Dana Maglio

Determination of the In Vivo Pharmacodynamic Profile of Cefepime against Extended-Spectrum-Beta-Lactamase-Producing Escherichia coli at Various Inocula

ABSTRACT 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 105 CFU of E. coli per thigh. The increased MICs observed in vitro for the ESBL-producing strains at 107 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 107 CFU/thigh. Compared to the cefepime exposure in tests with the lower inoculum (105 CFU/thigh), less exposure was required when the starting inoculum was 107 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.

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.

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.

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.

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 β-lactamases, and AmpC β-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.

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.

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.

Pharmacodynamic Profile of Ertapenem against Klebsiella pneumoniae and Escherichia coli in a Murine Thigh Model

ABSTRACT 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 μg/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>MICfree). Mean values for the static exposure and 80% maximally effective exposure (ED80) were 19% (range, 2 to 38%) and 33% (range, 13 to 65%) T>MICfree, 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>MICfree correlated well with bactericidal activity for all isolates, and the static and ED80 exposures are consistent with those reported previously for carbapenems.

Pharmacokinetic Profile of Meropenem, Administered at 500 Milligrams Every 8 Hours, in Plasma and Cantharidin-Induced Skin Blister Fluid

ABSTRACT 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.

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.