The gut microbiome is now considered an organ unto itself and plays an important role in health maintenance and recovery from critical illness. The commensal organisms responsible for the framework of the gut microbiome are valuable in protection against disease and various physiological tasks. Critical illness and the associated interventions have a detrimental impact on the microbiome. While antimicrobials are one of the fundamental and often life-saving modalities in septic patients, they can also pave the way for subsequent harm because of the resulting damage to the gut microbiome. Contributing to many of the non-specific signs and symptoms of sepsis, the balance between the overuse of antimicrobials and the clinical need in these situations is often difficult to delineate. Given the potency of antimicrobials utilized to treat septic patients, the effects on the gut microbiome are often rapid and long-lasting, in which case full recovery may never be observed. The overgrowth of opportunistic pathogens is of significant concern as they can lead to infections that become increasingly difficult to treat. Continued research to understand the disturbances within the gut microbiome of critically ill patients and their outcomes is essential to help develop future therapies to circumvent damage to, or restore, the microbiome. In this review, we discuss the impact of the antimicrobials often used for the treatment of sepsis on the gut microbiota.

The pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m 2 receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (؎standard deviation) age, height, and weight were 42.2 ؎ 12.2 years, 64.8 ؎ 3.5 in, and 109.5 ؎ 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ؎ 1.9 liters/h), which could be inhibited to 85.5% ؎ 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ؎ 9.6 liters), and the intercompartment transfer constants (K 12 and K 21 ) of 8.04 ؎ 6.22 and 7.99 ؎ 5.46 h ؊1 , respectively. The areas under the curve for the 12-h dosing interval (AUC) were similar between moderately obese and morbidly obese groups: 130.3 ؎ 60.1 versus 109.2 ؎ 25.5 g · h/ml (P ‫؍‬ 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (r 2 ‫؍‬ 0.524), adjusted body weight (r 2 ‫؍‬ 0.587), lean body weight (r 2 ‫؍‬ 0.495), and ideal body weight (r 2 ‫؍‬ 0.398), but not with BMI (r 2 ‫؍‬ 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUC values similar to those seen in nonobese participants.

Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against S. aureus in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen S. aureus (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 g/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum fT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log 10 kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log 10 CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the fT>MICs required for stasis and a 1-log 10 kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum fT>MIC targets required in this lung infection model were similar to those observed with ceftaroline against S. aureus in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.T he prevalence of methicillin-resistant Staphylococcus aureus (MRSA) continues to rise and poses a significant health care burden (10,14). MRSA is one of the many potential pathogens that contribute to community-and hospital-acquired pneumonias (CAP and HAP, respectively). A survey among 59 U.S. hospitals between January 2002 and January 2004 identified MRSA as the pathogen responsible for 8.9% of CAP and 22.9% of HAP cases (10). Frequently, pneumonias caused by MRSA, especially strains that produce the Panton-Valentine leukocidin (PVL) toxin, can result in severe cases of necrotizing pneumonia, which is difficult to treat (14).Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, has a broad spectrum of in vitro activity against common Gram-negative and Gram-positive pathogens, including Streptococcus pneumoniae and MRSA (5, 15). Ceftaroline displays high affinity for penicillin binding protein PBP2a, which plays an important role in methicillin resistance in MRSA strains (12, 15). Ceftaroline fosamil is currently approved in the United States for the treatment of acute bacterial skin and skin structure infections and non-MRSA community-acquired bacterial pneumonia at a dose of 600 mg intravenously (i.v) every 12 h (5).The objective of this study was to evaluate the dose-response relationship of ceftaroline in the neutropeni...

Background Bloodstream infections (BSI) are a leading cause of morbidity and mortality in hospitalized patients. The IOAS (Improving Outcomes and Antimicrobial Stewardship) study seeks to evaluate the impact of the Accelerate PhenoTest® BC Kit (AXDX) on antimicrobial use and clinical outcomes in BSIs. Methods This multicenter, quasi-experimental study compared clinical and antimicrobial stewardship metrics, prior to and after implementation of AXDX testing, to evaluate the impact this technology has on patients with BSI. Laboratory and clinical data from hospitalized patients with BSI (excluding contaminants) were compared between two arms, one that underwent testing on AXDX (post-AXDX) and one that underwent alternative organism identification and susceptibility testing (pre-AXDX). The primary outcomes were time to optimal therapy (TTOT) within 96 hours of blood culture positivity and 30-day mortality. Results A total of 854 patients with BSI (435 pre-AXDX, 419 post-AXDX) were included. Median TTOT was 17.2 hours shorter in the post-AXDX arm (23.7 hours) compared to the pre-AXDX arm (40.9 hours; P<0.0001). Compared with pre-AXDX, median time to first antimicrobial modification (24.2 versus 13.9 hours; P<0.0001) and first antimicrobial de-escalation (36.0 versus 27.2 hours; P=0.0004) were shorter in the post-AXDX arm. Mortality (8.7% pre-AXDX versus 6.0% post-AXDX), length of stay (7.0 pre-AXDX versus 6.5 days post-AXDX), and adverse drug events were not significantly different between arms. Length of stay was shorter in the post-AXDX arm (5.4 versus 6.4 days; P=0.03) among patients with Gram-negative bacteremia. Conclusions For BSIs, use of AXDX was associated with significant decreases in TTOT, first antimicrobial modification, and time to antimicrobial de-escalation.

Doripenem pharmacokinetics were similar between ICU and non-ICU patients in this population. Optimal dosing regimens should be selected based on underlying renal function and suspected MIC of the infecting pathogen.