Suppression of resistance in a dense Pseudomonas aeruginosa population has previously been shown with optimized quinolone exposures. However, the relevance to -lactams is unknown. We investigated the bactericidal activity of meropenem and its propensity to suppress P. aeruginosa resistance in an in vitro hollow-fiber infection model (HFIM). Two isogenic strains of P. aeruginosa (wild type and an AmpC stably derepressed mutant [MIC ؍ 1 mg/liter]) were used. An HFIM inoculated with approximately 1 ؋ 10 8 CFU/ml of bacteria was subjected to various meropenem exposures. Maintenance doses were given every 8 h to simulate the maximum concentration achieved after a 1-g dose in all regimens, but escalating unbound minimum concentrations (C min s) were simulated with different clearances. Serial samples were obtained over 5 days to quantify the meropenem concentrations, the total bacterial population, and subpopulations with reduced susceptibilities to meropenem (>3؋ the MIC). For both strains, a significant bacterial burden reduction was seen with all regimens at 24 h. Regrowth was apparent after 3 days, with the C min /MIC ratio being <1.7 (time above the MIC, 100%). Selective amplification of subpopulations with reduced susceptibilities to meropenem was suppressed with a C min /MIC of >6.2 or by adding tobramycin to meropenem (C min /MIC ؍ 1.7). Investigations that were longer than 24 h and that used high inocula may be necessary to fully evaluate the relationship between drug exposures and the likelihood of resistance suppression. These results suggest that the C min /MIC of meropenem can be optimized to suppress the emergence of non-plasmid-mediated P. aeruginosa resistance. Our in vitro data support the use of an extended duration of meropenem infusion for the treatment of severe nosocomial infections in combination with an aminoglycoside.Bacterial resistance is a rapidly spreading and serious problem that threatens our therapeutic armamentarium. Given that the drug development process takes many years, it is imperative that the utilities of currently available agents be preserved through the judicious and optimal use of these agents. It has been shown that suboptimal dosing represents a selective pressure that is imposed on the bacteria and that facilitates the emergence of resistance (9, 11). On the other hand, all bacterial subpopulations are killed with optimal dosing, which results in the sustained suppression of both total and resistant populations over time. It has also previously been shown that the emergence of resistance in Pseudomonas aeruginosa could be suppressed by optimizing the exposure of quinolones (11, 28). However, it is less certain if the same is true for the -lactam antibiotics.The pharmacodynamics of -lactams have been relatively well elucidated. The time above the MIC (T Ͼ MIC) of the pathogen has repeatedly been shown to be the pharmacodynamic variable most closely linked to bactericidal activity (2, 21). However, the breakpoint of optimal activity is controversial, and none of the ...
Despite limited data, polymyxin B (PB) is increasingly used clinically as the last therapeutic option for multidrug-resistant (MDR) gram-negative bacterial infections. We examined the in vitro pharmacodynamics of PB against four strains of Pseudomonas aeruginosa. Clonal relatedness of the strains was assessed by random amplification of polymorphic DNA. Time-kill studies over 24 h were performed with approximately 10 5 and 10 7 CFU/ml of bacteria, using PB at 0, 0.25, 0.5, 1, 2, 4, 8, and 16؋ MIC. Dose fractionation studies were performed using an in vitro hollow-fiber infection model (HFIM) against a wild-type and a MDR strain. Approximately 10 5 CFU/ml of bacteria were exposed to placebo and three regimens (every 8 h [q8h], q12h, and q24h) simulating the steady-state unbound PB pharmacokinetics resulting from a daily dose of 2.5 mg/kg of body weight and 20 mg/kg (8 times the clinical dose). Samples were obtained over 4 days to quantify PB concentrations, total bacterial population, and subpopulation with reduced PB susceptibility (>3؋ MIC). The bactericidal activity of PB was concentration dependent, but killing was significantly reduced with a high inoculum. In HFIM studies, a significant reduction in bacterial load was seen at 4 h in all active regimens, but selective amplification of the resistant subpopulation(s) was apparent at 24 h with the clinical dose (both strains). Regrowth was eventually observed in all dosing regimens with the MDR strain, but its occurrence was prevented in the wild-type strain by using 8 times the clinical dose (regardless of dosing intervals). Our results suggested that the bactericidal activity of PB was concentration dependent and appeared to be related to the ratio of the area under the concentration-time curve to the MIC.
Our model reasonably described and predicted the time course of P. aeruginosa in time-kill studies, and provided quantitative information on the pharmacodynamics of meropenem. The structural model appeared robust and could be used to provide a realistic expectation of the killing performance of antimicrobial agents.
Aminoglycosides are often used to treat severe infections with gram-positive organisms. Previous studies have shown concentration-dependent killing by aminoglycosides of gram-negative bacteria, but limited data are available for gram-positive bacteria. We compared the in vitro pharmacodynamics of gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa. Five S. aureus strains were examined (ATCC 29213 and four clinical isolates). Time-kill studies (TKS) in duplicate (baseline inocula of 10 7 CFU/ml) were conducted to evaluate bacterial killing in relation to increasing gentamicin concentrations (0 to 16 times the MIC). Serial samples were obtained over 24 h to quantify bacterial burden. Similar TKS with P. aeruginosa ATCC 27853 were conducted, and the time courses of the all bacterial strains were mathematically modeled for quantitative comparison. A dose fractionation study (using identical daily doses of gentamicin) in an in vitro hollow-fiber infection model (HFIM) over 5 days was subsequently used for data validation for the two ATCC strains. Model fits to the data were satisfactory; r 2 values for the S. aureus and P. aeruginosa ATCC strains were 0.915 and 0.956, respectively. Gentamicin was found to have a partially concentration-dependent killing effect against S. aureus; concentrations beyond four to 8 times the MIC did not result in significantly faster bacterial killing. In contrast, a concentration-dependent profile was demonstrated in suppressing P. aeruginosa regrowth after initial decline in bacterial burden. In HFIM, thrice-daily gentamicin dosing appeared to be superior to once-daily dosing for S. aureus, but they were similar for P. aeruginosa. Different killing profiles of gentamicin were demonstrated against S. aureus and P. aeruginosa. These results may guide optimal dosing strategies of gentamicin in S. aureus infections and warrant further investigations.Aminoglycosides (e.g., gentamicin) are often used clinically in combination with other antimicrobial agents such as betalactams or glycopeptides for the treatment of serious infections with gram-negative and gram-positive organisms. Previous studies have repeatedly demonstrated a concentration-dependent killing effect of aminoglycosides against gram-negative bacteria (5, 6, 14, 25); optimal patient outcomes and suppression of resistance emergence are associated with peak concentration (maximum concentration of drug in serum [C max ])/MIC ratio (3,13,15) or area under the concentration-time curve (AUC)/MIC ratio (16). There is also strong evidence suggesting that the first dose of an aminoglycoside is the most important in the course of therapy. Adaptive resistance is a phenomenon in which bacteria exhibit down-regulation of drug uptake upon frequent and repeated exposures to antimicrobial agents (26). Consequently, the first dose of aminoglycoside has the most bactericidal effect on the bacterial population. It has also been reported that attainment of a pharmacodynamic target (C max /MIC Ն 10) within 48 h of therapy is associate...
The US Food and Drug Administration (FDA), concerned about the incidence of acute liver failure due to acetaminophen (Tylenol) overdose, has mandated new labeling on acetaminophen packaging. It is also considering (but has not enacted) reducing the maximum daily dose from 4 g (possibly to 3,250 mg), banning acetaminophen-narcotic combination products, and changing the current maximum single dose of 1 g to prescription status, making 650 mg the highest recommended nonprescription dose. We review the epidemiology, toxicology, and management of acetaminophen overdose and steps the FDA and physicians can take to prevent it.
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