Larry H. Danziger

A Randomized and Blinded Multicenter Trial of High-Dose Fluconazole plus Placebo versus Fluconazole plus Amphotericin B as Therapy for Candidemia and Its Consequences in Nonneutropenic Subjects

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases.

Given that Lactobacillus has been reported to be the causative pathogen in many types of infection despite debate regarding the organism’s clinical significance, a literature review was conducted to investigate the treatments and outcomes of Lactobacillus infections reported to date. In this article, the characteristics of over 200 reported cases of Lactobacillus-associated infections are summarized. Lactobacillus was found to be frequently associated with endocarditis and bacteremia. Lactobacillus was also associated with a variety of other infections including, but not limited to, peritonitis, abscesses, and meningitis. The species casei and rhamnosus were the most common. The isolates tended to be most sensitive to erythromycin and clindamycin and most resistant to vancomycin. The species that was most sensitive to vancomycin was acidophilus. The overall mortality rate was nearly 30%. There was a significant association between mortality and polymicrobial infection (P=0.004). In the subset of patients with bacteremia, increased mortality was associated with inadequate treatment (P=0.001) and polymicrobial bacteremia (P=0.044).

Early Bactericidal Activity of Paromomycin (Aminosidine) in Patients with Smear-Positive Pulmonary Tuberculosis

ABSTRACT The early bactericidal activity of the aminoglycoside paromomycin (aminosidine) in doses of 7.5 and 15 mg/kg of body weight was measured in 22 patients with previously untreated smear-positive pulmonary tuberculosis. The fall in log10 CFU per milliliter of sputum per day during the first 2 days of treatment for 7 patients receiving a paromomycin dosage of 7.5 mg/kg/day was 0.066, with a standard deviation (SD) of 0.216 and confidence limits from −0.134 to 0.266, and that for 15 patients receiving 15 mg/kg/day was 0.0924, with an SD of 0.140 and confidence limits from 0.015 to 0.170. The difference between the mean and zero was not significant for the 7.5-mg/kg dose group but was significant for the 15-mg/kg dose group (t = 2.55, P = 0.023). Since paromomycin has no cross-resistance with streptomycin and has no greater toxicity than other aminoglycosides, these results suggest that it has the potential to substitute for streptomycin in antituberculosis regimens and may be a particularly valuable addition to the drug armamentarium for the management of multidrug-resistant tuberculosis.

Multidrug-Resistant Acinetobacter Infections: An Emerging Challenge to Clinicians

OBJECTIVE: To review and evaluate clinically relevant epidemiology, microbiology, and clinical studies regarding the treatment of multidrug-resistant Acinetobacter infections. DATA SOURCES: Pertinent literature was identified by a MEDLINE search (1966-September 2003) and through secondary bibliographies of pertinent articles. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from data sources were evaluated for clinical relevance. DATA SYNTHESIS: Acinetobacter baumannii has emerged as a worldwide problem as a nosocomial pathogen in hospitalized patients. Acinetobacter spp. can cause a multitude of infections including pneumonia, bacteremia, meningitis, urinary tract infections, and skin and soft tissue infections, and the mortality associated with these infections is high. Isolates resistant to almost all commercially available antimicrobials have been identified, thus limiting treatment options. The development of new agents and reappraisal of older compounds (ie, polymyxins, ampicillin/sulbactam) are necessary as we consider the optimal treatment of these multidrug-resistant organisms. CONCLUSIONS: There is no simple answer to the treatment of Acinetobacter infections. Eradication of Acinetobacter spp. requires adherence to good infection control practices and prudent antibiotic use, as well as effective antimicrobial therapy. Alternative therapies such as colistin, ampicillin/sulbactam, and tetracycline are potential options, but prospective, randomized, controlled trials are still lacking.

Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

SummaryMetronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific Chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics.When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function.The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study.Drug interactions with warfarin, alcohol, disulfiram, phenytoin, lithium, phenobarbital, phenazone (antipyrine), prednisone, rifampicin, antacids and cholestyramine have been reported. No significant change in pharmacokinetics was observed with concurrent administration of theophylline, alprazolam, lorazepam, diazepam, ciprofloxacin or sulfasalazine. Studies conducted with cimetidine revealed varied findings.Metronidazole is generally well tolerated when administered in dosages of <2g per day. Some adverse reactions, such as gastrointestinal effects, neutropenia, neuropathies and certain central nervous system effects, appear to be related to the dosage and treatment duration.On the basis of the available data on metronidazole pharmacokinetics and microbiology, the traditional dosage recommendation of 500mg every 6h is more than adequate to treat most anaerobic infections. In fact, a regimen of 500mg every 8h can be expected to maintain serum concentrations above the minimum inhibitory concentrations of susceptible anaerobic organisms. Alternatively, once-daily administration has also been suggested. There is also some recent evidence to support a postantibiotic effect of metronidazole on certain anaerobic bacteria.The pharmacokinetics of other nitroimidazole derivatives are similar to those of metronidazole. They all have good oral absorption, and extensive hepatic metabolism and tissue distribution. The elimination half-lives of most of the derivatives are longer than that of metronidazole with the exception of nimorazole. Side effects of the derivatives are generally mild and they are usually well tolerated by patients. One notable exception is misonidazole; its use is often limited by frequent peripheral neuropathy.

Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies.

The incidence of emergent resistance and clinical factors affecting its development were evaluated by retrospective review of 173 studies encompassing over 14,000 patients. Eight antibiotic classes and 225 individual treatment regimens were evaluated. Emergent resistance occurred among 4.0% of all organisms and 5.6% of all infections treated. It appeared to be significantly more frequent with penicillin and aminoglycoside monotherapy, with significantly lower rates associated with imipenem‐cilastatin, aztreonam, and combination therapy. Clinical failure also appeared to be significantly more likely to occur after emergence of resistance among organisms treated with fluoroquinolones or aminoglycosides. Infections associated with higher resistance rates were cystic fibrosis, osteomyelitis, and lower respiratory tract infections. Resistance was most common in patients in intensive care units or receiving mechanical ventilation. It was also significantly frequent among studies performed in university or teaching hospitals. Organisms associated with high resistance rates were Pseudomonas aeruginosa, Serratia, Enterobacter, and Acinetobacter sp. Factors such as infection type, underlying diseases, type of institution, and specific pathogens warrant consideration when examining emergent resistance.

Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

ABSTRACT The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 μg/ml. In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r2 values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint—h 3 concentrations of a 6-h dosing interval—between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of ≤8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of ≤16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections.

Streptococcus milleri group: renewed interest in an elusive pathogen.

The following review examines the bacteriological characteristics, epidemiology, pathogenicity and antimicrobial susceptibility of the “Streptococcus milleri group”. “Streptococcus milleri group” is a term for a large group of streptococci which includesStreptococcus intermedius, Streptococcus constellatus andStreptococcus anginosus. Usually considered commensals, these organisms are often associated with various pyogenic infections including cardiac, abdominal, skin and central nervous system infections. Organisms of the “Streptococcus milleri group” are often unrecognized pathogens due to the lack of uniformity in classifications and difficulties in microbiological identification. Penicillin G, cephalosporins, clindamycin and vancomycin all possess activity against these streptococci. Use of agents with poor activity may promote infections with “Streptococcus milleri group” and allow it to exhibit its pathogenicity. An understanding of these organisms may aid in their recognition and proper treatment.

The macrolide antibiotics: a pharmacokinetic and pharmacodynamic overview.

The macrolide antimicrobial family is comprised of 14, 15 and 16 member-ringed compounds that are characterized by similar chemical structures, mechanisms of action and resistance, but vary in the different pharmacokinetic parameters, and spectrum of activity. The macrolides accumulate in many tissues such as the epithelial lining fluid and easily enter the host defense cells, predominantly macrophages and polymorphonuclear leukocytes (PMNs). Concentrations of the macrolides in respiratory tract tissues and extracellular fluids are in almost all cases higher than simultaneously measured serum concentrations, making them useful for respiratory tract infections. This review will focus on pharmacokinetic and pharmacodynamic aspects of the clinical relevant macrolides including azithromycin, clarithromycin, dirithromycin, erythromycin and roxithromycin.

Steady-State Plasma and Bronchopulmonary Concentrations of Intravenous Levofloxacin and Azithromycin in Healthy Adults

ABSTRACT The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (± standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 ± 4.52, 2.50 ± 0.97, and 1.24 ± 0.55 μg/ml; those for 750 mg of levofloxacin were 12.94 ± 1.21, 6.04 ± 0.39, and 1.73 ± 0.78 μg/ml; and those for azithromycin were 1.70 ± 0.74, 1.27 ± 0.47, and 2.86 ± 1.75 μg/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 ± 53.2, 18.3 ± 6.7, and 5.6 ± 3.2 μg/ml; those for 750 mg of levofloxacin were 81.7 ± 37.0, 78.2 ± 55.4, and 13.3 ± 6.5 μg/ml; and those for azithromycin were 650 ± 259, 669 ± 311, and 734 ± 770 μg/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections.