Ex Vivo Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects.

The ex vivo bactericidal activity and pharmacodynamics of fosfomycin in urine were evaluated in 18 healthy subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses or vice versa. Serial urine samples were collected before and up to 24 h after dosing on days 1 and 5. Eight bacterial strains with various genotypic and phenotypic susceptibilities to fosfomycin were used for all experiments (5 Escherichia coli, 2 Klebsiella pneumoniae, and 1 Proteus mirabilis). MICs were performed via agar dilution. Urinary bactericidal titers (UBTs) were performed via modified Schlichter test using participant's drug-free urine as the diluent. Urinary time-kill analyses were performed on pooled 24-h urine aliquots from days 1 and 5. All experiments were performed in triplicate with and without the addition of 25 mg/liter of glucose-6-phosphate (G6P). Mean 24-h urine concentrations of fosfomycin ranged from 324.7 to 434.6 mg/liter regardless of study day or dosing regimen. The urinary antibacterial activity of fosfomycin was also similar across study days and dosing regimens. UBT values did not correlate with MICs determined in the presence of G6P. Fosfomycin was reliably bactericidal in urine only against the 5 E. coli strains, regardless of genotype or MIC value. Together, these data do not support the use of oral fosfomycin tromethamine for pathogens other than E. coli or at a dosing frequency higher than QOD. Fosfomycin MICs determined in the presence of G6P may not accurately reflect the in vivo activity given the lack of G6P in human urine. (This study has been registered at ClinicalTrials.gov under identifier NCT02570074.).

In vitro activity of oritavancin alone or in combination against vancomycin-susceptible and -resistant enterococci.

OBJECTIVES: The optimal treatment for serious infections due to Enterococcus spp. is unknown although combination antimicrobial therapy is often recommended for invasive infections to achieve bactericidal activity and improve clinical outcomes. Oritavancin is a novel lipoglycopeptide agent with in vitro activity against enterococci, including vancomycin-resistant VanA-type Enterococcus faecium. Data on its activity in combination with other antibacterials are limited. The objective of this study was to evaluate the activity of oritavancin alone and in combination with ceftriaxone, daptomycin, gentamicin, linezolid and rifampicin against vancomycin-susceptible and -resistant enterococci in in vitro time-kill analyses. METHODS: Five enterococcal strains were used for all experiments: three vancomycin-resistant VanA-type E. faecium clinical bloodstream isolates, vancomycin-resistant VanA-type E. faecium ATCC 700221 and vancomycin-susceptible Enterococcus faecalis ATCC 29212. Individual drugs were tested at », ½, 1, 2 and 4× MIC. Oritavancin combination experiments were performed with each agent at »× MIC. RESULTS: Daptomycin was the most active single agent and was bactericidal against all strains at 4× MIC, followed by oritavancin, which was bactericidal against all three clinical VRE strains at ≥2× MIC. In combination experiments at »× MIC, oritavancin was synergistic with gentamicin against strains not displaying high-level aminoglycoside resistance. No other synergy against VRE strains was observed in any experiment. Strain- and drug-dependent antagonism was observed for many combinations. CONCLUSIONS: These in vitro data do not support the routine use of combination therapy with oritavancin in the treatment of infections due to VRE.

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).

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.

Levofloxacin penetration into epithelial lining fluid as determined by population pharmacokinetic modeling and monte carlo simulation.

Levofloxacin was administered orally to steady state to volunteers randomly in doses of 500 and 750 mg. Plasma and epithelial lining fluid (ELF) samples were obtained at 4, 12, and 24 h after the final dose. All data were comodeled in a population pharmacokinetic analysis employing BigNPEM. Penetration was evaluated from the population mean parameter vector values and from the results of a 1,000-subject Monte Carlo simulation. Evaluation from the population mean values demonstrated a penetration ratio (ELF/plasma) of 1.16. The Monte Carlo simulation provided a measure of dispersion, demonstrating a mean ratio of 3.18, with a median of 1.43 and a 95% confidence interval of 0.14 to 19.1. Population analysis with Monte Carlo simulation provides the best and least-biased estimate of penetration. It also demonstrates clearly that we can expect differences in penetration between patients. This analysis did not deal with inflammation, as it was performed in volunteers. The influence of lung pathology on penetration needs to be examined.

Multi-hospital analysis of antimicrobial usage and resistance trends.

We report a pilot study comparing antimicrobial usage and antimicrobial resistance trends for prominent nosocomial pathogens between 1994-1996. A convenience sample of ten hospitals participated in this retrospective review. We found a large variation in antimicrobial use and resistance trends and that many hospitals did not have data readily available to evaluate drug usage and resistance rates. A significant strong positive correlation was observed between the usage of ceftazidime and the prevalence of ceftazidime resistant Pseudomonas aeruginosa (r = 0.8, p = 0.005) and of ceftazidime resistant Enterobacter species (r = 0.8, p = 0.02). The presence of antibiotic control policies correlated with lower rates of some resistant strains and less antibiotic use. Our findings can be a useful starting point for hospitals that want to systematically measure antimicrobial use and resistance. Hospital laboratories, pharmacies, and infection control departments must work together to develop databases that will facilitate such measurements.

Postantibiotic effects of ABT-773 and amoxicillin-clavulanate against Streptococcus pneumoniae and Haemophilus influenzae.

This study determined the postantibiotic effect (PAE) of ABT-773 versus that of amoxicillin-clavulanate against clinical isolates of Streptococcus pneumoniae and Haemophilus influenzae. The PAEs of ABT-773 and amoxicillin-clavulanate ranged from 2.3 to 6.0 h and 0 to 2.2 h against S. pneumoniae and from 2.7 to 9.1 h and 0 to 0.8 h against H. influenzae, respectively.

Antimicrobial-coated/bonded and -impregnated intravascular catheters.

OBJECTIVE: To review the literature regarding the prevention of catheter colonization and catheter-related bloodstream infections (CRBIs) with the use of antimicrobial-coated/bonded and -impregnated intravascular catheters. DATA SOURCES: Primary and review English-language literature were identified using MEDLINE (1966-September 2000) pertaining to the key terms antibiotic, antimicrobial, antiseptic, silver, and bonded, coated, Impregnated catheters. In addition, textbooks and relevant reference lists were reviewed. DATA EXTRACTION: All articles identified through the data sources were evaluated. Information deemed relevant to the objectives of the review was included. DATA SYNTHESIS: Significant morbidity and mortality are associated with the development of CRBIs. Preventative measures such as modification of these catheters with antimicrobial coating/bonding have produced varying results. Trials evaluating cefazolin, teicoplanin, vancomycin, silver, and chlorhexidine-silver sulfadiazine (C-SS) used for coated/bonded intravascular catheters have not demonstrated a consistent decrease in the incidence of CRBIs. However, a meta-analysis of trials evaluating C-SS intravascular catheters demonstrated a statistically significant reduction in CRBIs. A larger reduction in CRBIs has been reported with minocycline-rifampin (M-R) versus C-SS intravascular catheters. Use of the M-R and C-SS catheters may result in a cost savings of $100 million and reduce as many as 12,000 CRBI-related deaths annually when used short term (<7 d). CONCLUSIONS: When used for short-term catheterization, M-R catheters appear to be superior to the currently available C-SS catheters at preventing CRBIs. Significant cost savings and reduction in mortality can be anticipated with the use of M-R catheters.

Mechanism of action of and resistance to quinolones.

A topoisomerase was identified as the bacterial target site for quinolone action in the late 1970s. Since that time, further study identified two bacterial topoisomerases, DNA gyrase and topoisomerase IV, as sites of antibacterial activity DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms, but this varies with the drug. Three mechanisms of resistance against quinolones are mutations of topoisomerases, decreased membrane permeability, and active drug efflux. Although these mechanisms occur singly, several resistance factors are often required to produce clinically applicable increases in minimum inhibitory concentrations. Appropriate drug selection and dosage and prudent human and veterinary interventions are important factors in controlling the emergence of resistance.

A prospective and retrospective analysis of the nephrotoxicity and efficacy of lipid-based amphotericin B formulations.

STUDY OBJECTIVE: To determine the usage patterns of the lipid-based amphotericin B formulations at our institution and to compare the observed nephrotoxicity and efficacy of these formulations. DESIGN: Prospective and retrospective observational study SETTING: Urban 350-bed teaching hospital. PATIENTS: Sixty-seven nonhemodialysis patients who were prescribed greater than 3 days of amphotericin B lipid complex (ABLC) or liposomal amphotericin B (L-AmB) from 1996-1999. MEASUREMENTS AND RESULTS: Forty-six patients received ABLC and 21 received L-AmB. Oncology patients accounted for most prescriptions of both formulations. Amphotericin B lipid complex most frequently was prescribed for treatment of documented fungal infections (50%), followed by treatment of neutropenic fever (33%). Liposomal amphotericin B most frequently was prescribed for treatment of neutropenic fever (62%), followed by treatment of documented fungal infections (29%). Seventy-eight percent of patients treated with ABLC and 90% of those who received L-AmB were started on the lipid-based formulation due to being refractory or intolerant to prior antifungal therapy. Two (4.4%) patients receiving ABLC and four (19%) patients receiving L-AmB experienced nephrotoxicity at the end of therapy (NS). Of the patients with a documented fungal infection, 20 out of 23 (87%) of those treated with ABLC and 4 out of 5 (80%) of those treated with L-AmB had a complete or partial response to therapy (NS). One patient with febrile neutropenia had a breakthrough fungal infection while receiving L-AmB. CONCLUSION: No significant differences in nephrotoxicity or efficacy were found between ABLC and L-AmB. Until further studies indicate clinically significant differences in nephrotoxicity between the two liposomal amphotericin B formulations, it is recommended that economics continue to be the major determinant for product selection.

Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects.

STUDY OBJECTIVE: To determine the steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levofloxacin and ciprofloxacin. DESIGN: Multiple-dose, open-label, randomized pharmacokinetic study. PARTICIPANTS: Thirty-six healthy, nonsmoking adult subjects were randomized either to oral levofloxacin, 500 or 750 mg once daily for five doses, or ciprofloxacin, 500 mg q12h for nine doses. INTERVENTIONS: Venipuncture, bronchoscopy, and BAL were performed in each subject at 4 h, 12 h, or 24 h after the last administered dose of antibiotic. MEASUREMENT AND RESULTS: Mean plasma concentrations of levofloxacin and ciprofloxacin were similar to those previously reported. For once-daily dosing of levofloxacin, 500 mg, the mean (+/- SD) steady-state concentrations at 4 h, 12 h, and 24 h in ELF were 9.9 +/- 2.7 microg/mL, 6.5 +/- 2.5 microg/mL, and 0.7 +/- 0.4 microg/mL, respectively; AM concentrations were 97.9 +/- 80.0 microg/mL, 36.7 +/- 23.4 microg/mL, and 13.8 +/- 16.0 microg/mL, respectively. For levofloxacin, 750 mg, the mean steady-state concentrations in ELF were 22.1 +/- 14.9 microg/mL, 9.2 +/- 5.3 microg/mL, and 1.5 +/- 0.8 microg/mL, respectively; AM concentrations were 105.1 +/- 65.5 microg/mL, 36.2 +/- 26.1 microg/mL, and 15.1 +/- 2.0 microg/mL, respectively. The concentrations of ciprofloxacin at 4 h and 12 h in ELF were 1.9 +/- 0.9 microg/mL and 0.4 +/- 0.1 microg/mL, respectively; AM concentrations were 34.9 +/- 23.2 microg/mL and 6.8 +/- 5.9 microg/mL, respectively. The differences in the ELF concentrations of the two levofloxacin groups vs those of the ciprofloxacin group were significant (p < 0.05) at each sampling time. CONCLUSIONS: Levofloxacin was more extensively distributed into intrapulmonary compartments than ciprofloxacin and achieved significantly higher steady-state concentrations in plasma and ELF during the 24 h after drug administration.

Quinupristin-dalfopristin: an overview.

Synercid (RP 59500), the first injectable streptogramin antibiotic, is composed of two semisynthetic pristinamycin derivatives, quinupristin and dalfopristin. Individually, each component has bacteriostatic activity against staphylococci and streptococci, but together, the agents exhibit synergy, leading to bactericidal activity. The combination drug, however, is bacteriostatic against Enterococcus faecium and has poor activity against Enterococcus faecalis. Despite a short half-life, an extended postantibiotic effect allows the agent to be dosed every 8-12 hours. Both drugs are largely hepatically metabolized and excreted in bile. Although not metabolized by cytochrome P450 3A4, quinupristin-dalfopristin can inhibit agents that are metabolized through this pathway. Dosage adjustments may be necessary in patients with hepatic dysfunction. Alterations in renal function have minimal effects on the agent's pharmacokinetics. Adverse events include arthralgia, myalgias, and infusion-related pain. Based on available data, quinupristin-dalfopristin appears to have a role in treating severely ill patients with infections due to multiresistant gram-positive pathogens.

Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma.

Prolonged use of prednisone is associated with serious side effects, such as osteoporosis, particularly among elderly individuals. Macrolide antibiotics exhibit anti-inflammatory effects that are distinct from their antimicrobial properties. Thus, the purpose of this case report is to describe the effects of prolonged treatment with clarithromycin, 500 mg bid, in reducing prednisone requirements in three elderly patients with prednisone-dependent asthma. Three patients (one woman and two men) aged 63 to 69 years, who had been treated with 5 to 10 mg prednisone daily for at least the last 12 months, were given clarithromycin, 500 mg bid. They were followed regularly for changes in daily prednisone dose, spirometry, quality of life, and adverse events. The prednisone dose was tapered in a stepwise fashion at each clinic visit. Within 3 to 6 months of initiation of treatment with clarithromycin, and throughout the 12-month follow-up, two of three patients discontinued prednisone therapy, while the third patient displayed increased spirometry readings and noted an increasingly better quality of life. Pulmonary function tests were stable or improved over this time period, with no reported adverse events, including increased rate of infections. One patient relapsed upon discontinuation of clarithromycin therapy but has since responded to re-initiation of treatment. Long-term oral clarithromycin may have a role in reducing prednisone requirements in elderly patients with prednisone-dependent asthma.

Early bactericidal activity of paromomycin (aminosidine) in patients with smear-positive pulmonary tuberculosis.

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 log(10) 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.

In vitro activities of a new ketolide, ABT-773, alone and in combination with amoxicillin, metronidazole, or tetracycline against Helicobacter pylori.

The in vitro activity of ABT-773, a new ketolide, was compared with those of clarithromycin, amoxicillin, metronidazole, and tetracycline against 15 strains of Helicobacter pylori. The MIC of ABT-773 at which 90% of isolates were inhibited was 0.25 microg/ml, which was 3 dilutions higher than that of the most active agent, clarithromycin. Synergy and antagonism were not seen with any combinations. Additive activity was seen with tetracycline, metronidazole, and amoxicillin in 100, 60, and 40% of the combinations, respectively.

Postantibiotic effects and bactericidal activities of clarithromycin-14-hydroxy-clarithromycin, versus those of amoxicillin-clavulanate, against anaerobes.

The bactericidal activities and postantibiotic effects (PAE) of clarithromycin-14-hydroxy-clarithromycin and amoxicillin-clavulanate against Bacteroides fragilis and Peptostreptococcus anaerobius were determined. A concentration of twice the MIC resulted in bactericidal activity against four of four and three of four organisms at 24 h with clarithromycin-14-hydroxy-clarithromycin and amoxicillin-clavulanate, respectively. The PAE of clarithromycin-14-hydroxy-clarithromycin was 1.44 to 3.20 h, compared to the less than 1 h of amoxicillin-clavulanate. Clarithromycin-14-hydroxy-clarithromycin possesses good activity against susceptible anaerobes.

Bactericidal activity and postantibiotic effect of levofloxacin against anaerobes.

The bactericidal activity and postantibiotic effect (PAE) of levofloxacin against nine anaerobes were determined. Levofloxacin at concentrations of the MIC and twice the MIC was bactericidal at 24 h to five of nine and nine of nine strains, respectively. The PAE of levofloxacin following a 2-h exposure ranged from 0.06 to 2.88 h.

In-vitro synergy of paromomycin with metronidazole alone or metronidazole plus hydroxymetronidazole against Helicobacter pylori.

The in-vitro activities of paromomycin and metronidazole alone or paromomycin and metronidazole plus hydroxymetronidazole (2:1 ratio) were studied against 19 Helicobacter pylori isolates using an in-vitro chequerboard technique. Partial synergy was demonstrated for the majority of isolates (11/19) for both combinations tested. When hydroxymetronidazole was added to the parent compound, the number of metronidazole-sensitive isolates demonstrating synergy increased to 5/12, compared with 1/12 for the combination that did not include the metabolite. In metronidazole-resistant isolates there was a shift from an additive effect to partial synergy for the combination containing hydroxymetronidazole. The in-vitro activity of paromomycin and the synergic effect that is achieved in combination with metronidazole and hydroxymetronidazole render paromomycin suitable for further investigation as a treatment option for H. pylori infection.

Pharmacoeconomic analysis of ampicillin-sulbactam versus cefoxitin in the treatment of intraabdominal infections.

We conducted a retrospective pharmacoeconomic analysis of a prospective, multicenter, double-blind, randomized, controlled trial comparing the beta-lactamase inhibitor combination ampicillin-sulbactam (96 patients) and the cephalosporin cefoxitin (101) in the treatment of intraabdominal infections. An institutional perspective was adopted for the analysis. The primary outcomes of interest were cure and failure rates, development of new infection, and antibiotic-related adverse events. Epidemiologic data pertaining to outcomes was retrieved primarily from the trial, although results of other published studies were taken into consideration through extensive sensitivity analyses. Data pertaining to potential resource use and economic impact were retrieved mainly from the University Health Consortium and hospital-specific sources. When considering only costs associated with drug acquisition through cost-minimization analysis, a potential savings of $37.24/patient may be realized with ampicillin-sulbactam relative to cefoxitin based on an average 7-day regimen. Outcome data collected for the entire hospitalization during the trial revealed an approximately 9% greater frequency of failure with cefoxitin relative to ampicillin-sulbactam. When considering all outcomes of interest in the initial base-case analysis, a potential cost savings of approximately $890/patient may be realized with ampicillin-sulbactam relative to cefoxitin. In assessing the impact of the significant variability in probability and cost estimates, Monte Carlo analysis revealed a savings of $425/patient for ampicillin-sulbactam over cefoxitin (95% CI -$618 to $1516 [corrected]). Given the model assumptions, our analysis suggests a 78% certainty level that savings will be experienced when ampicillin-sulbactam is chosen over cefoxitin.