Evaluation of telithromycin against Streptococcus pneumoniae with ribosomal mutations utilizing in vitro time-kill methodology.

In a recent study, our in vivo data suggested that clinically achievable levels of telithromycin are more effective than azithromycin against selected Streptococcus pneumoniae isolates with ribosomal mutations in 23S rRNA gene alleles and L22 region mutations. In the current study, we attempt to investigate further the antibacterial activity of telithromycin against these isolates to better delineate the disparity between isolates based on allelic differences. Four isolates of S. pneumoniae with ribosomal mutations were tested using in vitro time-kill methodology. Isolates were exposed to telithromycin at concentrations of 0.5-8 x the minimum inhibitory concentration (MIC). At these exposures, telithromycin demonstrated concentration-dependent killing for three of the four isolates. Against the fourth isolate, telithromycin affected only a 1 log decrease in colony-forming units/mL despite exposures of 8 x MIC. These data demonstrate the in vitro killing profile of telithromycin against S. pneumoniae isolates with ribosomal and L22 mutations. Whilst telithromycin did not demonstrate bactericidal activity against all isolates in these time-kill studies, the in vivo human-simulated exposures did result in a high degree of bacterial kill. Full evaluation of the potential utility of new antimicrobial agents against these emerging genotypic profiles requires both in vitro and in vivo assessments.

Assessment of the efficacy of telithromycin simulating human exposures against S. pneumoniae with ribosomal mutations in a murine pneumonia model.

Telithromycin (TEL) is a ketolide antimicrobial agent with in vitro activity against Streptococcus pneumoniae (SPN), including macrolide resistant strains. The purpose of this study was to assess the efficacy of TEL against clinical SPN isolates with various genotypic mutations including the newly recognized ribosomal mutations. Pneumonia was induced in either immunocompetent and immunosuppressed mice. Six isolates were included in the study and all were resistant to azithromycin (AZI) by MIC testing. Three oral regimens of TEL were chosen to simulate the human pharmacokinetic (PK) exposures observed in young healthy, healthy elderly (> or =65 years), and infected subjects. An additional group was given AZI in human simulated doses. Bacterial density in lung was determined after each treatment. Telithromycin administered simulating infected patients showed greater efficacy (i.e., change in logCFU) than the azithromycin treated group for all isolates except P1660008. The immune system was responsible for increased efficacy (ranging from 45-146%) for all but one of the telithromycin treatment regimens. Unlike other isolates studied in this in vivo model, P1660008 displayed a highly variable response to therapy, such that the reductions in CFU were not consistent with the microbiological and PK profiles of either compound. For all other isolates, the activity of AZI was comparable with untreated controls. Human simulated exposures of TEL displayed 0.5-3.4 log kill in vivo despite the ribosomal mutations studied. These data support the in vivo efficacy of TEL against a variety of genotypic resistance profiles observed in pneumococci, however, additional studies are required to fully characterize the killing profile of the compound against these recently determined ribosomal mutations.

Pharmacodynamic profile of telithromycin against macrolide- and fluoroquinolone-resistant Streptococcus pneumoniae in a neutropenic mouse thigh model.

The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae, including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were < or =0.5 microg/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 10(5) to 10(6) CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae, regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.

Prevalence of extended spectrum beta-lactamase producing Escherichia coli and Klebsiella isolates in a large community teaching hospital in Connecticut.

The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESC) and Klebsiella (KS) among consecutive non-urine isolates were evaluated. Twenty-four of 392 isolates produced ESBLs. Among these half were from respiratory sites and all were susceptible to meropenem. Pulse field-gel electrophoresis (PFGE) showed 12 clonally distinct ESBLs and iso-electric focusing (IEF) revealed that most (83%) produced multiple enzymes.

Determination of the pharmacodynamic profile of daptomycin against Streptococcus pneumoniae isolates with varying susceptibility to penicillin in a murine thigh infection model.

BACKGROUND: Daptomycin has demonstrated in vitro activity against gram-positive organisms, including Streptococcus pneumoniae. However, the pharmacodynamic (PD) profile of daptomycin is needed to relate the activity of the drug to biologically achievable concentrations. METHODS: The PD profile of daptomycin against four S. pneumoniae isolates was determined using the immunocompromised murine thigh model. Due to the high protein binding of this agent, PD parameters were calculated based on free drug exposures. Efficacy was assessed by the change in log colony-forming units (CFU) in thighs after 24 h of drug treatment. RESULTS: Daptomycin produced a 7.1 (95% confidence interval 7.0-7.2) log(10) CFU kill. The ratio between overall drug exposure and the minimum inhibitory concentration (MIC) (AUC/MIC) was the most predictive of the PD parameters. The S. pneumoniae AUC/MIC required for static effects was 12 (95% confidence interval 10-14). Eighty percent and 99% of maximal kill was achieved at ratios of 35 (95% confidence interval 32-39) and 184 (95% confidence interval 160-208), respectively. CONCLUSIONS: Clinically achievable serum drug exposures produced by the lowest dose of daptomycin currently studied in humans (4 mg/kg/day) should result in a potent in vivo bactericidal effect against infections due to S. pneumoniae such as bacteremia, where serum drug concentrations adequately reflect the concentration at the site of infection.

Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem.

Prolonging the infusion of meropenem over 3 hours increases the percentage of the dosing interval that drug concentrations remain above the minimum inhibitory concentration (MIC), thereby maximizing the pharmacodynamics of this agent and adhering to drug stability constraints. Monte Carlo simulation was employed to determine pharmacodynamic target attainment rates for several prolonged infusion (PI) meropenem dosage regimens as compared with the traditional 30-minute infusion (TI) against Enterobacteriaceae, Acinetobacter species, and Pseudomonas aeruginosa populations. Percent time above the MIC (%T>MIC) exposures for 1000 mg TI q8h, 2000 mg TI q8h, 500 mg PI q8h, 1000 mg PI q12h, 1000 mg PI q8h, 2000 mg PI q12h, and 2000 mg PI q8h were simulated for 10,000 subjects. Variability in pharmacokinetic parameters and MIC distributions were derived from studies in healthy volunteers and the MYSTIC surveillance program, respectively. The probabilities of attaining bacteriostatic (30% T>MIC) and bactericidal (50% T>MIC) exposures were high for all dosage regimens against populations of Enterobacteriaceae. Against Acinetobacter species and Pseudomonas aeruginosa, the 2000-mg PI q8h dosage regimen provided the highest target attainment rates. For mild to moderate infections caused by Enterobacteriaceae, prolonged infusion regimens of 500 mg PI q8h and 1000 mg PI q12h would provide equivalent target attainment rates to the traditional 30-minute infusion while requiring less drug over 24 hours. For more serious infections presumably caused by Acinetobacter species or Pseudomonas aeruginosa, a dose of 2000 mg PI q8h is recommended because of its high bactericidal target attainment rate against these pathogens. Further study of these dosage recommendations in clinical trials is suggested.

Pharmacokinetics of meropenem 0.5 and 2 g every 8 hours as a 3-hour infusion.

STUDY OBJECTIVE: To assess the pharmacokinetics of meropenem administered as a 3-hour infusion. DESIGN: Randomized, crossover, open-label study. SETTING: Clinical research center. SUBJECTS: Six healthy adult male volunteers. INTERVENTION: Each subject received meropenem 0.5 or 2 g every 8 hours as a 3-hour infusion for three doses and then crossed over to the other dosage regimen. MEASUREMENT AND MAIN RESULTS: Pharmacokinetic parameters of both regimens were compared, and no significant differences between 0.5- and 2-g doses for the dose-independent parameters (half-life, clearance, and volume of distribution at steady state) were observed. The regimens displayed dose proportionality and were consistent with that of a traditional 0.5-hour infusion. The 3-hour infusion optimized the pharmacodynamic profile of meropenem and worked within the constraints of stability at room temperature stability. CONCLUSION: Prolonging the percentage of time above the minimum inhibitory concentration is a feasible option with meropenem; however, further studies are needed to quantify how this increase translates to efficacy.

Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection model.

OBJECTIVE: To describe the pharmacodynamic profile of daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) and Enterococci species based on bacterial density in an immunocompromised mouse thigh infection model. MATERIALS AND METHODS: The pharmacodynamic (PD) profile of daptomycin was determined against two MRSA, one vancomycin-resistant Enterococcus faecium, and one vancomycin-susceptible Enterococcus faecalis using the immunocompromised murine thigh model. Efficacy was assessed by the change in log10 cfu in thighs after 24 h of drug treatment. RESULTS: Daptomycin produced a maximal kill of 4.5-5 log10 cfu against the MRSA and 1.5-2 log10 for the Enterococcus species. AUC/MIC was the most predictive of the PD parameters. Utilizing MICs determined in serum or broth in the calculation of the PD parameters had minimal effect on this correlation. AUCfree/MICbroth required for static effects with MRSA and Enterococcus species were 12-36 and 5-13, whereas 99% of maximal kill was achieved at ratios of 171-442 and 38-157, respectively. CONCLUSIONS: These data reveal the potent in vivo bactericidal activity of daptomycin against MRSA and Enterococcus species using clinically achievable drug exposures (dose 4-6 mg/kg per day) currently under investigation in man.

Utilization of extended-spectrum beta-lactamase (ESBL) detection systems in microbiology laboratories: survey of Connecticut hospitals from 1998-2002.

There has been recent concern raised over the detection, prevalence, and clinical implications of infection with Escherichia coli and Klebsiella spp. which produce extended-spectrum beta-lactamases (ESBLs). These enzymes hydrolyze beta-lactams including the cephalosporins (i.e., ceftazidime, ceftriaxone, cefotaxime), thus frequently leading to treatment failures. Standard in vitro testing may report these isolates as susceptible when in fact they are resistant in vivo. As a result of this phenomenon, additional testing for suspected isolates is recommended nationally. We surveyed 28 Connecticut hospitals from 1998-2002 to determine if these institutions utilized screening and confirmation methods for suspected isolates. The number of hospitals which have implemented ESBL detection systems doubled from 11 to 22 over the study period. Currently, 15 of the 22 laboratories conduct both screening and confirmatory testing. This expanded testing will be of great assistance to clinicians in optimizing the clinical care of patients with Gramnegative infections.

Pharmacodynamic considerations for the selection of oral cephalosporins in the treatment of rhinosinusitis.

The elimination of an infection occurs when the antibiotic reaches the site of the pathogen in adequate concentrations for an appropriate length of time. To predict whether an antibiotic will achieve this goal, one must have a familiarity with pharmacodynamic concepts that integrate the drug's microbiological activity, its pharmacokinetic properties, and its mode of bacterial killing. For the cephalosporins, it is the time or duration that the concentrations in serum or interstitial fluid remain above their mean inhibitory concentration for the pathogen that best correlates with clinical outcomes. The application of this pharmacodynamic profile can assist in the decision process to distinguish one oral cephalosporin from another and, therefore, provides an opportunity for maximizing the probability of good clinical outcomes while minimizing the potential for the selection of resistance.