Treatment and outcomes of Candida osteomyelitis: review of 53 cases from the PATH Alliance® registry.

Candida osteomyelitis is associated with significant morbidity; however, data on the management of Candida osteomyelitis are limited. The Prospective Antifungal Therapy (PATH) Alliance® registry is a comprehensive, multicenter, prospective, observational registry that collected data on patients with invasive fungal infections between 2004 and 2008. The aim of this descriptive analysis was to evaluate the clinical characteristics, treatment, and outcomes of patients with Candida osteomyelitis. Using the PATH Alliance® registry, we performed a review of all patients with a proven diagnosis of Candida osteomyelitis who received a minimum of 14 days of antifungal treatment and/or a therapeutic surgical intervention (n = 53). The epidemiology, diagnosis, treatment, and outcomes of these patients were assessed at 12 weeks. C. albicans (56.6 %) was the most commonly identified organism, followed by C. parapsilosis (18.9 %), C. glabrata (9.4 %), and C. tropicalis (9.4 %). The mean treatment duration was 54.9 days. Multiple different treatment regimens were administered to patients. These included fluconazole (56.0 %), echinocandins (29.3 %), amphotericin B formulations (10.7 %), and voriconazole (4.0 %). Twenty-eight patients (52.8 %) also had a therapeutic surgical intervention. Clinical response was improved in 38 (71.7 %) patients (43.4 % complete and 28.3 % partial response), stable in 11 (20.8 %), and worse in one (1.9 %); three (5.7 %) patients had unknown response. The 12-week survival rate was 93.8 %. In summary, C. albicans was the predominant pathogen, and fluconazole was the most commonly administered agent. However, treatment patterns vary and remain non-standardized. Concurrent candidemia was infrequent, and 12-week survival was notably good in this series of 53 patients with Candida osteomyelitis.

Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial.

BACKGROUND: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting. OBJECTIVE: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy. DESIGN: An open randomized, controlled, multicenter trial, powered for equivalence. SETTING: 60 oncology centers in 10 countries. PATIENTS: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy. INTERVENTION: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution. MEASUREMENTS: Defervescence, breakthrough fungal infection, drug-related adverse events, and death. RESULTS: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days. CONCLUSIONS: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.

Amphotericin B lipid complex in pediatric patients with invasive fungal infections.

BACKGROUND: Lipid formulations of amphotericin B have been recently introduced for treatment of invasive fungal infections. However, little is known about their role in pediatric populations. METHODS: We studied the safety and antifungal efficacy of amphotericin B lipid complex (ABLC, Abelcet) in 111 treatment episodes in pediatric patients through an open label, emergency use multicenter study. Patients with invasive fungal infections were enrolled if they had mycoses refractory to conventional antifungal therapy, if they were intolerant of previous systemic antifungal agents or concomitant nephrotoxic drugs or if they had preexisting renal disease. RESULTS: All 111 treatment episodes were evaluable for safety and 54 were evaluable for efficacy. The mean serum creatinine for the study population did not significantly change between baseline (1.23 +/- 0.11 mg/dl) and cessation of ABLC therapy (1.32 +/- 0.12 mg/dl) during 6 weeks. There were no significant differences observed between initial and end-of-therapy levels of serum potassium, magnesium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and hemoglobin. However, there was an increase in mean total bilirubin (3.66 +/- 0.73 to 5.31 +/- 1.09 mg/dl) at the end of therapy (P = 0.054). Among 54 cases fulfilling criteria for evaluation of antifungal efficacy, a complete or partial therapeutic response was obtained in 38 patients (70%) after ABLC therapy. Complete or partial therapeutic response was documented in 56% of cases with aspergillosis (n = 25) and in 81% (n = 27) with candidiasis. Among premature infants (n = 8) and allogeneic marrow recipients (n = 14), response rates were 88 and 57%, respectively. Response was similar in those patients enrolled because of intolerance to previous antifungal therapy or because of progressive infection. CONCLUSIONS: These data support the use of ABLC for treatment of invasive fungal infections in pediatric patients who are intolerant of or refractory to conventional antifungal therapy.

Protease inhibitor-induced lipodystrophy.

The development of lipodystrophy as evidenced by central obesity, "moon facies," and a "buffalo hump" is a classical feature of Cushing's disease. Recently an association of "lipodystrophy" with the use of protease inhibitors has been reported. We describe a patient with lipodystrophy secondary to protease inhibitor therapy for HIV infection.

Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases.

The safety and antifungal efficacy of amphotericin B lipid complex (ABLC) were evaluated in 556 cases of invasive fungal infection treated through an open-label, single-patient, emergency-use study of patients who were refractory to or intolerant of conventional antifungal therapy. All 556 treatment episodes were evaluable for safety. During the course of ABLC therapy, serum creatinine levels significantly decreased from baseline (P < .02). Among 162 patients with serum creatinine values > or = 2.5 mg/dL at the start of ABLC therapy (baseline), the mean serum creatinine value decreased significantly from the first week through the sixth week (P < or = .0003). Among the 291 mycologically confirmed cases evaluable for therapeutic response, there was a complete or partial response to ABLC in 167 (57%), including 42% (55) of 130 cases of aspergillosis, 67% (28) of 42 cases of disseminated candidiasis, 71% (17) of 24 cases of zygomycosis, and 82% (9) of 11 cases of fusariosis. Response rates varied according to the pattern of invasive fungal infection, underlying condition, and reason for enrollment (intolerance versus progressive infection). These findings support the use of ABLC in the treatment of invasive fungal infections in patients who are intolerant of or refractory to conventional antifungal therapy.

An outbreak of Burkholderia cepacia lower respiratory tract infection associated with contaminated albuterol nebulization solution.

An outbreak of Burkholderia cepacia lower respiratory tract colonization and infection occurred in the adult intensive-care units in various geographic locations throughout our hospital. Forty-four patients became colonized or infected over an 11-month period, whereas B cepacia had been isolated from only 13 patients in the preceding 48 months. Environmental cultures revealed the source to be extrinsically contaminated albuterol nebulization solution. Polymerase chain reaction-ribotyping confirmed the genetic relatedness of the B cepacia patient isolates and the contaminated albuterol. After extensive infection control training for the respiratory therapy staff, including attention to nebulization technique, washing and drying the nebulizer cup, and good handwashing, there have not been any new cases.

Acanthamoeba endophthalmitis in acquired immunodeficiency syndrome.

PURPOSE: To report the findings of Acanthamoeba endophthalmitis in a patient with acquired immunodeficiency syndrome (AIDS). METHODS: A 35-year-old man with AIDS and Acanthamoeba infection of the skin and lungs was treated for a granulomatous uveitis in the left eye. RESULTS: The left eye developed mutton-fat keratic precipitates, iris granulomas, cataract, hypotony, and choroidal infiltrates. Aqueous and vitreous specimens were positive for Acanthamoeba cysts. Topical and systemic antiamebic medications decreased the inflammation but failed to control the infection. CONCLUSIONS: Acanthamoeba infection should be considered in the differential diagnosis of uveitis in patients with AIDS.

Failure of systemic empirical treatment with amphotericin B to prevent candidemia in neutropenic patients with cancer.

We undertook a retrospective review of all patients with hematologic malignancies in whom candidemia developed during chemotherapy-induced neutropenia in 1989 and 1990. Candidemia developed in 11 patients; five were receiving therapeutic doses of amphotericin B at the time of infection. Disseminated infection occurred in 2 of 5 patients with breakthrough infection and 3 of 6 patients with candidemia before receipt of amphotericin B. Among patients with breakthrough candidemia there was a trend toward more-prolonged neutropenia prior to infection (P = .069), but otherwise they were indistinguishable from other candidemic patients with regard to risk factors for candidemia. Amphotericin B-susceptible Candida albicans was isolated from two patients and Candida krusei from three patients with breakthrough infection. All patients were treated with amphotericin B; all breakthrough infections responded to treatment. Neutropenic patients with breakthrough candidemia were clinically similar to those whose candidemia preceded amphotericin B therapy, and there was no increase in morbidity and mortality among individuals with breakthrough infection.

Intraventricular cryptococcal cysts.

The case of a 55-year-old immunocompetent woman with central nervous system cryptococcosis and multiple intraventricular cysts is presented. The cysts did not enhance on MR and had signal characteristics similar to cerebrospinal fluid on T1- and T2-weighted images; their intensity was lower than cerebrospinal fluid on proton density-weighted images.

Discrimination of epidemic and sporadic isolates of Acinetobacter baumannii by repetitive element PCR-mediated DNA fingerprinting.

In 1990, there was a significant increase in the number of lower respiratory tract infections and surgical wound infections in the adult intensive care units of our tertiary care teaching hospital caused by Acinetobacter baumannii compared with the number in 1989. During the 5-month period from April through August 1990, 84 isolates of A. baumannii were recovered from 50 hospitalized patients. Biotyping, comparison of antibiograms, plasmid analysis, and DNA polymorphisms of 20 isolates from 20 different patients, determined by the use of repetitive element PCR with primers aimed at repetitive extragenic palindromic sequences and enterobacterial repetitive intergenic consensus sequences, were used to investigate this apparent outbreak. Biotyping, antibiograms, plasmid analysis, and enterobacterial repetitive intergenic consensus PCR were not useful epidemiologically. Repetitive element PCR-mediated DNA fingerprinting using repetitive extragenic palindromic primers discriminated between epidemic and sporadic strains of A. baumannii and demonstrated four discrete clusters which were unique epidemiologically.

Infections of implantable cardioverter defibrillators: approach to management.

Implantable cardioverter defibrillators are being used with increasing frequency for the treatment of life-threatening ventricular arrhythmias. Nevertheless, no guidelines exist for the management of infections of these devices. We report our experience with infections of these devices and review the English-language literature. In all cases, patients presented with local signs of generator infection; systemic signs of infection and bacteremia were often absent. Most infections are due to staphylococcus. Risk factors for the development of infection include placement of the device via median sternotomy during another cardiac surgical procedure, reoperation, and intercurrent infection at another site. Infections are most reliably treated with full explantation of the device and antibiotics. In rare cases, patients may respond to a combination of intravenous antibiotics and removal and replacement of only the generator.

Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in hospitals. Current antimicrobial regimens for eradicating colonizing strains are not well defined and are often complicated by the emergence of resistance. The combination of novobiocin plus rifampin in vitro and in vivo was found to prevent the emergence of resistant populations of initially susceptible strains of MRSA, particularly resistance to rifampin. We therefore studied, in a randomized, double-blind, multicenter comparative trial, the combination of novobiocin plus rifampin versus trimethoprim-sulfamethoxazole (T/S) plus rifampin in order to determine the efficacy of each regimen in eradicating MRSA colonization and to further characterize the host factors involved in the response to this antimicrobial therapy. Among the 126 individuals enrolled in the study, 94 (80 patients; 14 hospital personnel) were evaluable. Among the 94 evaluable subjects, no significant demographic or medical differences existed between the two treatment groups. Successful clearance of the colonizing MRSA strains was achieved in 30 of 45 (67%) subjects receiving novobiocin plus rifampin, whereas successful clearance was achieved in 26 of 49 (53%) subjects treated with T/S plus rifampin (P = 0.18). The emergence of resistance to rifampin developed more frequently in 14% (7 of 49) of subjects treated with T/S plus rifampin than in 2% (1 of 45) of subjects treated with novobiocin plus rifampin (P = 0.04). Restriction endonuclease studies of large plasmid DNA demonstrated that the same strain was present at pretherapy and posttherapy in most refractory cases (24 of 29 [83%] subjects). Among the 56 successfully treated subjects, clearance of MRSA was age dependent: 29 of 36 (80%) subjects in the 18- to 49-year-old age group, 19 of 35 (54%) subjects in the 50- to 69-year-old age group, and 8 of 23 (35%) in the 70- to 94-year-old age group (P < 0.01). Clearance was also site dependent; culture-positive samples from wounds were related to a successful outcome in only 22 (48%) of 46 subjects, whereas culture-positive samples from sites other than wounds (e.g., nares, rectum, and sputum) were associated with a success rate of 34 of 48 (71%) subjects (P = 0.02). Foreign bodies in wounds did not prevent the eradication of MRSA by either regimen. T/S plus rifampin was less effective in clearing both pressure and other wounds, whereas novobiocin plus rifampin was equally effective in clearing both pressure and other wounds. There were no significant differences in toxicity between the two regimens. Thus, the combination of novobiocin plus rifampin, in comparison with T/S plus rifampin, was more effective in preventing the emergence of resistance to rifampin and demonstrated a trend toward greater activity in clearing the MRSA carrier state. The response to either combination depended on host factors, particularly age and the site of MRSA colonization.

Diagnosis of invasive candidiasis by a dot immunobinding assay for Candida antigen detection.

A dot immunobinding assay which uses a polyclonal rabbit anti-Candida immunoglobulin G as the primary antibody and colloidal gold coated with goat anti-rabbit immunoglobulin G as the secondary antibody for the detection of Candida cytoplasmic antigens is described. It was able to detect as little as 1 ng of total Candida protein per ml when a cytoplasmic extract of Candida albicans was seeded into buffer and 10 ng/ml when the same extract was seeded into pooled human serum. Serial serum samples from four groups of patients were assayed for Candida antigen: (i) 22 patients with candidemia, (ii) 16 patients at high risk for invasive candidiasis, (iii) 3 patients with other deep mycoses, and (iv) 50 hospitalized patients at low risk for serious Candida infection. Of the 22 candidemic patients, 19 had invasive candidiasis and 3 had transient candidemia. Antigenemia was detected in 16 of the 19 patients with invasive candidiasis (including patients with C. albicans, Candida tropicalis, Candida glabrata, Candida krusei, and Candida parapsilosis) and in 4 of 16 patients at high risk for invasive candidiasis. There was no detectable antigen in 12 high-risk control patients, 3 patients with transient candidemia, 3 patients with other deep mycoses, and 50 relatively low-risk patients. The sensitivity for detecting invasive disease in candidemic patients and specificity for all patients studied were 84.2 and 94.4%, respectively. The positive predictive value was 80%; the negative predictive value was 95.7%. The sensitivity for neutropenic patients with invasive disease was 85.7%. This assay is rapid and accurate and appears to be useful in identifying candidemic patients with invasive candidiasis.

Methicillin-resistant Staphylococcus aureus outbreak at a Veterans' Affairs Medical Center: importance of carriage of the organism by hospital personnel.

The reported prevalence of nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) by hospital personnel averages 2.5%. From August 1985 to September 1987, 155 patients at our Veterans' Affairs Medical Center (VAMC) were colonized or infected with MRSA. In December 1986, only two (2.1%) of 94 healthcare workers were identified as nasal carriers. Prompted by a sharp increase in the number of patients with MRSA in early 1987, contact tracing identified 450 employees, of whom 36 (8%) were nasal carriers. Thirty-five percent of surgical residents (7 of 20) were nasal carriers. Prior to being identified as a nasal carrier, one surgical resident was associated with the inter-hospital spread of the VAMC MRSA strain to the burn unit of the affiliated university hospital. Three family members of two employee carriers were also found to harbor the epidemic strain. All 36 carriers were decolonized with various antimicrobial combinations. Vigorous infection control measures were effective in controlling the epidemic. The frequency of MRSA carriage by hospital personnel at our medical center during the epidemic proved higher than previously appreciated. Thus, healthcare workers may comprise a sizable MRSA reservoir. During an MRSA epidemic, infection control should attempt to identify and decolonize this hospital reservoir, as these individuals can disseminate MRSA both within the hospital as well as into the community.

Pharmacodynamics of trimethoprim-sulfamethoxazole in Listeria meningitis: a case report.

Infections in the cerebrospinal fluid (CSF) occur in an area of impaired host defenses; therefore, bactericidal antibiotics that reach adequate concentrations in the CSF are necessary for treatment. Measurements of antibiotic penetration into the CSF include CSF inhibitory and bactericidal titers, the absolute antibiotic concentration in the CSF, and the CSF: serum concentration ratio. We present the case of a patient with Listeria monocytogenes meningitis who failed to respond clinically to standard therapy, and whose organism demonstrated tolerance to Ampicillin (MBC: MIC = 258:1) that successfully responded to trimethoprim-sulfamethoxazole (TMP-SMX). The CSF peak bactericidal titer to TMP-SMX was 1:8, corresponding to that reported as necessary for successful outcome in patients with meningitis. The CSF peak: MBC ratios for TMP and SMX were less than 3:1 and equal to 3:1, respectively. These individual ratios are lower than those suggested for successful treatment of meningitis; however, the recommended ratios were established using single agents and did not account for synergistic activity with a drug combination such as TMP-SMX. The failure of standard therapy in this patient underscores the importance of MIC/MBC testing when tolerance is suspected or when CSF penetration of antibiotics is relatively poor. In addition, measurements of CSF inhibitory and bactericidal titers, which incorporate the antibiotic concentration in the CSF, susceptibility of the infecting microorganism, and host defense factors, may be useful in monitoring patients with meningitis.