involved, the adequacy of debridement, the type of soft-tissue wound cover, and wound vascularity (A-II); and for osteomyelitis, generally at least 46 weeks is required, but a shorter duration is sufficient if the entire infected bone is removed, and probably a longer duration is needed if infected bone remains (B-II). 13. If an infection in a clinically stable patient fails to respond to 1 antibiotic courses, consider discontinuing all antimicrobials and, after a few days, obtaining optimal culture specimens (C-III). 14. Seek surgical consultation and, when needed, intervention for infections accompanied by a deep abscess, extensive bone or joint involvement, crepitus, substantial necrosis or gangrene, or necrotizing fasciitis (A-II). Evaluating the limb's arterial supply and revascularizing when indicated are particularly important. Surgeons with experience and interest in the field should be recruited by the foot-care team, if possible. 15. Providing optimal wound care, in addition to appropriate antibiotic treatment of the infection, is crucial for healing (A-I). This includes proper wound cleansing, debridement of any callus and necrotic tissue, and, especially, off-loading of pressure. There is insufficient evidence to recommend use of a specific wound dressing or any type of wound healing agents or products for infected foot wounds. 16. Patients with infected wounds require early and careful follow-up observation to ensure that the selected medical and surgical treatment regimens have been appropriate and effective (B-III). 17. Studies have not adequately defined the role of most adjunctive therapies for diabetic foot infections, but systematic reviews suggest that granulocyte colony-stimulating factors and systemic hyperbaric oxygen therapy may help prevent amputations (B-I). These treatments may be useful for severe infections or for those that have not adequately responded to therapy, despite correcting for all amenable local and systemic adverse factors. 18. Spread of infection to bone (osteitis or osteomyelitis) may be difficult to distinguish from noninfectious osteoarthropathy. Clinical examination and imaging tests may suffice, but bone biopsy is valuable for establishing the diagnosis of osteomyelitis, for defining the pathogenic organism(s), and for determining the antibiotic susceptibilities of such organisms (B-II). 19. Although this field has matured, further research is much needed. The committee especially recommends that adequately powered prospective studies be undertaken to elucidate and validate systems for classifying infection, diagnosing osteomyelitis, defining optimal antibiotic regimens in various situations, and clarifying the role of surgery in treating osteomyelitis (A-III).

• Littenberg B, Mushlin AI and the Diagnostic Technology Assessment Consortium. Technetium bone scanning in the diagnosis of osteomyelitis. A meta-analysis of test performance. J Gen Inter Med 7:158-163, 1992. A relatively poor test. In many clinical situations, the specificity of the bone scan will not be high enough to confirm the diagnosis of osteomyelitis.

• Lowy FD: Staphylococcus Aureus Infections. New Engl J Med 339:520-532, 1998. "In an elegant series of clinical observations and laboratory studies in 1880 and 1882, Ogston described staphylococcal disease and its role in sepsis and abscess formation. More than 100 years later, Staphylococcus aureus remains a versatile and dangerous pathogen in humans. The frequencies of both community-acquired and hospital acquired staphylococcal infections have increased steadily with little change in overall mortality. Treatment of these infections has become more difficult because of the emergence of drug-resistant strains."....Of the 11 types of microcapsular polysaccharide serotypes, "types 5 and 8 account for 75% of human infections"..."Staphylococci produce numerous toxins that are grouped on the basis of their mechanism of action": cytoxins, pyrogenic toxin, enterotoxins (toxic shock syndrome and food poisoning) and exfoliative toxins... "Humans are a natural reservoir of S.aureus. Thirty to 50 percent of healthy adults of healthy adults are colonized, with 10 to 20 percent persistently colonized. Both methicillin-sensitive and methicillin-resistant isolates are persistent colonizers. Patients colonized with S. aureus are at increased risk for subsequent infection". Comments: We have provided but a few excerpts from this paper. It is a good overall recent review of the Staphylococcus and is recommended to the interested reader. A resistant Staphylococcus on the rampage is a frightening thing to behold.

• Maki DG, Stolz SM, Wheeler S, and Mermel LA:Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter. A Randomized, controlled trial. Ann Intern Med 127:257-266, 1997. Authors' conclusions: The chlorhexidine-silver sulfadiazine catheter is well tolerated, reduces the incidence of catheter-related infection, extends the time that noncuffed central venous catheters can be safely left in place for the short term, and should allow cost savings. Comments: The indwelling intravenous catheter has become more important today as HMO's force patients to be discharged from the hospital to receive long-term antibiotics at home. In an editorial accompanying this article, Pearson and Abrutyn point out that central venous catheters account for an estimated 90% of all nosocomial bloodstream infections with multiple lumen catheters especially having a high risk. In a companion article, Raaad et al report similar success in reducing infection with their antibiotic-coated (rifampin and minocycline) catheter. Finally, Marr et all recount their experience with catheter-related bacteremia in patients undergoing hemodialysis; 40% of 102 patients developed 62 episodes of bacteremia over 16081 catheter days resulting in infective endocarditis in 4 patients and death in 2 patients. We have no such problems with our local antibiotic approach.

• Mempel M, Schnopp C, Hojka M et al: Invasion of human keratinocytes by Staphylococcus aureus and intracellular bacterial persistence represent haemolysin-independent virulence mechanisms that are followed by features of necrotic and apoptotic keratinocyte cell death. Br J Dermatol 146:943-51, 2002. BACKGROUND: Colonization of human skin by Staphylococcus aureus is a characteristic feature of several inflammatory skin diseases, which is often followed by tissue invasion and severe cell damage. A crucial role has been attributed to staphylococcal haemolysins in the cytotoxicity to epidermal structures. OBJECTIVES: To investigate haemolysin-independent virulence to human keratinocytes. METHODS: The stable alpha-haemolysin, beta-haemolysin double-negative S. aureus mutant DU 5720 was compared with the fully virulent parent strain 8325-4 and with its isogenic fibronectin-binding protein A/B-negative variant DU 5883 in an invasion model. RESULTS: This assay showed dose-dependent internalization of all the strains investigated by human HaCaT keratinocytes, with reduced internalization of DU 5883. Transmission electron microscopy revealed adhesion of staphylococci to cellular pilus-like extrusions, followed by the embedding of the bacteria in cellular grooves. Following attachment to the keratinocytes the staphylococci were engulfed into vesicles within the cytoplasm where some bacteria persisted for 24-48 h. Addition of cytochalasin D strongly reduced the bacterial uptake, suggesting an active keratinocyte process. Bacterial invasion was followed by severe keratinocyte cell damage showing the morphological changes of cytotoxic and, to a lesser extent, apoptotic cell death as determined by the trypan blue exclusion test and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling assay. The highest levels of lethal cytotoxicity were observed in haemolysin-producing strains, whereas the induction of apoptosis seemed to depend on internalization. CONCLUSIONS: Staphylococcal invasion of human keratinocytes represents a potent staphylococcal virulence factor, which, independently of alpha- and beta-haemolysins, leads to necrotic and apoptotic cell damage.

• Miyazaki H, Yanagitani S, Matsumoto T et al: Hypercoagulopathy with Piperacillin Administration in Osteomyelitis. Internal Mediicine 39: 424-427, 2000. Abstract: A 51-year-old man with osteomyelitis developed acute renal failure and superior mesenteric venous (SMV) thrombosis after piperacillin (PIPC) treatment. Coagulation profile disclosed disseminated intravascular coagulation (DIG). The serum levels of IgE and eosinophil cationic protein showed significant increases, while a lymphocyte stimulation test with PIPC also demonstrated an extremely high index. These observations suggest that hypersensitivity to PIPC might play a role in the pathogenesis of acute renal failure and SMV thrombosis due to hypercoagulopathy. Withdrawal of PIPC and anticoagulation therapy resulted in clinical improvement and normalization of the affected laboratory data. This is the first report to describe PIPC-induced hypercoagulopathy. Comments: Clinical deterioration in patients with osteomyelitis is easily attributed to sepsis and may lead to early amputations. Here PIPC withdrawal and anticoagulation proved important. Would the reader have thought of hypersensitivity?

• Nelson CL, McLaren SG, Skinner RA, Smeltzer MS, Thomas JR, Olsen KM: The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets. J Orthop Res. 20:643-7, 2002. Calcium sulfate was used as a biodegradable delivery system for the administration of antibiotics in musculoskeletal infection. New Zealand white rabbits were infected with Staplylococcus aureus, debrided, and randomized to one of four treatment groups: calcium sulfate pellets with 10% tobramycin sulfate, placebo calcium sulfate pellets and IM tobramycin, placebo calcium sulfate pellets, or debridement. Serum and wound exudate tobramycin concentrations and serum calcium levels were measured. Radiographs, cultures, and histology were analyzed for efficacy and treatment. Rabbits treated with 10% tobramycin sulfate pellets showed a significantly higher eradication of infection (11/13) than rabbits treated with debridement only (5/12), placebo pellets and IM tobramycin (5/14). or placebo pellets (3/13). In the group receiving 10% tobramycin sulfate pellets, serum tobramycin concentrations peaked 3 h post-operatively at 5.87 microg/ml and were non-detectable after day 1. In the group receiving placebo pellets and IM tobramycin, serum concentrations peaked at 7.82 microg/ml 1 h post-operatively, fell to 6.12 microg/ml on day 2, and averaged 4.18 microg/ ml for the remainder of the treatment period. The wound exudate tobramycin concentrations in the animals treated with tobramycin sulfate pellets peaked at 11.9 mg/ml on day 1 and dropped to 2.5 microg/ml on day 7. There was no significant difference in the serum calcium levels in any of the treatment groups. Calcium sulfate containing tobramycin sulfate has potential utility as a biodegradable local antibiotic delivery system in the treatment of musculoskeletal infections.

• Newman Lg, Waller J, Palestro J, Schwartz M, Klein MJ et al: Unsuspected osteomyelitis in diabetic foot ulcers. Diagnosis and monitoring by leukocyte scanning with Indium in 111 oxyquinoline. JAMA 266:1246-1251. 1991. As determined by bone biopsy and culture, osteomyelitis was found to underlie 28 (68%) of 41 ulcers. 9/28 were clinically diagnosed. 19/28 no evidence of inflammation. All patients with exposed bone had osteomyelitis. In diagnosing the osteomyelitis, the leukocyte scan had an 89% sensitivity. The image intensity decreased by 16-34 days of antibiotic therapy and normalized by 36-54 days.

• Newman LG, Waller J, Palestro CJ, Hermann G, Klein MJ et al: Leukocyte scanning with 111 In is superior to magnetic resonance imaging in diagnosis of clinically unsuspected osteomyelitis in diabetic foot ulcers. Diabetes Care 15: 1527-1530, 1992. Sixteen foot ulcers in 12 diabetic patients studied with scans both with 111In leukocytes and MRI... then bone biopsy and culture. Biopsy-proven osteomyelitis in 7 (44%), clinically suspected in none, seen on leukocyte scan 100% and on MRI in 29% (specificities 67% & 78% respectively). The + and - predictive values (70% & 100%) respectively) for the leukocyte scan were greater than for the MRI (50 & 58%).

• Niinikoski J: Hyperbaric oxygen therapy of diabetic foot ulcers, transcutaneous oxymetry in clinical decision making. Wound Repair Regen. 11:458-61, 2003. The foot ulcer is one of most common and devastating complications of diabetes and is associated with considerable morbidity and mortality. The major causes of these ulcers are ischemia/hypoxia, neuropathy, and infection, and they often coexist. Despite conventional therapy including revascularization procedures when appropriate, three situations lead frequently to amputation: persistent critical limb ischemia, soft tissue infection, and impaired wound healing from osteomyelitis. In these conditions, hyperbaric oxygen therapy may be used as an adjunctive treatment and is associated with a better outcome. Randomized, prospective, controlled trails have shown the benefit of hyperbaric oxygen therapy in diabetic ulcers of the lower extremity. Transcutaneous oxygen measurement performed under hyperbaric oxygen therapy has a prognostic significance when used to select patients who are the most likely to benefit from therapy. Hyperbaric oxygen should be added to conventional treatment if the transcutaneous oxygen tension close to the trophic lesion in 2.5 ATA hyperbaric oxygen is over 200 mmHg. Peri-wound transcutaneous oxygen tensions over 400 mmHg in 2.5 ATA hyperbaric oxygen or over 50 mmHg in normobaric pure oxygen predict healing success with adjuncted hyperbaric oxygen therapy with high accuracy. Comments: Increasing the delivery of oxygen to the tissues is, of course, the goal of therapy. To do this, one must either increase arterial flow or the amount of oxygen in a given amount of blood. As tissue hypoxia is a most potent vasodilator, it's relief with hyperbaric oxygen would tend to decrease blood flow. The oxygen content of blood (CaO2)is given by the formula: CaO2 = Hb (gm/dl) x 1.34 ml O2/gm Hb x SaO2 + PaO2 x (.003 ml O2/mm Hg/dl) where Hb is the hemoglobin, SaO2 the hemoglobin O2 saturation, and PaO2 the arterial partial pressure of oxygen. While the partial pressure of oxygen in the air is 20% of 760 mmHg or 152 mmHg, the partial pressures of nitrogen, carbon dioxide and water reduce it to about 100 mmHg in the alveoli. For a patient with normal lungs, a hemoglobin of 14 grams, an oxygen saturation of 95%, an alveolar PO2 of 100 and a PaO2 of 95, CaO2 would equal 18.1 ml O2 with 98.3% of the oxygen carried on the hemoglobin. Giving the patient 100% oxygen by mask rids the lungs of the nitrogen but not the water vapor and carbon dioxide; the alveolar PO2 might approximate 508 mmHg. the hemoglobin O2 saturation rise to 100% and the dissolved O2 content rises to about 1.5 ml, altogether raising the CaO2 to 20.4 (an increase of 12.7%). In an environment of 100% oxygen and 2.5 atmospheres, the oxygen tension becomes 1890 mmHg which administered too long can produce significant oxygen toxicity. If all 1890 mmHg (no alveolar block and no CO2 or water vapor)reached the blood, the dissolved O2 rises to 5.7 ml and the hemoglobin saturation rises to 100%. The hemoglobin carries now 18.7 ml and the CaO2 is 24.4 ml O2. The oxygen content of the blood, hence, is increased by about one third. In our vascular testing library, one learns that normal transcutaneous PO2 in room air is over 40 mmHg and that healing can be expected if it is over 30 mmHg. One might calculate if one had a transcutaneous PO2 of 22.5 mmHg and lived in a hyperbaric chamber on 100% oxygen at 2.5 atmospheres, the treatment would raise the tissue PO2 to 30 mm Hg (blood flow remaining equal). Likewise, one might calculate that if one had a baseline transcutaneous oxygen of 44.5 mmHg, it would rise to 50 mmHG with the application of the pure oxygen mask. These various calculations are somewhat favorable to hyperbaric oxygen therapy, however, as the administration of oxygen either by mask or in the hyperbaric chamber may significantly reduce oxygen-stimulated respiratory drive resulting in carbon dioxide retention and reductions in alveolar oxygen and arterial oxygen tensions....Points to consider: (a) the hemoglobin concentration is much more important than the alveolar PO2; a small improvement in blood flow (perhaps from 5% of normal to 10% of normal) is much more effective in raising tissue oxygen levels than a large rise in alveolar PO2; and (b) in any case for the oxygen tension to rise with either an oxygen mask at one atmosphere or 2.5 atmospheres, there must be some blood flow to the periwound area. What would be impressive is not claimed here: wound healing in patients with baseline oxygen tensions under 20 mmHg.

• Niezgoda, J: PW116 - Circulator Boot Therapy to Heal Diabetic Foot Ulcers with Osteomyelitis. Poster Session at Third Congress of the World Union of Wound Healing Societies, June 2008, Toronto, Canada. Goals and Objectives: 1. Discuss impact of osteomyelitis and digit amputation in the diabetic population. 2. Define diastolic pneumatic compression and identify potential patients. Purpose: Current standard of care for osteomyelitis associated with diabetic foot ulcers (DFU) is surgical resection of the infected bone and systemic antibiotics. Despite aggressive therapy amputation is common leaving the patient at risk for additional amputations and an associated five-year mortal;ity rate of 39-68%. Preventing amputation therefore critical to maintaining quality of life. Circulator boot therapy (CBT) utilizes end diastolic pneumatic compression to improve arterial circulation in the leg, thereby promoting wound healing. CBT has been used in the management of DFU complicated by osteomyelitis by combining compression with local injection of antibiotics into the affected area. We have validated the effectiveness of this technique to treat patients with DFU and underlying osteomyelitis. Methods: The study group consisted of patients with DFU and radiographically diagnosed osteomyelitis who failed to heal despite antibiotics, aggressive offloading and appropriate local wound care. Surgical debridement was refused by all study patients. Patients received three, forty-five minute CBT sessions per week plus weekly local injections of antibiotic solution into the wound as determined by culture results. Aggressive offloading and appropriate local wound care efforts were continued. Results: We present a series of healed patients who completed a 4-6 week course of CBT plus local injection of an antibiotic. Discussion/Conclusion: Osteomyelitis complicating a DFU is often associated with amputation. CBT combined with local antibiotic injection has been shown to be effective in the management of selected patients in this group and should be considered prior to amputation.

• O'Grady NP, Alexander M, Dellinger EP, Gerberding JL, Heard SO, Maki DG, Masur H, McCormick RD, Mermel LA, Pearson ML, Raad II, Randolph A, Weinstein RA; Healthcare Infection Control Practices Advisory Committee.: Guidelines for the prevention of intravascular catheter-related infections. Infect Control Hosp Epidemiol. 23:759-69, 2002. BACKGROUND: Although many catheter-related bloodstream infections (CRBSIs) are preventable, measures to reduce these infections are not uniformly implemented. OBJECTIVE: To update an existing evidenced-based guideline that promotes strategies to prevent CRBSIs. DATA SOURCES: The MEDLINE database, conference proceedings, and bibliographies of review articles and book chapters were searched for relevant articles. STUDIES INCLUDED: Laboratory-based studies, controlled clinical trials, prospective interventional trials, and epidemiologic investigations. OUTCOME MEASURES: Reduction in CRBSI, catheter colonization, or catheter-related infection. SYNTHESIS: The recommended preventive strategies with the strongest supportive evidence are education and training of healthcare providers who insert and maintain catheters; maximal sterile barrier precautions during central venous catheter insertion; use of a 2% chlorhexidine preparation for skin antisepsis; no routine replacement of central venous catheters for prevention of infection; and use of antiseptic/antibiotic-impregnated short-term central venous catheters if the rate of infection is high despite adherence to other strategies (ie, education and training, maximal sterile barrier precautions, and 2% chlorhexidine for skin antisepsis). CONCLUSION: Successful implementation of these evidence-based interventions can reduce the risk for serious catheter-related infection.Comments: The cost-savings of outpatient parenteral antimicrobial-drug therapy have been emphasized by many authors who would avoid hospitalization. Catheters are commonly used for long-term antibiotic administration in the hospital also, however. Whereever used, they may be associated with complications that necessitate hospitalization. Potential complications include sterile phlebitis in 2-10%, large vein thrombosis soon after or many months after catheter placement, pulmonary emboli, superior vena cava syndrome, air embolism (potentially fatal), catheter fragment embolization, catheter tip migration to the right atrium or the jugular vein, catheter erosion through a vein or the right atrium (producing pericardial tamponade), intracatheter clots, fluid leaks through small holes in the catheter causing fluid extravasation or contiguous mass formation, rare idiosyncratic hypersensitivity reactions to the catheter substance, and exit-site infections, tunnel infections and catheter-related bloodstream infections. Finally, a rare form of infective endocarditis may occur when a malpositioned catheter traumatizes the tricuspid valve resulting in platelet-fibrin thrombi that become infected. Gilbert et al (Outpatient parenteral antimicrobial-drug therapy. N Engl J Med 337: 829-838, 1997) point out that infusions should not be prescribed if there is an equally effective and safe oral antibiotic regimen. Central venous catheters may account for an estimated 90% of all nosocomial bloodstream infections with multiple lumen catheters especially having a high risk. The risk of such infections can be reduced at added expense with the use of antiseptic- or antibiotic-coated catheters. In this article, O'Grady et al provide us with common sense on how to decrease the risk of infection.

• Pathare NA, Sathe SR: Antibiotic combinations in polymicrobic diabetic foot infections. Indian J Med Sci 55(12):655-62, 2001. OBJECTIVE: The aim of this study was to evaluate synergistic potential of antibiotic combinations against pathogenic microorganisms isolated from patients with diabetic foot wounds. RESEARCH DESIGN AND METHODS: 272 diabetic foot patients were studied prospectively over a two-year period. Tissue curettage samples from ulcer base were processed microbiologically to isolate aerobic as well as anaerobic pathogens. [775 isolates] Antibiotic susceptibility testing [MIC/MBC], from amongst these organisms revealed 75 multiresistant organisms, of which only 69 strains could be further studied to assess synergistic effect of various antibiotic combinations by the microtitre checkerboard assay technique. RESULTS: The checkerboard synergy studies showed that overall, synergy could be demonstrated in 21.74% to 59.57%. Amongst the 14 combinations tested, it was found that four combinations could be of worthwhile clinical significance, namely Amikacin/Piperacillin [AK + PP] [77.50%]; Ampicillin-Sulbactum/Piperacillin [AS + PP] [76.92%]; Ampicillin Sulbactum/Cefoperazone [AS + CP] [74.47%], and Ofloxacillin/Cefotaxime [OF + CT] [71.43%]. CONCLUSIONS: Amikacin/Piperacillin is a combination that has been proven to be of synergistic potential. This study not only confirms this observation but also showed that Ampitum-Sulbactum in combination with either Piperacillin or Cefoperazone was equally efficacious. Furthermore, it was also observed that Ofloxacillin/Cefotaxime combination could be almost equally useful. The study thus emphasizes that antibiotic combinations which are synergistic can be of great clinical significance in the management of patients with diabetic foot infections.

• Perry CR, Hulsey RE, Mann FA, Miller GA, Pearson RL: Treatment of acutely infected arthroplasties with incision, drainage, and local antibiotics delivered via an implantable pump. Clin Orthop. 281:216-23, 1992. Twelve patients with acutely (symptomatic less than ten weeks) infected arthroplasties were treated with minimal debridement and intraarticular antibiotic, amikacin, delivered via an implantable pump. The infection was suppressed in ten cases. Intraarticular levels of amikacin were obtained in eight cases. These levels ranged from greater than 150 micrograms/ml to 1688 micrograms/ml. The systemic level of amikacin remained below 10 micrograms/ml in all but one case. Duration of hospitalization averaged 19 days. There were no significant toxic side effects to amikacin.Comments: This was the last of several publications from this group dating back to 1986 involving an antibiotic pumping device for the treatment of osteomyelitis. Daily injections of antibiotics obviate the need for a pump and its complications. Booting helps disseminate the antibiotic around the joint space without greatly increasing systemic antibiotic levels (no renal or ear toxicity).

• Ramsey SD, Newton K, Blough D et al: Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care 22:382-7,1999. OBJECTIVE: To determine the incidence of foot ulcers in a large cohort of patients with diabetes, the risk of developing serious complications after diagnosis, and the attributable cost of care compared with that in patients without foot ulcers. RESEARCH DESIGN AND METHODS: Retrospective cohort study of patients with diabetes in a large staff-model health maintenance organization from 1993 to 1995. Patients with diabetes were identified by algorithm using administrative, laboratory, and pharmacy records. The data were used to calculate incidence of foot ulcers, risk of osteomyelitis, amputation, and death after diagnosis of foot ulcer, and attributable costs in foot ulcer patients compared with patients without foot ulcers. RESULTS: Among 8,905 patients identified with type 1 or type 2 diabetes, 514 developed a foot ulcer over 3 years of observation (cumulative incidence 5.8%). On or after the time of diagnosis, 77 (15%) patients developed osteomyelitis and 80 (15.6%) required amputation. Survival at 3 years was 72% for the foot ulcer patients versus 87% for a group of age- and sex-matched diabetic patients without foot ulcers (P < 0.001). The attributable cost for a 40- to 65-year-old male with a new foot ulcer was $27,987 for the 2 years after diagnosis. CONCLUSIONS: The incidence of foot ulcers in this cohort of patients with diabetes was nearly 2.0% per year. For those who developed ulcers, morbidity, mortality, and excess care costs were substantial compared with those for patients without foot ulcers. The results appear to support the value of foot-ulcer prevention programs for patients with diabetes.

• Raymakers JT, Houben AJ, van der Heyden JJ, Tordoir JH, Kitslaar PJ, Schaper NC: The effect of diabetes and severe ischaemia on the penetration of ceftazidime into tissues of the limb. Diabet Med. 18:229-34, 2001. AIMS: To determine the effect of diabetes and of different degrees of ischaemia on the penetration of ceftazidime into different tissues. METHODS: Sixteen patients (10 with diabetes mellitus) undergoing lower extremity amputation for severe ischaemia (in 12 in combination with infection), received 2000 mg ceftazidime intravenously as a bolus 30 min prior to the operation. Skin perfusion was determined by transcutaneous oxygen pressure measurements (TcPO2) on the dorsal side of the midfoot. After amputation bone, skin and muscle samples were obtained from the forefoot, midfoot and proximal tibia. Tissue and plasma concentrations were determined by HPLC. The tissue concentrations were corrected for blood contamination. RESULTS: No differences were observed in skin, muscle or bone ceftazidime levels between diabetic and non-diabetic patients. Multiple regression analysis suggested that tissue perfusion was a major determinant of skin and bone ceftazidime concentrations, predicting 40-47% of the ceftazidime concentrations at several biopsy sites. CONCLUSIONS: The present study suggests that tissue perfusion is the major determinant of the penetration of a third generation cephalosporin into the tissues of the ischaemic (diabetic) foot. Diabetes alone however, has no major effects upon this penetration.

• Sapico FL, Witte JL, Canawati HN, Montgomerie JZ and Bessman AN: The infected foot of the diabetic patient: Quantitative microbiology and analysis of clinical features. Rev Infectious Dis 6 (Suppl 1) : S171-S176, 1984. Study of 32 amputated diabetic limbs: 6 only aerobes, 1 only anerobes, and 25 a mixtureof aerobes and anaerobes... a mean of 4.81 species isolated. Cultures obtained by curettage of base of ulcers correlated better with deep tissue cultures than did needle aspiration or swabs of the ulcer. Anaerobes associated with higher frequency of fever and foul smelling lesions. Prior antibiotic therapy did not appear to influence the nature of the microorganisms isolated.

• Scher KS and Steele FJ: The septic foot in patients with diabetes. Surgery 104:661-666, 1988. 65 lower extremity amputations in diabetics over 3 years (98 in nondiabetics not included). Chronic planter ulcer most frequent cause of infection. Other causes included ischemic gangrene, trauma, and web-space fissures. Advanced ischemia infrequent (32.3%) and defined as arm-ankle indices 0.5). 23.5% died and 35.3% stumps failed when closed amputation was done in 35 patients vs no deaths and 12.9% stump failures when open amputations done. Recommends guillotine transmalleolar amputation with later BK for highest success.

• Seabrook GR, Edminston CE, Schmitt DD, Krepel C, Bandyk DF and Towne JB: Comparison of serum and tissue antibiotic levels in diabetes-related foot infections. Surgery 110:671-677, 1991. 26 patients given one dose of gentamycin/clindamicin, ticarcillin/clavulanate, or ampicillin/sulbactam one hour before surgical debridement when serum and tissue levels measured. Adequate antibiotic levels were reached in the serum in 16 and in the tissues in 6 patients. Initial intravenous antibiotic administration provides inadequate tissue concentrations for treating foot infections in diabetics.

• Senneville E, Melliez H, Beltrand E, Legout L, Valette M, Cazaubiel M, Cordonnier M, Caillaux M, Yazdanpanah Y, Mouton Y: Culture of percutaneous bone biopsy specimens for diagnosis of diabetic foot osteomyelitis: concordance with ulcer swab cultures. Clin Infect Dis 42:57-62, 2006. BACKGROUND: We assessed the diagnostic value of swab cultures by comparing them with corresponding cultures of percutaneous bone biopsy specimens for patients with diabetic foot osteomyelitis. METHODS: The medical charts of patients with foot osteomyelitis who underwent a surgical percutaneous bone biopsy between January 1996 and June 2004 in a single diabetic foot clinic were reviewed. Seventy-six patients with 81 episodes of foot osteomyelitis who had positive results of culture of bone biopsy specimens and who had received no antibiotic therapy for at least 4 weeks before biopsy constituted the study population. RESULTS: Pathogens isolated from bone samples were predominantly staphylococci (52%) and gram-negative bacilli (18.4%). The distributions of microorganisms in bone and swab cultures were similar, except for coagulase-negative staphylococci, which were more prevalent in bone samples (P < .001). The results for cultures of concomitant foot ulcer swabs were available for 69 of 76 patients. The results of bone and swab cultures were identical for 12 (17.4%) of 69 patients, and bone bacteria were isolated from the corresponding swab culture in 21 (30.4%) of 69 patients. The concordance between the results of cultures of swab and of bone biopsy specimens was 42.8% for Staphylococcus aureus, 28.5% for gram-negative bacilli, and 25.8% for streptococci. The overall concordance for all isolates was 22.5%. No adverse events--such as worsening peripheral vascular disease, fracture, or biopsy-induced bone infection--were observed, but 1 patient experienced an episode of acute Charcot osteoarthropathy 4 weeks after bone biopsy was performed. CONCLUSIONS: These results suggest that superficial swab cultures do not reliably identify bone bacteria. Percutaneous bone biopsy seems to be safe for patients with diabetic foot osteomyelitis.Comments: Hopefully an article with ten authors offers valid information. Kessler et al above arrived at the same conclusions.

• Shompole S, Henon KT, Liou LE et al: Biphasic intracellular expression of Staphylococcus aureus virulence factors and evidence for Agr-mediated diffusion sensing. Mol Microbiol 49:919-27, 2003. Staphylococcus aureus invades a variety of mammalian cells and escapes from the endosome to multiply in the cytoplasm. We had previously hypothesized that the molecular events leading to escape of S. aureus from the endosome involved the Agr virulence factor regulatory system. In this report we demonstrate that temporal changes in intracellular activation of the Agr regulon correlates with expression of membrane active toxins. Also, the initial expression of Agr by even small numbers of staphylococci resulted in the permeabilization of the endosomal membrane and the eventual escape of bacteria into the cytoplasm by 3 h post invasion. After Agr downregulation, a second peak of expression coincided with increased permeability of the host cell membrane. In contrast to the parental strain, an Agr-mutant was unable to escape into the cytoplasm and was observed in intact endosomes as late as 5 h post invasion. These data provide evidence that staphylococcal virulence factor production during invasion of host cells is mediated by an Agr-dependent process that is most accurately described in the context of diffusion sensing.

• Smith AJ, Daniels T and Bohnen JMA: Soft tissue infections and the diabetic foot. Am J Surg 172 (suppl 6A):7S-12S, 1966. Abstract: Soft tissue infections are classified as local or spreading. Spreading soft tissue infections are potentially life-threatening conditions, requiring prompt diagnosis and treatment. The information presented is based on a literature review and the author's clinical experience. Diagnosis of soft tissue infection is aimed at determining the level of infection (skin, fascia, muscle) and whether necrosis is present. The bacteriology of these infections is varied and of secondary importance. Treatment of skin infections that have no dead tissue is with antibiotics alone. Infections at the fascial or muscle level and those with necrosis at any level require surgical debridement and adjuvant antibiotics. The feet of diabetic patients are prone to plantar forefoot ulcers associated with tissue destruction and infection. The vast majority are caused by mechanical factors. If localized immune defenses are adequate, bacterial colonization occurs without infection. Most diabetic foot ulcers will respond to relief of pressure, which may require total contact casting. Antibiotics and debridement are required in infected or deep ulcers, or when the ulcer does not respond to total contact casting. Comments: Smith et al provide us with the current surgical gospel. Perusal of our case histories will show that we break virtually all of his rules quite effectively. The Joslin group has reported that they consider cellulitis over a few centimeters as an ominous sign. Such cellulitis may spread in spite of antibiotics and surgical debridement may merely create an open wound in inflamed tissue. A tender enlarging red area with a low transcutaneous PO2 and a high PCO2 and detectable PPG pulse waves commonly portends significant cellulitis. We infiltrate the area with gentamicin or other antibiotic and disseminate it locally with the boot virtually sterilizing the area immediately. When abscesses form, we aspirate them dry and may irrigate them with Sea Soaks and appropriate antibiotics. Then again, we infiltrate the local area with antibiotics and pump on the foot... no wide debridement or large surgical wound. Contact casting makes wound observation difficult and our local measures impossible. Rather, we use a walking air cast with padding to relieve pressure points.... Again, we do most all cases as outpatients hospitalizing only those with other illnesses that require the hospital.

• Smith DG, Stuck RM, Ketner L, Sage RM and Pinzur MS: Partial calcanectomy for the treatment of large ulcerations of the heel and calcaneal osteomyelitis. J Bone and Joint Surg 74A: 571-576, 1992. 12 patients with arm/ankle index >0.45, TcPO2>28 mm Hg, serum albumen >3.0, lymphocyte count >1500 and availaable soft tissue adequate to cover the hind foot. Wound healed in 10 of the 12 and 9 maintained their preoperative level of mobility.

• Spanu T, Santangelo R, Andreotti F et al: Antibiotic therapy for severe bacterial infections: correlation between the inhibitory quotient and outcome. Int J Antimicrob Agents 23:120-8, 2004. In severe bacterial infections, treatment failure can occur even when the infecting organism has displayed in vitro susceptibility to the antibiotics used. Several pharmacokinetic-pharmacodynamic parameters show better correlation with therapeutic outcome than susceptibility results. This study was devised to assess the relation between the inhibitory quotient (IQ), i.e., the ratio of achievable antibiotic concentration at the infection site to the minimum inhibitory concentration for the infecting organism, and both clinical and bacteriological outcomes in 290 severe bacterial infections. Multivariate analysis showed that the IQ was a strong predictor of therapeutic outcome ( P< 0.001-0.002): values <4 predicted failure, and those >or=6 cure. This simple parameter could be routinely used to guide effective antibiotic therapy. Comments: Obviously the local injection of antibiotics will produce an IQ well over 6 in the area of th4e injection.

• Spittell JA et al: Concentration of orally administered erythromycin and tetracycline in ischemic tissue. Proc Staff Meet May Clin. 36:11, 1961. High dose antibiotics do reach ischemic tissue.

• Tascini C, Gemignani G et al: Clinical and Microbiological Efficacy of Colistin Therapy in Combination With Rifampin and Imipenem in Multidrug-Resistant Pseudomonas aeruginosa Diabetic Foot Infection With Osteomyelitis. Int J Low Extrem Wounds. 5(3):213-6, 2006. The evaluation of the safety and effectiveness of colistin in association with rifampin and imipenem in 1 diabetic patient with severe diabetic foot infection (DFI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa, complicated by osteomyelitis, is presented in this "Case Report". The patient received colistin after other ineffective antimicrobial treatment when an MDR P aeruginosa strain was isolated by cultural examination, together with a multidisciplinary care approach including surgical debridement and adequate offloading. The efficacy of combination colistin plus rifampin plus imipenem was observed with a checkerboard method and bactericidal activity of the serum. The patient received colistin combination therapy for 6 weeks with cure of the infection and without renal toxicity. These data suggest that colistin, in combination with rifampin and imipenem, is safe and effective, in promoting healing in DFI due to MDR P aeruginosa and suggest the need for controlled clinical studies. Resistant Pseudomonas can be a problem. Our case #155 lost his leg because none of us could rid him of his Pseudomonas.

• Taylor LM Jr, Porter JM: The clinical course of diabetics who require emergent foot surgery because of infection or ischemia. J Vasc Surg 6:454-459, 1987. All acute diabetic foot problems were treated on vascular surgery service where aggressive local surgery emphasized. 114 diabetics, 138 limbs, and 212 urgent operations... followed 1 month to 11 years... 36 major amputations in 33 patients over 0-86 months from presentation.

• Thordarson DB, Perry JR and Patzakis J: Tetanus complicating a polymicrobial diabetic foot infection: Case presentation and review of current treatment. Foot and Ankle International 16: 97-99, 1995. The authors point out the rarity of tetanus in the United States, approximately 100 cases per year primarily among persons who have not been immunized or had not received the recommended booster immunization. They describe a patient with a clinical course like tetanus from whom they never isolated the tetanus organism. They had difficulty controlling the lesion which presented as a plantar wound approximately 5 mm in diameter without drainage. Subsequently, the web space was debrided, a second debridement was done, an open 2nd ray amputation was performed and later a beneath-the-knee amputation was performed. Their patient had many complications including contractions they attributed to tetanus. They point out that left untreated 80% of these patients would die, while with appropriate therapy (aggresssive debridement of toxin-containing tissue, tetanus toxoid, tetanus immune globulin, appropriate antibiotics that also include penicillin, and support of vital functions as needed in an intensive care unit) 10 to 20% may die, with the higher rates occurring in the elderly. We all have seen very sick patients with sepsis from foot lesions and did not consider the possibility of tetanus. This article reminds us that the possibility should be considered because the patient may die without proper therapy.

• Unkila-Kallio L, Markku JT, Kallio MD et al: Serum C-Reactive Protein, Erythrocyte Sedimentation Rate, and White Blood Cell Count in Acute Hematogenous Osteomyelitis of Children. Pediatrics 93:59-62, 1994. Objective. The aim of this prospective study was to compare the clinical value of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cell (WBC) count in diagnosis and follow-up of acute hematogenous osteomyelitis in children. Design. Forty-four children aged 2 weeks to 14 years with bacteriologically confirmed acute hematogenous osteomyelitis were examined. Staphylococcus aureus was responsible in 39 cases (89%), Haemophilus influenzae type b in 3 cases (7%), pneumococcus in 1 case (2%), and a microaerophilic streptococcus in 1 case (2%). ESR was measured at the time of admission and on days 3, 5, 7, 10, 14, 19, and 29 of treatment, and CRP was measured on the same days as ESR but also on days 2, 9, 12, 17, and 23. WBC count was examined at the time of admission and on days 5, 10, 19, and 29. Results. ESR was elevated (ge20 mm/h) initially in 92% of the cases; the mean value was 45 mm/h, and the peak values (mean 58 mm/h) were reached on days 3 to 5. After this the levels slowly returned to normal in approximately 3 weeks (mean 18 days). CRP was elevated (>19 mg/L) at the time of admission in 98% of the cases, the mean value being 71 mg/L. The peak CRP value was reached on day 2 (mean 83 mg/L). The decrease was very rapid, normal values being reached within a week (mean 6.9 days). The WBC count was a poor indicator of acute hematogenous osteomyelitis, since only 35% of the children had leukocytosis (WBCs > 12 x 109/L) at the time of admission. Conclusions. In patients with acute hematogenous osteomyelitis, CRP increased and especially decreased significantly faster than ESR, reflecting the effectiveness of the therapy given and predicting recovery more sensitively than ESR or WBC count.

• Van GH, Siney H, Danan J-P, Sachon C, Grimaldi A: Treatment of osteomyelitis in the diabetic foot. Diabetes Care 19: 1257-1260, 1996. Healing and duration of treatment were compared in two groups of diabetics with similar characteristics other than calendar time of treatment. The first 32 were treated with the antibiotics available from 1986 to 1993, offloading and wound care. The second group of 32 patients were treated with the antibiotics available from September 1993 to march 1995, offloading, wound care and conservative orthopedic surgery performed by the same surgeon ( limited resection of the infected part of the phalanx or metatarsal bone under the wound with no other resection, with removal of the ulcer site). The antibiotics were given by the oral route when there was no cellulitis of general signs of infection and otherwise by the parenteral route. Healing occurred in 57% of the first group and 78% of the second (P<0.008) and the duration of healing was reduced from 462±98 days in the first group to 181±30 days (P<0.008) in the second group. Comments: The authors do not tell us what differences in antibiotic regimes were used over the nine year course of the study. Nor do they tell us which patients were hospitalized. Presumably those receiving intravenous antibiotics were hospitalized at least initially and presumably those receiving surgery were hospitalized again at least initially. Hospitalization affords opportunity for better wound care, improved glycemic control and bed rest... all significant factors likely to benefit the surgical group. Treatment was prolonged in both groups, six to fifteen months. With the use of locally injected antibiotics and boot therapy, we like to feel we can beat these statistics anytime.

• Vann JM, Proctor RA: Ingestion of Staphylococcus aureus by bovine endothelial cells results in time- and inoculum-dependent damage to endothelial cell monolayers. Infect Immun 55:2155-63, 1987. Cultured endothelial cells phagocytize Staphylococcus aureus, but the resultant effects are unknown. Monolayers of cultured bovine endothelial cells with or without [3H]adenine label were exposed to 100, 10, or 1 S. aureus organism per endothelial cell for 3.5 h. Lysostaphin was then applied to all cultures to destroy extracellular but not phagocytized S. aureus. In cultures treated for only 20 min with lysostaphin, S. aureus multiplied exponentially after a 9- to 12-h lag period. In cultures treated continuously with lysostaphin, numbers of S. aureus remained constant or decreased. These results indicate that S. aureus became extracellular and multiplied but did not multiply intracellularly. In parallel experiments, the release of 3H-adenine from prelabeled endothelial cell monolayers was assayed to indicate cytotoxicity. Results indicated that the loss of 3H-adenine from endothelial cell monolayers depended on the following: (i) the size of the S. aureus inoculum, (ii) the strain of S. aureus, and (iii) the length of time after exposure to S. aureus. S. aureus endocarditis and persistent septicemia could arise, at least in part, from ingestion of S. aureus by host endothelium. The intracellular location would afford S. aureus protection from host defenses and antibiotics. Eventual damage to endothelial cells could expose collagen, thus resulting in platelet adherence and vegetation formation. Intracellular S. aureus would be continuously released into the circulation, possibly accounting for the persistent bacteremia that is found in S. aureus endovascular infections.

• Venkatesan P, Macfarlane RM, Fletcher EM, Finch RG Jeffcoate WJ: Conservative management of osteomyelitis in the feet of diabetic patients. Diabetic Medicine 14: 487-490, 1997. Abstract: Experience of conservative management of osteomyelitis in a specialized, multidisciplinary, diabetic foot clinic was reviewed. The records of all patients attending the clinic over a 10-year period were examined retrospectively, and 22 patients with overt osteomyelitis were identified. Median age was 66 (31-87) years. In 12 cases the bone infection was a complication of a pre-existing ulcer.; the most prevalent organism cultured from swabs was Staphylococcus aureus. The main site of infection was the first toe. The total duration of antibiotic treatment was 12 weeks (median, range 5-72), and clindamycin was the most commonly used oral agent. Four patients did not respond to initial conservative therapy and proceeded to amputation, while one patient responded clinically but had a recurrence of osteomyelitis at the same site 6 years later. In the remaining 17 patients resolution of osteomyelitis was achieved with conservative management over a median period of follow-up of 27 (range 5-73) months. The success of conservative therapy with prolonged courses of oral antibiotics challenges conventional advice that excision of infected bone is essential in the management of osteomyelitis affecting the foot in diabetes. Comments: A small series and reasonably good results.

• von Eiff C, Becker K, Metze D et al: Intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with darier's disease. Clin Infect Dis 32:1643-7, 2001. Intracellular persistence assays were performed with small-colony variants (SCVs) derived from a patient with Darier's disease from whom different phenotypes and genotypes of Staphylococcus aureus were isolated over a 28-month period; the assays revealed that >100-fold more SCV cells persisted intracellularly relative to the normal phenotype. The presence of intracellular S. aureus SCVs may protect against host defenses and antibiotic therapy and thus may have contributed to this patient's very prolonged skin infection.

• Walenkamp GH, Kleijn LL, de Leeuw M: Osteomyelitis treated with gentamicin-PMMA beads: 100 patients followed for 1-12 years. Acta Orthop Scand. 69:518-22, 1998. We treated 100 patients having osteomyelitis with debridement and gentamicin-PMMA beads and followed them for 5 (1-12) years. 66 of the infections were chronic, in 18 cases combined with arthritis and in 3 cases with pseudarthrosis. They underwent 117 "treatment periods", consisting of one or more operations (total 152), in most cases with an interval of 2 weeks. No systemic antibiotics were necessary besides the local antibiotic treatment in 52 of the treatment periods. Healing was achieved in 92 patients, in 78 after a single treatment period which included 1-5 operations, in 14 after two or three treatment periods. Healing was more difficult to achieve when the infection was chronic, especially with a duration of more than 6 years or when caused by elective surgery. Local antibiotic treatment with gentamicin PMMA beads has the advantage that the wound can be closed primarily and that a higher local antibiotic concentration in the tissues can be achieved, often making systemic antibiotic treatment unnecessary.

• Weaver LK, Churchill S: Pulmonary edema associated with hyperbaric oxygen therapy. Chest 120:1407-9, 2001. We report three cases of pulmonary edema associated with hyperbaric oxygen therapy, including one fatality. All three patients had cardiac disease and reduced left ventricular (LV) ejection fractions (EFs). Two patients had diabetes, and one patient had severe aortic stenosis. Hyperbaric oxygen therapy may contribute to pulmonary edema by increasing LV afterload, increasing LV filling pressures, increasing oxidative myocardial stress, decreasing LV compliance by oxygen radical-mediated reduction in nitric oxide, altering cardiac output between the right and left hearts, inducing bradycardia with concomitant LV dysfunction, increasing pulmonary capillary permeability, or by causing pulmonary oxygen toxicity. We advise caution in the use of hyperbaric oxygen therapy in patients with heart failure or in patients with reduced cardiac EFs. Comments: Heart disease, of course, is common in diabetics with peripheral vascular disease. Indeed, heart disease is one reason physicians may refer their patient for treatments other than surgical revascularization. Hopefully the problems described here are not to be commonly expected in such patients.

• Weinstein D, Wang A, Chambers R, Stewart CA and Motz HA: Evaluation of magnetic resonance imaging in the diagnosis of osteomyelitis in diabetic foot infections. Foot & Ankle 14:18-22, 1993. Forty-seven patients with possible osteomelitis, nonhealing foot ulcer or soft tissue infection. MRI significantly more sensitive than plain x-rays and technesium and gallium scans. At early follow-up, complete resection of abnormal bone on MRI correlated with clinical healing.

• Weigelt J, Itani K, Stevens D et al: Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 49: 2260-6, 2005. Skin and soft tissue infections (SSTIs) are a common cause of morbidity in both the community and the hospital. An SSTI is classified as complicated if the infection has spread to the deeper soft tissues, if surgical intervention is necessary, or if the patient has a comorbid condition hindering treatment response (e.g., diabetes mellitus or human immunodeficiency virus). The purpose of this study was to compare linezolid to vancomycin in the treatment of suspected or proven methicillin-resistant gram-positive complicated SSTIs (CSSTIs) requiring hospitalization. This was a randomized, open-label, comparator-controlled, multicenter, multinational study that included patients with suspected or proven methicillin-resistant Staphylococcus aureus (MRSA) infections that involved substantial areas of skin or deeper soft tissues, such as cellulitis, abscesses, infected ulcers, or burns (<10% of total body surface area). Patients were randomized (1:1) to receive linezolid (600 mg) every 12 h either intravenously (i.v.) or orally or vancomycin (1 g) every 12 h i.v. In the intent-to-treat population, 92.2% and 88.5% of patients treated with linezolid and vancomycin, respectively, were clinically cured at the test-of-cure (TOC) visit (P=0.057). Linezolid outcomes (124/140 patients or 88.6%) were superior to vancomycin outcomes (97/145 patients or 66.9%) at the TOC visit for patients with MRSA infections (P<0.001). Drug-related adverse events were reported in similar numbers in both the linezolid and the vancomycin arms of the trial. The results of this study demonstrate that linezolid therapy is well tolerated, equivalent to vancomycin in treating CSSTIs, and superior to vancomycin in the treatment of CSSTIs due to MRSA.

• Wheat LJ, Allen SD, Henry M, Kernek CB, Siders JA, Kuebler T, Fineberg N and Norton J: Diabetic foot infections, Bacteriologic analysis. Arch Intern Med 146:1935-1940, 1986. "Unreliable" cultures were in contact with the ulcer or other openly draining lesion..."Reliable" cultures obtained by aspiration of bullae or abscesses or by surgical biopsy of bone or soft tissue had minimal contact with ulcers or draining lesion. Reliable aerobes: Staphylococcal species, Enterococcus species, Cornybacterium species and various Enterobacteriaceae. Reliable anaerobes: Peptostreptococcus magnus and prevotii and Bacteroides species. Reliable and unreliable cultures agreed in 27% of 26 patients while antibiotics selected to cover the unreliable results would have covered the reliable cultures in 93% of cases. Empirical coverage possibilities: (1) Clindamycin, ampicillin and gentamicin; (2) cefoxitin, pipercillin and gentamicin; (3) clindamycin, pipercillin, and gentamicin; (4) moxalactam and ampicillin; (5) 3rd generation cephalosporin, clindamycin and ampicillin; and (6) Imipenem...all potentially effective in 90% of patients. Aminoglycosides alone poor coverage for gram negative bacteria because of low concentrations in infected tissues. "Osteomyelitis" soft tissue infection accompanied by x-ray changes of erosion or demineralization.

• Wilson CL, Cameron J, Powell SM, Cherry G and Ryan TJ: High incidence of contact dermatitis in leg-ulcer patients -implications for management. Clin and Exper Dermatol 16:250-253, 1991. Summary: A retrospective review of patch test results from all new patients with venous leg ulcers was performed for the preceding 11 months. Eighty-one patients referred from general practitioners and district nurses with venous stasis ulcers were included. Positive patch tests were found in 54 patients (67%), including a high incidence to lanolin and topical antibiotics. Multiple allergies were found in 48 patients (58%). In addition, a new problem of allergy to cetearyl alcohol, a constituent of commonly used creams and paste bandages, was identified in 13 patients. There is a continuing high incidence of contact sensitivity in patients with venous stasis ulcers which has important implications for the management of these patients. Comments: The authors comment that there is no absolute proof that contact dermatitis reduces healing of ulcers but believe in their experience that it is an adverse factor. One can imagine redness, swelling and oozing mistaken for evidence of cellulitis and leading to inappropriate treatments. The authors recommend soft parrafin as a simple, cheap and effect emollient.

• Wolcott RD, Rhoads DD: A study of biofilm-based wound management in subjects with critical limb ischaemia. J Wound Care 17(4):145-8, 2008. OBJECTIVE: Bacterial biofilms cause or complicate numerous medical conditions, including chronic wounds. Biofilm-based wound care (BBWC) management strategies that suppress biofilm have been designed and are used extensively at the Southwest Regional Wound Care Center in Lubbock, Texas and are described in this article. This retrospective single-centre study was designed to evaluate the frequency of complete healing in subjects with a chronic wound in a limb with critical limb ischaemia (CLI) when managed using BBWC. METHOD: Of the 4500 subjects admitted with wounds between August 2002 and January 2006, 1400 subjects' TCpO2 levels were measured, and 266 included were identified as having CLI (TCpO2 < 20mmHg). Of these, 190 subjects were considered in the analysis because they received a substantial course of therapy (more than five visits). Each subject was individually managed to reinforce natural healing and suppress bacterial biofilm. Successful healing was defined as complete closure by March 2007. RESULTS: Of the 190 subjects with CLI, 146 (77%) healed completely, and 44 (23%) were categorised as non-healing.The healed group included 47% (68/146) with osteomyelitis and 69% (101/146) with diabetes mellitus. In the non-healed group, 75% (33/44) had osteomyelitis and 77% (34/44) had diabetes mellitus. Ninety-one per cent (30/33) of the subjects without osteomyelitis or diabetes mellitus healed, and 67% (53/79) of the subjects with both osteomyelitis and diabetes mellitus healed. CONCLUSION: When comparing the healing frequency in this study with a previously published study, BBWC strategies significantly improved healing frequency. These findings demonstrate that effectively managing the biofilm in chronic wounds is an important component of consistently transforming 'non-healable' wounds into healable wounds. Comments: Of 4500 patients with wounds, 1400 had TcPO2 measured and 266 had levels under 20 mmHg designating them for the study as patients with CLI (no other vascular data provided to justify the diagnosis). Of the 266, 50 deemed not candidates for limb salvage giving an intention-to-treat group of 216. Of the latter 26 drop out by the 4th week giving the group of 190 constituting the report. On the first visit, noninvasive vascular tests were done (not reported) and some patients were referred for revascularization (not told how many or the results). The subject of the report being biofilm infection, the patients hence all presumably had infection; aerobic bacteria causing necrotizing cellulitis, of course, can lower the TcPO2 even in well vascularized feet and appropriate antibiotic care may raise the value without altering blood flow. The abstract of the article is accompanied by a declaration of Dr. Wolcott’s interest in his therapeutic agents used to treat the biofilm infection: the combination of lactoferrin and xylitol.

• Zuluaga AF, Galvis W Saldarriaga JG, Agudelo M , Salazar BE : Etiologic diagnosis of chronic osteomyelitis: a prospective study. Arch Intern Med 166:95-100, 2006. BACKGROUND: Although bone specimens were established 25 years ago as the gold standard for etiologic diagnosis of chronic osteomyelitis, recent studies suggest that nonbone specimens are as accurate as bone to identify the causative agent. We examined concordance rates between cultures from nonbone and bone specimens in 100 patients. METHODS: Prospective study conducted at Hospital Universitario San Vicente de Paul, a 750-bed university-based hospital located in Medellin, Colombia. We included patients with chronic osteomyelitis who had been free of antibiotic therapy for at least 48 hours, excluding those with diabetic foot and decubitus ulcers. At least 1 nonbone and 1 bone specimen were taken from each individual and subjected to complete microbiologic analysis. RESULTS: Bone cultures allowed agent identification in 94% of cases, including anaerobic bacteria in 14%. Cultures of nonbone and bone specimens gave identical results in 30% of patients, with slightly better concordance in chronic osteomyelitis caused by Staphylococcus aureus (42%) than by all other bacterial species (22%). However, statistical concordance determined by the Cohen kappa statistic was less than 0 (-0.0092+/-0.0324), indicating that the observed concordance was no better than that expected by chance alone (P>.99). CONCLUSIONS: Appropriate diagnosis and therapy of chronic osteomyelitis require microbiologic cultures of the infected bone. Nonbone specimens are not valid for this purpose.