David M. Bamberger

Osteomyelitis in the feet of diabetic patients: Long-term results, prognostic factors, and the role of antimicrobial and surgical therapy

Fifty-one diabetic patients with osteomyelitis of the foot were studied to determine potential prognostic factors and the role of antimicrobial therapy. Most of the patients were elderly, with diminished pulses, a sensory neuropathy, and a polymicrobial infection. Twenty-seven patients had a good outcome, defined as clinical resolution at the time of the last follow-up examination, without the need for amputation. The mean duration of follow-up for these patients was 19 months. Fifteen patients had a below-knee amputation, and nine had 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 four weeks intravenously, or combined intravenously and orally for 10 weeks, predicted a good outcome. Diabetic foot osteomyelitis, in the absence of extensive necrosis or gangrene, usually responds to antimicrobial therapy without the need for an ablative surgical procedure.

Treatment of Histoplasmosis With Fluconazole in Patients With Acquired Immunodeficiency Syndrome

PURPOSE This study assesses the efficacy and safety of fluconazole therapy in patients with acquired immunodeficiency syndrome (AIDS) and mild to moderately severe manifestations of disseminated histoplasmosis. PATIENTS AND METHODS This was a multicenter, open-label, nonrandomized prospective trial. All patients had AIDS and disseminated histoplasmosis. Patients were treated with 1,200 mg of fluconazole given by mouth once on the first day, then 600 mg once daily for 8 weeks, and those patients who improved clinically were then assigned fluconazole maintenance therapy 200 mg once daily for at least 1 year. Interim analysis revealed a high failure rate (10 of 20, 50%), causing revision of the protocol to increase the fluconazole dose to 1,600 mg given once on the first day, then 800 mg once daily, and the duration to 12 weeks for induction therapy and then 400 mg daily for 1 year for maintenance therapy. MEASUREMENTS AND MAIN RESULTS Thirty-six of 49 patients (74%; 95% confidence interval [CI]: 59% to 85%) with mild to moderately severe clinical manifestations who entered into the revised study responded to 800 mg of fluconazole daily for 12 weeks as induction therapy. Of the seven patients who failed induction therapy because of progression of histoplasmosis, one died of the infection. Of 36 patients who entered into the maintenance phase of the study receiving 400 mg of fluconazole daily for 1 year, 11 (30.5%) relapsed, including one who died (2.8%). Two of the 49 patients (4.1%) were removed because of grade 4 adverse events, alkaline phosphatase elevation for one and aspartate aminotransferase elevation in the other. The relapse-free rate at 1 year was 53% (95% CI: 32% to 89%), prompting closure of the study. CONCLUSIONS Fluconazole 800 mg daily is a safe and moderately effective induction therapy for mild or moderately severe disseminated histoplasmosis in patients with AIDS. On the basis of historic comparison, fluconazole 400 mg daily is less effective than itraconazole 200 to 400 mg daily or amphotericin B 50 mg given weekly as maintenance therapy to prevent relapse.

Multicenter Case-Control Study of Risk Factors for Histoplasmosis in Human Immunodeficiency Virus-Infected Persons

We conducted a multicenter case-control study to identify risk factors for histoplasmosis among persons with acquired immunodeficiency syndrome (AIDS) and to evaluate predictors of a poor outcome (defined as death or admission to the intensive care unit). Patients with histoplasmosis were each matched by age, sex, and CD4 lymphocyte count to 3 controls. From 1996 through 1999, 92 case patients and 252 controls were enrolled. Of the case patients, 81 (89%) were men, 50 (55%) were black, 78 (85%) had a CD4 lymphocyte count of <100 cells/microL, 80 (87%) were hospitalized, and 11 (12%) died. Multivariable analysis found that receipt of antiretroviral therapy and of triazole drugs were independently associated with a decreased risk of histoplasmosis. Chronic medical conditions and a history of infections with herpes simplex virus were associated with poor outcome. Triazoles should be considered for chemoprophylaxis for persons with AIDS, especially those who take part in high-risk activities that involve frequent exposure to soil, who have CD4 lymphocyte counts of <100 cells/microL, and who live in areas where histoplasmosis is endemic.

Histoplasmosis in Patients With Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS): Multicenter Study of Outcomes and Factors Associated With Relapse

AbstractAlthough discontinuation of suppressive antifungal therapy for acquired immunodeficiency syndrome (AIDS)-associated histoplasmosis is accepted for patients with immunologic recovery, there have been no published studies of this approach in clinical practice, and minimal characterization of individuals who relapse with this disease. We performed a multicenter retrospective cohort study to determine the outcome in AIDS patients following discontinuation of suppressive antifungal therapy for histoplasmosis.Ninety-seven patients were divided into a physician-discontinued suppressive therapy group (PD) (38 patients) and a physician-continued suppressive therapy group (PC) (59 patients). The 2 groups were not statistically different at baseline, but at discontinuation of therapy and at the most recent follow-up there were significant differences in adherence to therapy, human immunodeficiency virus (HIV) RNA, and urinary Histoplasma antigen concentration. There was no relapse or death attributed to histoplasmosis in the PD group compared with 36% relapse (p < 0.0001) and 5% death (p = 0.28) in the PC group. Relapse occurred in 53% of the nonadherent patients but not in the adherent patients (p < 0.0001). Sixty-seven percent of patients with initial central nervous system (CNS) histoplasmosis relapsed compared to 15% of patients without CNS involvement (p = 0.0004), which may be accounted for by nonadherence. In addition, patients with antigenuria above 2.0 ng/mL at 1-year follow-up were 12.82 times (95% confidence interval, 2.91–55.56) more likely to relapse compared to those with antigenuria below 2.0 ng/mL.Discontinuation of antifungal therapy was safe in adherent patients who completed at least 1 year of antifungal treatment, and had CD4 counts >150 cells/mL, HIV RNA <400 c/mL, Histoplasma antigenuria <2 ng/mL (equivalent to <4.0 units in second-generation method), and no CNS histoplasmosis.

Efficacies of various antimicrobial agents in treatment of Staphylococcus aureus abscesses and correlation with in vitro tests of antimicrobial activity and neutrophil killing.

A rabbit perforated-capsule model was utilized to study antimicrobial efficacy in treating 2-week-old Staphylococcus aureus abscesses. Animals received either ciprofloxacin (30 mg/kg), cefazolin (100 mg/kg), or ciprofloxacin (30 mg/kg) plus rifampin (20 mg/kg) every 8 h for 8 days or no antibiotic. Antibiotic levels within the abscess exceeded the MIC for the test organism. At the end of treatment, ciprofloxacin was no more effective than the control, animals receiving cefazolin had a mean log10 fall of 2.41 CFU/ml, and animals receiving ciprofloxacin plus rifampin had a mean log10 reduction of 5.06 CFU/ml (P = less than 0.01). Six days after completion of therapy, all abscesses in animals receiving ciprofloxacin plus rifampin were culture negative. Surviving organisms in animals receiving ciprofloxacin or rifampin did not develop resistance to the treatment antibiotics. In vitro time-kill curves performed with logarithmic- and stationary-phase organisms in broth, serum, and abscess fluid supernatants did not correlate with the in vivo results. Neutrophil killing studies of S. aureus pretreated with antibiotics revealed greater killing of organisms pretreated with ciprofloxacin plus rifampin than of those pretreated with cefazolin or ciprofloxacin alone. In conclusion, ciprofloxacin plus rifampin was effective therapy in this staphylococcal abscess model, compared with the moderate efficacy of cefazolin and no effect observed with ciprofloxacin alone. Enhanced neutrophil killing of S. aureus pretreated with antibiotics may be an important mechanism by which bacteria are killed in suppurative infections.

Successful Treatment of Multiple Cerebral Histoplasmomas with Itraconazole

midbrain and brain stem (figure 1). The lesions enhanced after revealed a decrease in the number and size of the lesions and in intravenous injection of gadolinium, and some had surrounding the surrounding edema. She continued to receive itraconazole for edema. An abdominal CT scan showed the left adrenal to be 3.4 1 year. Another MRI scan done 4 months after discontinuation of 1 3.9 cm with a hypodense center and hyperdense rim. A chest therapy revealed no change from the scan at the end of therapy. radiograph was normal. A fine-needle adrenal aspirate showed More than 2.5 years after discontinuing therapy, the patient renondiagnostic results. On CSF testing, the following values were mains asymptomatic. noted: glucose, 52 mg/dL; protein, 61 mg/dL; RBCs, 0/mm; The patient described had evidence of cerebral histoplasmomas, WBCs, 1/mm (100% mononuclear). Bone marrow and CSF culdespite the lack of a brain biopsy. H. capsulatum was found in tures were negative. The Histoplasma capsulatum polysaccharide the adrenal gland, antibodies to H. capsulatum were present in antigen level in serum was 0.5 U and in CSF was 0.7 U. The CSF, and the lesions and symptoms responded to antifungal therpatient was negative for IgG antibodies to Echinococcus species apy. Negative cultures of CSF and a negative result on CSF hisand HIV and IgM antibodies to Toxoplasma species in serum. Her toplasma polysaccharide antigen testing are observed in about half serum was positive for IgG antibodies to Toxoplasma species, but of cases of CNS histoplasmosis [1]. It is likely that her disease the ratio of Toxoplasma IgG antibodies to total IgG was twofold was related to the immunosuppressive effects of the corticostegreater in serum than in CSF. Her titer of complement fixation roids, despite discontinuation of corticosteroids 3 weeks before antibody to H. capsulatum in CSF was 1:2 for the mycelial antigen her neurological symptoms began. and 1:4 for the yeast antigen. An open adrenal biopsy revealed Two cases of cerebral histoplasmomas have been successfully extensive necrosis, granulomatous inflammation, and organisms treated with ketoconazole after relapse following therapy with inconsistent with histoplasmosis. Culture of adrenal tissue yielded travenous amphotericin B [2, 3]. There has also been a report of H. capsulatum. treatment failure with ketoconazole therapy for cerebral histoplasThe patient refused therapy with amphotericin B. She began momas [4]. Ketoconazole has been associated with treatment failreceiving itraconazole, 200 mg three times daily for 3 days, folures in immunocompromised patients with histoplasmosis and has lowed by 200 mg twice daily. Her neurological signs and symppoor penetration into CSF [1]. Two reported cases of CNS histotoms improved over the next 3 months, and repeat MRI scans plasmosis have been treated with fluconazole, which crosses the

Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection

ABSTRACT The murine d-galactosamine (d-gal) model of tumor necrosis factor alpha (TNF-α) hypersensitization was used as an initial tool to investigate the potential contribution of TNF-α to lethal intraperitoneal (i.p.) infection with Enterococcus faecalis. d-gal sensitized mice to lethal E. faecalis infection, whereas dexamethasone and neutralizing anti-TNF-α antibody protected d-gal-treated, E. faecalis-infected mice, implicating TNF-α in the lethal response to E. faecalis infection in d-gal-treated mice. Circulating TNF-α was undetectable for at least 8 h following i.p. E. faecalis infection, although low peritoneal levels of TNF-α were detected within 3 h, suggesting that localized TNF-α production contributed to the lethal response to E. faecalis infection in d-gal-treated mice. Although i.p. E. faecalis infection failed to induce a detectable systemic TNF-α response, circulating Interleukin-6 (IL-6) was detected within 3 h of infection. IL-6 was also detected in the peritoneum within an hour of infection, prior to the appearance of peritoneal TNF-α. In striking contrast to in vivo results, E. faecalis induced a potent and rapid TNF-α response from both mouse peritoneal macrophages and the RAW 264.7 cell line in vitro. This led us to hypothesize that TNF-α production in response to E. faecalis infection is suppressed by IL-6 in vivo. In vitro experiments demonstrated a statistically significant, but modest, inhibitory effect of IL-6 on TNF-α production by RAW cells stimulated with E. faecalis. Collectively, these data indicate that acute, lethal E. faecalis infection appears to induce an unusual cytokine response that differs in character from that previously described for most other gram-positive and gram-negative bacteria.

Effects of Neutrophils on Cefazolin Activity and Penicillin-Binding Proteins in Staphylococcus aureus Abscesses

ABSTRACT Bacteria survive within abscesses despite antimicrobial therapy, usually necessitating drainage. Our previous work showed that bacterial killing is diminished within the neutrophils of animals with abscesses. To further assess the role of neutrophils in Staphylococcus aureus survival and the poor activities of β-lactams in abscesses, tissue cage abscess-bearing rats were given polymorphonuclear leukocyte (PMN)-depleting antibody prior to and several times following inoculation of the tissue cages with S. aureus. Cefazolin (300 mg/kg of body weight/day) was administered to all animals in appropriately divided doses. After 7 days of antimicrobial therapy, the 17 animals that received anti-PMN serum had significantly fewer abscess neutrophils than the 18 controls and fewer abscess bacteria (5.55 versus 3.79 log10 CFU/ml [P = 0.04]) than the 18 controls. The data were consistent with the premise that cefazolin is more effective in abscesses depleted of neutrophils. To investigate further, S. aureus was incubated with rat peritoneal neutrophils; and bacterial cell membrane proteins were isolated, labeled with biotinylated ampicillin, separated by electrophoresis, blotted onto nitrocellulose, and stained for biotin reactivity. PBP 2 expression was consistently and significantly decreased after a brief, nonkilling PMN exposure. These experiments showed that PMN depletion enhanced the activity of cefazolin in the abscess milieu. Furthermore, altered bacterial cell wall cefazolin targets may be the mechanism by which the PMN diminishes antimicrobial activity, suggesting the importance of the staphylococcus-PMN interaction in the outcome of established infections.

Nonengagement in HIV Care A Descriptive and Qualitative Study in Hospitalized Patients and Community-Based Analysis

Nonengagement in HIV care is a major clinical and public health challenge. To identify the risk factors and reasons, we performed (1) a retrospective study of patients admitted to the hospital with advanced HIV disease, (2) a prospective qualitative study, and (3) a population-based area-wide telephone interview. In the retrospective study, clinic care engagement was associated with age (43.9 ± 9.1 years vs 37.9 ± 7.2 years, P = .005) and improved from 23% to 44% (P = .03) after hospitalization. Survival was higher (93% vs 73%, P = .03) among those who engaged in care. Twelve inpatients were interviewed in the qualitative study. Themes identified for nonengagement were social stigma, indifference, or lack of understanding of care needs/denial and life care issues. In the population-based study, 145 patients were interviewed. In all, 49 denied the need for HIV care and 28 denied their HIV status. Stigma, denial, and indifference or lack of understanding of need are significant barriers to care engagement.

beta-Lactamase-mediated inactivation and efficacy of cefazolin and cefmetazole in Staphylococcus aureus abscesses.

12694668 Clinical reports and animal models have demonstrated that cefazolin may have decreased efficacy against some strains of Staphylococcus aureus because of type A beta-lactamase-mediated hydrolysis. We sought to measure biologically active cefazolin concentrations within abscesses with high concentrations of S. aureus and compare the concentrations with those of cefmetazole, a beta-lactamase-stable cephamycin. A type A beta-lactamase-producing strain of S. aureus with a demonstrated inoculum effect against cefazolin (MIC at an inoculum of 5 x 10(5) CFU/ml, 1.0 micrograms/ml; MIC at an inoculum of 5 x 10(7) CFU/ml, 32.0 micrograms/ml) but not cefmetazole (MICs at inocula of 5 x 10(5) and 5 x 10(7) CFU/ml, 2.0 micrograms/ml) was used. Cefazolin or cefmetazole (100 mg/kg of body weight every 8 h for 8 days) was administered to rabbits with infected tissue cages. No differences in the concentrations of the two drugs in the uninfected tissue cages were observed. Higher concentrations of cefmetazole than cefazolin were found in infected tissue cages at day 3 (5.9 +/- 0.7 versus 2.2 +/- 0.3 micrograms/ml; P < 0.01), day 5 (9.1 +/- 2.6 versus 3.6 +/- 0.7 micrograms/ml; P = 0.02), and day 8 (9.4 +/- 1.4 versus 4.8 +/- 0.9 micrograms/ml; P = 0.01) after infection. Cefazolin and cefmetazole were equally effective in reducing the bacterial concentration in the abscess. In vitro experiments demonstrated greater cefazolin than cefmetazole degradation by S. aureus, but the differences were greater in serum than in abscess fluid supernatants. We conclude that abscess cefazolin concentrations are diminished by type A beta-lactamase-producing S. aureus, but this did not affect drug efficacy in this model.