Benjamin A. Lipsky, Anthony R. Berendt, H. Gunner Deery, John M. Embil, Warren S. Joseph, Adolf W. Karchmer, Jack L. LeFrock, Daniel P. Lew, Jon T. Mader, Carl Norden, and James S. Tan Medical Service, Veterans Affairs Puget Sound Health Care System, and Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington; Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford, United Kingdom; Northern Michigan Infectious Diseases, Petoskey, Michigan; Section of Infectious Diseases, Department of Medicine, University of Manitoba, Winnipeg, Manitoba; Section of Podiatry, Department of Primary Care, Veterans Affairs Medical Center, Coatesville, Pennsylvania; Division of Infectious Diseases, Department of Medicine, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts; Dimensional Dosing Systems, Sarasota, Florida; Department of Medicine, Service of Infectious Diseases, University of Geneva Hospitals, Geneva, Switzerland; Department of Internal Medicine, The Marine Biomedical Institute, and Department of Orthopaedics and Rehabilitation, University of Texas Medical Branch, Galveston, Texas; Department of Medicine, New Jersey School of Medicine and Dentistry, and Cooper Hospital, Camden, New Jersey; and Department of Internal Medicine, Summa Health System, and Northeastern Ohio Universities College of Medicine, Akron, Ohio

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) (Table 1). 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). Table 1. Infectious Diseases Society of America–United States Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines

The foot is the most common site of infection in the diabetic individual, and one of every four diabetics eventually seeks medical care for a foot problem. This article examines pathologic conditions of the lower extremity from a variety of views, including pathophysiology, classification, microbiology, infections, osteomyelitis, treatment, and prevention strategies.

To compare the effectiveness of cefotetan administered at 2 g once a day with cefoxitin at 1 or 2 g three times a day in the treatment of hospitalized patients with skin and superficial soft tissue infections, 194 patients from eight centers were enrolled in an open, randomized trial. Most of the 104 evaluable patients in the cefotetan group and 50 in the cefoxitin group were young men with community-acquired, moderate or severe cellulitis, or abscesses of the upper and lower extremities caused by Staphylococcus aureus, Streptococcus species, Escherichia coli, Proteus mirabilits, Bacterioides fragilis and other species of bacteroides, peptococcus species, and peptostreptococcus species. The mean duration of treatment was 7.5 days for cefotetan and 7.1 days for cefoxitin. A successful clinical response was achieved in 97 percent of the cefotetan patients and in 94 percent of the cefoxitin patients. Of the 88 and 39 bacteriologically evaluable patients in the cefotetan and cefoxitin groups, respectively, a satisfactory bacteriologic response occurred in 96 percent and 87 percent of the patients. No clinicaly significant changes in clinical laboratory determinations were noted. The incidence of adverse reactions in the cefotetan group (17 percent) was significantly different from that for the cefoxitin group (6 percent) (p<0.05); however, the incidence of treatment-related reactions was not significant and the events were mild. Discontinuation of therapy was necessary only in two patients in whom allergic-type reactions developed. A one-daily regimen of cefotetan was as effective as thrice-daily cefoxitin in this study in the treatment of primarily polymicrobial, moderate, or severe infections of the skin and superficial soft tissue.

Pedal puncture wounds are a relatively common injury seen predominantly during the warm weather months and in children. Although most of these injuries heal completely with no sequelae, up to 10% may become infected and produce late complications. Of these, osteomyelitis caused by P. aeruginosa is the most devastating, and it may progress to bone destruction that will require extensive surgical debridement. If instituted early, adequate primary care usually provides the best chance of prevention of these infections.

• Aztreonam was used in the initial treatment of infection of the urinary tract (23 cases), respiratory tract (17 cases), skin and soft tissue (12 cases), abdominal cavity (three cases), endocarditis (two cases), septicemia (eight cases), and osteomyelitis (two cases). In 26 of 60 evaluable infectious episodes, aztreonam was used alone. Clinical cure was observed in 35 of 60, improvement in 24 of 60, and failure in one of 60 cases. Ten patients developed subsequent superinfection. Aztreonam was well tolerated, although one case of exfoliative dermatitis and one of pseudomembranous colitis occurred. However, these cases were complicated by proximal administration of other antibiotics. (Arch Intern Med1987;147:325-328)

The antimicrobial activity of carumonam (formerly RO-17-2301), a monocyclic beta-lactam antibiotic, was compared with those of aztreonam, cefotaxime, cefoperazone, ceftazidime, piperacillin, and gentamicin against 455 bacterial isolates. Carumonam did not possess activity against gram-positive cocci and was generally comparable to aztreonam and ceftazidime for most gram-negative bacilli. However, carumonam was the most active beta-lactam against gentamicin-resistant Pseudomonas aeruginosa strains (90% MIC, 8 micrograms/ml).

The antimicrobial activity of cefmetazole was compared with those of cefmenoxime, ceftizoxime, cefamandole, cefoperazone, cefotaxime, cephalothin, and latamoxef. In general, the activity of cefmetazole was less than those of the other cephalosporins. The in vitro activity of cefmetazole suggests that it will not prove useful as a broad-spectrum antimicrobial against gram-positive and gram-negative pathogens.

Twenty-six volunteers with various degrees of renal function were given a single 1-g dose of cefotetan intravenously over 30 min. Concentrations of cefotetan and cefotetan tautomer in plasma and urine were determined by high-performance liquid chromatography. The pharmacokinetic parameters for cefotetan were calculated according to a two-compartment open model. The mean plasma cefotetan concentration at the end of the intravenous infusion did not vary with renal function and ranged between 122 and 126 micrograms/ml. The mean terminal half-life was 4.2 h in normal volunteers and 9.9 h in volunteers with moderate renal impairment. There was a significant linear correlation between the systemic clearance of cefotetan and creatinine clearance. The cumulative amount of cefotetan excreted in the urine over 24 h in normal volunteers was approximately 49% of the dose, but this was reduced in volunteers with moderate renal impairment. The mean urinary cefotetan concentrations generally peaked during the 2- to 4-h interval after dosing. Cefotetan tautomer was sporadically detected in the plasma and urine of approximately 50% of the volunteers. The mean plasma cefotetan tautomer concentrations and mean total cumulative urinary recoveries of cefotetan tautomer were only minimal compared with those for cefotetan. The mean percentage of the dose excreted in the urine as cefotetan tautomer was not significantly affected by the degree of renal impairment. Recommendations for the dosing of cefotetan in renal-impaired patients are given.

The in vitro antimicrobial activity of two new aryl-fluoroquinolone antibiotics, A-56619 and A-56620, was compared with those of norfloxacin and several other antibiotics against 448 bacterial isolates. A-56620 was the most active agent tested. The usual 90% MIC of A-56620 was less than or equal to 2 micrograms/ml, except for enterococci, gentamicin-resistant Serratia marcescens, and gentamicin-resistant Pseudomonas aeruginosa, for which the 90% MIC was 4 micrograms/ml. A-56619 and norfloxacin were generally severalfold less active than A-56620. Cross resistance was observed between the quinolone antibiotics and other unrelated antibiotic classes.

Group G streptococci were isolated from various clinical sites in 64 patients hospitalized between 1979 and 1983. Oropharyngeal and wound infections occurred most commonly, although some of these isolates represented colonization. Ten patients had serious infections including five with endocarditis. Patients with endocarditis tended to be older, had underlying conditions predisposing them to infection, and responded poorly to single agent therapy with penicillin G or other β-lactam agents, despite exquisitein vitro susceptibility. Patients with serious infections but without endocarditis tended to be younger, had fewer underlying disorders and responded rapidly to therapy with β-lactam antibiotics. All isolates were susceptible to penicillin G, cephalothin, vancomycin and newer β-lactam agents. Occasional tolerance was observed. Combinations of penicillin G with an aminoglycoside and of vancomycin with an aminoglycoside or rifampin were bactericidal against the tolerant strains. Although none of the organisms isolated from patients with endocarditis were tolerant, this infection should be treated with combination antibiotic therapy.

Ticarcillin, a broad-spectrum penicillin [l], is susceptible in inactivation by a number of beta-lactamases. Clavulanic acid, a naturally occurring beta-lactamase inhibitor, has been shown to prevent the enzymatic degradation of beta-lactam antibiotics by a number of bacterial species [2]. In vitro studies have shown that in combination, ticarcillin and clavulanic acid may be synergistic in activity [3,4]. In the current study, we evaluated the clinical efficacy and safety of this combination in hospitalized patients with skin and skin structure infections. PATIENTS AND METHODS Patient Population. This research protocol was approved by the Human Studies Committee at both Hahnemann University Hospital and St. Michael’s Medical Center. The 79 patients in this study were adults hospitalized at either of the just mentioned medical centers, and informed consent was obtained by the investigators from each patient who entered the study. Each patient had either an acute or chronic skin or skin structure infection caused by an organism or organisms known or suspected to be susceptible to the combination of ticarcillin plus clavulanic acid. Patients excluded from the study included: pregnant or lactating women; recipients of an antimicrobial agent within the previous 72 hours to which the pathogen was susceptible; subjects with a known hypersensitivity to penicillin; and patients with known moderate to severe renal or hepatic dysfunction. Laboratory Studies. The following laboratory determinations were made before, during, and after treatment with ticarcillin plus clavulanic acid: complete hemogram, prothrombin time, quantitative platelet count, direct Coombs’ test, alkaline phosphatase, bilirubin, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, lactic dehydrogenase, serum concentrations of sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, serum creatinine, blood glucose, and urinalysis. Blood, purulent exudates from wounds, pus from abscesses, and excised tissue were obtained before, during, and after antibiotic therapy for aero