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.

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.

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.

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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.

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 g/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.Ertapenem is presently approved in the United States to treat complicated intra-abdominal infections, complicated skin and skin structure infections, community-acquired pneumonia, complicated urinary tract infections, and acute pelvic infections (Invanz package insert; Merck & Co., Inc, Whitehouse Station, N.J.). These infections are often characterized as polymicrobial in nature. In addition, convincing data have associated inadequate empirical therapy with increased failure rates and increased mortality for many of these infections (8). Therefore, initiation of treatment with a potent, broad-spectrum agent is essential.Ertapenem has demonstrated considerable in vitro potency against a wide range of pathogenic gram-positive and gramnegative organisms, excluding nonfermentating organisms. In addition, the in vivo activity of ertapenem against Streptococcus pneumoniae has previously been described (10). However, many fewer data exist to describe the in vivo pharmacodynamics of this agent in gram-negative infections. The objective of this study was to evaluate the killing activity of ertapenem against Escherichia coli and Klebsiella pneumoniae clinical isolates, two of the most commonly recovered pathogens in the above-mentioned infections, in a neutropenic thigh infection model. Four isolates were extended-spectrum beta-lactamase (ESBL) producers. We focused the analysis on the percentage of the dosing interval that the concentration of free ertapenem was in excess of the MIC (%TϾMIC), since this parameter has been repeatedly identified as the parameter correlating best with carbapenem efficacy (9). In vivo efficacy at a high inoculum (10 7 CFU/ml) was additionally evaluated in a subset of isolates to assess the impact of a larger inoculum size on the pharmacodynamic characteristics of ertapenem. MATERIALS AND METHODSAnti...

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.In the United States, meropenem is Food and Drug Administration approved for intra-abdominal infections and bacterial meningitis (Merrem package insert; AstraZeneca Pharmaceuticals, Wilmington, Del., 2001). However, this agent has also been found effective for lower respiratory tract, skin and soft tissue, gynecologic, and complicated urinary tract infections as well as empirical therapy in the febrile neutropenic patient (2-4, 6, 9, 11). While these clinical findings may be anticipated from its plasma profile, it is the drug concentration at the site of infection that best supports clinical efficacy. In the context of skin and soft tissue infections, evaluation of drug concentrations in blister fluid may best approximate drug exposure at the infection site, since this fluid has been noted to resemble the situation within an infected tissue (1). In this study, we evaluated the steady-state pharmacokinetic profile of meropenem, administered at 500 mg every 8 h, in both blister fluid and plasma.Study design and population. Ten volunteers were enrolled in this multiple-dose, open-label study after approval was granted from the Hartford Hospital Institutional Review Board, and written informed consent was obtained. Volunteers were 21 to 42 years of age (mean age, 26.8 years), weighed between 68 and 118 kg (mean weight, 86.2 kg), and had a mean height of 1.8 m (range, 1.68 to 1.88 m). Volunteers underwent two complete physical exams within 21 days and 48 h before the study and were considered normal. Laboratory evaluations, including blood chemistries, hematology, and urinalysis, revealed no abnormalities.Blister induction and drug administration. Volunteers received intravenous doses of 500 mg of meropenem (lot no. 6199C; AstraZeneca Pharmaceuticals) in 250 ml of normal saline over 30 min every 8 h for a total of three doses. After the first dose, and approximately 14 h before pharmacokinetic sampling, 0.2-ml drops of an ointment containing 0.25% cantharidin made from cantharidin powder (Sigma Laboratories, St. Louis, Mo.) and standard ointment base were applied to the anterior forearms of the volunteers to produce a total of six blisters per volunteer. The integrity of the blisters was maintained by spraying them with a fast-drying plastic dressing (New-Skin Liquid Bandage Spray; Medtech Laboratories, Inc., Jackson, Wyo.). Volunteers were allowed to take food and drink ad libitum. Caffeine intake was not permitted.Pharmacokinetic sampling. Blood samples were collected into heparinized Vacutainers from an ind...