Simulation of antibiotic pharmacodynamic exposure for the empiric treatment of nosocomial bloodstream infections: a report from the OPTAMA program.

OBJECTIVE: We developed a model to predict the pharmacodynamic exposure of antibiotics against bacteria commonly implicated in nosocomial bloodstream infections to determine which dosage regimens would provide the greatest likelihood of obtaining a bactericidal effect. METHODS: Pharmacodynamic exposures were simulated for 5000 subjects receiving standard doses of ceftazidime, cefepime, piperacillin/tazobactam, meropenem, imipenem, or ciprofloxacin. Exposures were indexed to the MICs of bacteria weighted by their prevalence in causing nosocomial bloodstream infections, derived from 2002 SENTRY data. Enterococci were excluded. MIC data were derived from the 2003 Meropenem Yearly Surveillance Test Information Collection resistance study. The probabilities of achieving bactericidal exposures (ie, target attainment) for each antibiotic regimen were compared. The effect of increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) on attainment of bactericidal targets was tested. RESULTS: All dosage regimens except ciprofloxacin and ceftazidime 1 g q8h achieved >90% likelihood of bactericidal exposure. The rank order of target attainment was as follows: imipenem 500 mg q6h, 100.0%; imipenem 1 g q8h, 99.9%; cefepime 2 g q12h, 99.4%; meropenem 1 g q8h, 98.4%; cefepime 1 g q12h, 98.2%; piperacillin/tazobactam 3.375 g q6h, 97.9%; piperacillin/tazobactam 4.5 gq8h, 95.0%; ceftazidime 2 g q8h, 94.2%; ceftazidime 1 g q8h, 71.7%; ciprofloxacin 400 mg q8h, 63.3%; and ciprofloxacin 400 mg q12h,63.0%. Target attainments dropped to <90% for all agents when MRSA was modeled at > or =10% prevalence. CONCLUSIONS: The results of this model analysis suggest that standard doses of the carbapenems, piperacillin/tazobactam, and cefepime, and higher doses of ceftazidime, may provide optimal likelihood of achieving bactericidal exposure against pathogens implicated in nosocomial bloodstream infections, excluding MRSA and enterococci. When MRSA rates are > or =10%, therapy with an antibiotic that has activity against this phenotype should be empirically initiated.

Impact of pharmacodynamics on dosing of macrolides, azalides, and ketolides.

The study of pharmacodynamics characterizes the relationship between changing drug concentrations over time and antimicrobial and toxicologic effects and thereby offers a targeted approach to the design of dosing regimens for many antimicrobials. Distinct patterns of antimicrobial dynamics have been elucidated from these relationships and pharmacodynamic parameters (peak-MIC, AUC-MIC, T > MIC) have been used to quantify antimicrobial effects in relation to drug exposure. These relationships can be used to predict efficacy of a given dosing regimen. The accuracy of these predictions is influenced, in part, by the completeness of the model in which they are studied. This article discusses various in vitro and in vivo studies and clinical data that have contributed to the understanding of pharmacodynamics of the macrolides, azalides, and ketolides.

Characterization of the penetration of garenoxacin into the breast milk of lactating women.

The primary objective of this study was to characterize the extent of excretion of garenoxacin, a novel des-F(6)-quinolone antimicrobial, into the breast milk of lactating women. A secondary objective was to determine the time after dose administration that garenoxacin was no longer detected in breast milk so as to define when a mother may resume breastfeeding if it was interrupted for garenoxacin administration. Six healthy, lactating women (age [mean +/- SD]: 32 +/- 6 years; weight: 68.3 +/- 19.8 kg; body mass index: 26 +/- 5 kg/m(2)) who had completed weaning their infants were administered a single 600-mg oral dose of garenoxacin. Plasma samples were collected predose and repeatedly up to 72 hours postdose. Breast milk was collected predose and for 6- to 12-hour intervals repeatedly up to 120 hours postdose. Breast milk/plasma concentration ratios for garenoxacin ranged from 0.35 to 0.44 up to 24 hours postdose, and the mean peak breast milk concentration was 3.0 microg/mL (0- to 6-h collection interval). Overall, garenoxacin exposure in breast milk was minimal, with a mean of 0.07% of the administered dose recovered within 120 hours. Indeed, garenoxacin was undetectable in the breast milk of a majority of subjects within 84 hours of dosing. As such, an infant nursing from a mother who had received a single 600-mg oral dose of garenoxacin could theoretically be exposed to 0.42 mg of garenoxacin (0.105 mg/kg/day for a 4-kg infant over the period of 5 days of nursing). If extrapolated to a 14-day course of garenoxacin 600 mg once daily, total exposure would be approximately 5.88 mg. These findings indicate that, like other quinolone antimicrobials, garenoxacin is secreted in breast milk.

Extended interval aminoglycoside dosing: from concept to clinic.

Extended-interval aminoglycoside dosing (EIAD), while a relatively recent concept in mainstream clinical practice, actually has its roots in the mid 1970s. Early trial and error approaches of manipulating the dosage regimen to avoid toxicity and improve efficacy have helped to characterize the pharmacodynamic properties of these drugs. The increasing successful use of EIAD and improved understanding of pharmacodynamics has helped this dosing regimen gain acceptance into routine clinical practice. A 1998 United States survey demonstrated that approximately 75% of hospitals have adopted EIAD into routine patient care. However, controversy still exists regarding some aspects of infrequent aminoglycoside administration, such as length of the drug-free interval and patient exclusion criteria. After more than 50 years of experience with the aminoglycosides we continue to learn how to most appropriately use these drugs.

Production and resolution of cantharidin-induced inflammatory blisters.

While inflammatory blisters have long been utilized as a means of evaluating antimicrobial disposition to aid in the development of new treatments for skin and skin structure infections, sparse data are available regarding the healing of the blisters once the experiment has been completed. We report the blister induction technique and resolution time in ten volunteers enrolled in a pharmacokinetic study using the cantharidin-induced inflammatory blister technique.

Efficacy of clarithromycin against Streptococcus pneumoniae expressing mef(A)-mediated resistance.

As a result of macrolide resistance rates of 25% for pneumococci in the US, the clinical use of this class as empirical therapy has been questioned. However, macrolides continue to be used with clinical success. Using an immunocompromised murine pneumonia model, this study evaluated in vivo efficacy of human simulated exposures of clarithromycin for 62 isolates of Streptococcus pneumoniae considered resistant by current methods of breakpoint determinations. Changes in bacterial density were compared between treated animals and untreated controls. Inhibition of bacterial growth was consistently observed for the majority of isolates tested with mean (S.D.) reductions in logCFU per lung of -0.88 (0.69), -1.02 (0.87), -0.47 (0.79), -0.84 (0.66), -0.25 (0.26), -0.80 (0.72) and -0.58 (0.47) for MICs of 1, 2, 4, 8, 16, 32 and 64 mg/l, respectively. A beneficial treatment effect was clearly noted for isolates with clarithromycin MICs <==8 mg/l. However, the sample size of isolates tested beyond the MIC of 8 mg/l was diminished due to mortality in both treated and untreated animals. Consistent suppression of bacterial growth observed in this neutropenic model provides support for the in vivo efficacy of clarithromycin with low-level macrolide-resistant S. pneumoniae.

Bactericidal effect of cethromycin (ABT-773) in an immunocompetent murine pneumococcal pneumonia model.

The efficacy of cethromycin was assessed against isolates of Streptococcus pneumoniae in the presence of neutrophils. Comparison with data from our previous neutropenic model revealed that the presence of neutrophils enhanced the bacteriostatic and bactericidal effect of cethromycin by an average of two- to four-times, respectively.

Pleconaril, a novel antipicornaviral agent.

Despite the availability of therapy for selected symptoms, no specific antiviral agents are available to treat or prevent infections due to the viruses of the Picornaviridae family--rhinoviruses and enteroviruses. Characterization of the three-dimensional structure of picornaviruses in the 1980s allowed development of compounds targeted at the virus itself. Pleconaril is a novel, orally available, systemically acting molecule whose pharmacokinetics are characterized by a two-compartment open model with first-order absorption and with a safety profile similar to that of placebo. It shows promising results in treatment of picornaviral respiratory tract infections, meningitis, and other life-threatening infections.

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.

Economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts.

The economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts is described. The pharmacodynamics of novel meropenem dosing regimens were compared with FDA-approved regimens by using Monte Carlo simulation with 5000 subjects. Using the meropenem NCCLS-susceptibility breakpoint of 4 micrograms/mL, the percentage of the dosing interval that drug concentration remained above the minimum inhibitory concentration (%t > MIC) was calculated for each regimen. Probability distributions for half-life and volume of distribution using previously published pharmacokinetic data from healthy volunteers were developed. Cost-minimization analysis was performed from the institution's perspective using both drug acquisition and supply costs. Daily costs for the lower dosage regimens were calculated using 2001 average wholesale prices. The mean %t > MIC for meropenem 500 mg administered every six hours (43.91% [95% confidence interval (CI), 36.77-51.46%]) was similar to that of 1000 mg every eight hours (45.77% [95% CI, 40.06-50.69%]). The mean %t > MIC for meropenem 1000 mg administered every six hours (61.02% [95% CI, 54.71-67.43%]) was similar to the regimen of 2000 mg every eight hours (57.77% [95% CI, 51.84-63.76%]). The 500-mg regimen reduced drug costs by $38.64 per day compared with the standard regimen of 1000 mg administered every eight hours. A pharmacodynamically influenced dosage strategy for meropenem resulted in %t > MIC exposure similar to standard regimens and required a lesser amount of the drug, thereby reducing costs without compromising efficacy.

Pharmacodynamic profiling of modithromycin: assessment in a pneumococcal murine pneumonia model.

The pharmacodynamic profile of modithromycin (EDP-420, EP-013420, S-013420), a novel bicyclolide, was evaluated in a neutropenic pneumococcal murine pneumonia model. Streptococcus pneumoniae median minimum inhibitory concentrations (MICs) for five genotypically diverse isolates ranged from 0.016 µg/mL to 0.125 µg/mL and were unaffected by macrolide or penicillin resistance determinants. The modithromycin dosing regimens (total daily doses of 3.125-1000 mg/kg/day) were derived from the pharmacokinetic profile of the compound in infected mice and were selected to produce a wide range of exposures. Dose-response relationships characterised using the Emax model demonstrated high correlations both with the ratio of the area under the concentration-time curve to MIC (AUC/MIC) and the ratio of the maximum drug concentration to MIC (Cmax/MIC). However, dose fractionation studies suggest that the AUC/MIC is the predominant driver of in vivo efficacy. The free drug AUC/MIC (fAUC/MIC) required for stasis and for 80% of maximum activity ranged from 4 to 53 and 25-99, respectively. The fAUC/MIC needed to achieve a 1 log reduction in bacterial density, which is a conventional measure of the required exposure in man to reliably predict efficacy, ranged from 9 to 69. These data demonstrate the in vitro and in vivo potency of modithromycin against S. pneumoniae irrespective of its phenotypic profile to the macrolides or penicillin.

Defining the need for new antimicrobials: clinical and economic implications of resistance in the hospitalised patient.

Resistance among pathogens causing the most common infections encountered in hospitalised patients is increasing. Due to this resistance, the clinical efficacy of current antimicrobial agents is decreasing against many pathogens, including Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Pseudomonas aeruginosa, extended-spectrum beta-lactamases, and AmpC beta-lactamase-producing organisms. Studies assessing the impact of these resistance mechanisms on clinical outcomes have been performed; however, studies determining the economic impact of resistance have been limited. Strategies to retain the clinical efficacy of currently available agents include the initiation of antimicrobials with efficacy against the suspected pathogen(s) based on data obtained from local antibiograms, the use of combination therapy, and pharmacodynamic optimisation. Once a broad-spectrum regimen has been initiated, de-escalation to narrow, targeted antimicrobial therapy based on susceptibility data is warranted. Despite these efforts, new antimicrobials with novel mechanisms of action are eagerly anticipated to extend the current armamentarium against the growing population of multi-drug-resistant pathogens.

Pharmacodynamic profile of ertapenem against Klebsiella pneumoniae and Escherichia coli in a murine thigh model.

The pharmacodynamic profile of ertapenem was evaluated in a neutropenic mouse thigh infection model. Extended-spectrum beta-lactamase (ESBL)-positive and ESBL-negative clinical strains of Escherichia coli and Klebsiella pneumoniae were studied. MICs ranged from 0.0078 to 0.06 microg/ml with standard inoculum tests. Ertapenem doses were administered once to five times daily to achieve various exposures, reported as the percentage of the dosing interval that the concentration of free ertapenem was in excess of the MIC (%T>MIC(free)). Mean values for the static exposure and 80% maximally effective exposure (ED(80)) were 19% (range, 2 to 38%) and 33% (range, 13 to 65%) T>MIC(free), respectively. Differences in exposure requirements based on the presence of an ESBL resistance mechanism or bacterial species were not evident. In addition, experiments using a 100-fold higher inoculum did not decrease the magnitude of the reduction in bacterial density from baseline achieved compared to lower-inoculum studies. The pharmacodynamic parameter of %T>MIC(free) correlated well with bactericidal activity for all isolates, and the static and ED(80) exposures are consistent with those reported previously for carbapenems.

Efficacy of pulsatile amoxicillin and clarithromycin dosing alone and in combination in a murine pneumococcal pneumonia model.

OBJECTIVES: Amoxicillin and clarithromycin have been proven to be effective in the treatment of community-acquired pneumonia. This study investigated the in vivo bactericidal efficacy of a novel, pulsatile dosing strategy for amoxicillin and clarithromycin, when used as monotherapy and combination therapy. METHODS: A neutropenic murine pneumonia model was used to assess the bactericidal activity of amoxicillin and clarithromycin, when the same total daily dose was administered as a traditional regimen (every 8 h and every 12 h, respectively) or as a pulsatile regimen (four doses of antibiotic given every 2 h over the first 6 h of the day) against three isolates of Streptococcus pneumoniae of varying resistance profiles. The three isolates consisted of SP21 (macrolide and penicillin susceptible), SP100 [mef(A) gene], and SP107 [mef(A) + erm(B) genes]. RESULTS: Pulsatile dosing showed similar reductions in bacterial density for amoxicillin and clarithromycin when either drug was given alone compared with traditional dosing regimens against all three bacterial isolates. When amoxicillin and clarithromycin were combined, improved activity was found compared with monotherapy. Overall, when comparing the different combination regimens, the pulsatile regimens provided similar activity compared with the traditional regimens. For one isolate, SP107, pulsatile amoxicillin combination regimens were less effective compared with traditionally dosed amoxicillin combination regimens. CONCLUSIONS: Pulsatile dosing resulted in comparable bactericidal activity against the three isolates tested and may represent an alternative dosing strategy, which may help to alleviate problems with patient adherence to drug therapy.

Pharmacokinetic profile of meropenem, administered at 500 milligrams every 8 hours, in plasma and cantharidin-induced skin blister fluid.

The pharmacokinetic disposition of meropenem, administered at 500 mg every 8 h, in plasma and cantharidin-induced blister fluid is described. Peak meropenem concentrations in blister fluid lagged behind peak meropenem concentrations in plasma, while a lower elimination rate from blister fluid was also noted. The mean penetration of meropenem into blister fluid was 67%. The pharmacokinetic profile of meropenem in blister fluid supports the utility of this dose in the management of skin and soft tissue infections.

Determination of the in vivo pharmacodynamic profile of cefepime against extended-spectrum-beta-lactamase-producing Escherichia coli at various inocula.

Cefepime was evaluated in vivo against two inoculum sizes of four strains of Escherichia coli that produced extended-spectrum beta-lactamases (ESBLs) in a murine neutropenic thigh infection model to characterize the pharmacodynamic activity of cefepime in the presence of ESBL-producing bacteria and to evaluate if differences in lengths of cefepime exposure are required with various inocula. Three strains possessed a single enzyme each: TEM-10, TEM-12, and TEM-26. The fourth strain possessed two TEM-derived ESBLs and a third uncharacterized enzyme. Two non-ESBL-producing E. coli strains were included for comparison. Mice received various doses of cefepime to achieve a spectrum of percentages of time the drug was above the MIC (%T>MICs) for each isolate at both inocula. No significant difference in cefepime exposure was required to achieve similar bactericidal effects for ESBL- and non-ESBL-producing isolates when the starting inoculum was 10(5) CFU of E. coli per thigh. The increased MICs observed in vitro for the ESBL-producing strains at 10(7) CFU/ml did not predict the amount of exposure required to achieve a comparable level of bactericidal activity in vivo at the corresponding starting inoculum of 10(7) CFU/thigh. Compared to the cefepime exposure in tests with the lower inoculum (10(5) CFU/thigh), less exposure was required when the starting inoculum was 10(7) CFU/thigh (%T>MIC, 6% versus 26%), such that similar doses (in milligrams per kilogram of body weight) produced similar bactericidal effects with both inocula of ESBL-producing isolates. Equivalent exposures of cefepime produced similar effects against the microorganisms regardless of the presence of ESBL production. Pharmacodynamic profiling undertaken with conventional cefepime MIC determinations predicted in vivo microbial outcomes at both inoculum sizes for the ESBL-producing isolates evaluated in this study. These data support the use of conventional MIC determinations in the pharmacodynamic assessment of cefepime.

Differential efficacy of clarithromycin in lung versus thigh infection models.

BACKGROUND: Differences in clarithromycin disposition and the resulting changes in bacterial density were studied using mouse lung and thigh infection models. METHODS: Clarithromycin activity was evaluated against seven Streptococcus pneumoniae isolates with efflux-mediated resistance in both murine lung and thigh infection models. Intrapulmonary disposition of clarithromycin was also studied. RESULTS: Consistent bacterial kill was observed in the lung model, whereas no drug effect was observed in the thigh model. CONCLUSION: These differences in bacterial density were supported by high concentrations observed in epithelial lining fluid as compared to serum.