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Background: Sulbactam dosing for Acinetobacter baumannii infections has not been standardized due to limited available pharmacokinetics/pharmacodynamics (PK/PD) data. Herein, we report a comprehensive PK/PD analysis of ampicillin-sulbactam against A. baumannii pneumonia., Methods: Twenty-one A. baumannii clinical isolates were tested in the neutropenic murine pneumonia model. For dose-ranging studies, groups of mice were administered escalating doses of ampicillin-sulbactam. Changes in log10cfu/lungs relative to 0 h were assessed. Dose-fractionation studies were performed. Estimates of the percentage of of time during which the unbound plasma sulbactam concentrations exceeded the MIC (%fT > MIC) required for different efficacy endpoints were calculated. The probabilities of target attainment (PTA) for the 1-log kill plasma targets were estimated following clinically utilized sulbactam regimens., Results: Dose-fractionation studies demonstrated time-dependent kill. Isolates resistant to both sulbactam and meropenem required three times the exposures to achieve 1-log kill; median [IQR] %fT > MIC of 60.37% [51.6-66.8] compared with other phenotypes (21.17 [16.0-32.9] %fT > MIC). Sulbactam standard dose (1 g q6h, 0.5 h infusion) provided >90% PTA up to MIC of 4 mg/L. Sulbactam 3 g q8h, 4 h inf provided greater PTA for isolates with sulbactam-intermediate susceptibility (8 mg/L, 100% versus 86% following the standard dose). Despite the higher exposure following 3 g q8h, 4 h inf, PTA was ≤57% among sulbactam-resistant/meropenem-resistant isolates., Conclusion: Sulbactam standard dose is a valuable regimen across sulbactam-susceptible isolates while the high-dose extended-infusion provides additional benefit against sulbactam-intermediate isolates. Given that most of the sulbactam-resistant A. baumannii isolates are meropenem-resistant, high-dose prolonged-infusion regimens are not expected to be effective as monotherapy against infections due to these isolates., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO., Methods: Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen., Results: Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ± standard deviation parameters were: CL0, 15.21 ± 6.52 L/h; Vc, 10.13 ± 2.26 L; K12, 2.45 ± 1.16 h-1 and K21, 1.76 ± 0.49 h-1 for imipenem, and 6.95 ± 1.34 L/h, 9.81 ± 2.69 L, 2.43 ± 1.13 h-1 and 1.52 ± 0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L., Conclusions: Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Multi-drug resistance among Pseudomonas aeruginosa in hospitals, and particularly intensive care units, has achieved alarming rates. Some combination antimicrobial therapies have demonstrated promising synergistic effects and an ability to overcome resistance without increasing drug-related toxicities. Nevertheless, rapid and feasible methods to identify synergy have not been routinely implemented in clinical microbiology laboratories. Synergistic activity of meropenem plus tobramycin or levofloxacin against clinical P. aeruginosa isolates (N=21) was assessed by two different methods using gradient diffusion strips (GDSs). A 90° angle was created at the intersection of the minimum inhibitory concentration (MIC) of each drug by the standard method, and by a novel method, the cross was placed at clinically relevant steady-state concentrations (C ss ) based on recommended dosing regimens. Fractional inhibitory concentration indexes were determined to describe antibiotic interactions. Time-kill analyses were performed over 24 h in duplicate for instances of discordance between the standard cross method and the novel method. Synergy between meropenem and tobramycin by the novel method was observed in one (4.8%) isolate and between meropenem and levofloxacin in two (9.5%) isolates. Agreement with the standard method was 86-100% for meropenem plus tobramycin and meropenem plus levofloxacin combinations, respectively. Time-kill studies resulted in agreement with GDSs crossed at C ss in two of three instances of discordance between GDS methods. This novel method of synergy testing that involves crossing GDSs at steady-state concentrations may be a rapid and feasible tool for routine practice. Further comparisons of this novel procedure with time-kill methods are needed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We describe the levels of agreement between broth microdilution, Etest, Vitek 2, Sensititre, and MicroScan methods to accurately define the meropenem MIC and categorical interpretation of susceptibility against carbapenemase-producing Klebsiella pneumoniae (KPC). A total of 46 clinical K. pneumoniae isolates with KPC genotypes, all modified Hodge test and bla(KPC) positive, collected from two hospitals in NY were included. Results obtained by each method were compared with those from broth microdilution (the reference method), and agreement was assessed based on MICs and Clinical Laboratory Standards Institute (CLSI) interpretative criteria using 2010 susceptibility breakpoints. Based on broth microdilution, 0%, 2.2%, and 97.8% of the KPC isolates were classified as susceptible, intermediate, and resistant to meropenem, respectively. Results from MicroScan demonstrated the most agreement with those from broth microdilution, with 95.6% agreement based on the MIC and 2.2% classified as minor errors, and no major or very major errors. Etest demonstrated 82.6% agreement with broth microdilution MICs, a very major error rate of 2.2%, and a minor error rate of 2.2%. Vitek 2 MIC agreement was 30.4%, with a 23.9% very major error rate and a 39.1% minor error rate. Sensititre demonstrated MIC agreement for 26.1% of isolates, with a 3% very major error rate and a 26.1% minor error rate. Application of FDA breakpoints had little effect on minor error rates but increased very major error rates to 58.7% for Vitek 2 and Sensititre. Meropenem MIC results and categorical interpretations for carbapenemase-producing K. pneumoniae differ by methodology. Confirmation of testing results is encouraged when an accurate MIC is required for antibiotic dosing optimization.

Background: Resistance among gram-negative bacteria is increasing within the US., Objective: To determine pharmacodynamic target attainment rates for 10 antimicrobials against selected gram-negative bacilli and compare these results with previous Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram (OPTAMA) assessments., Methods: A 5000-patient Monte Carlo simulation using data from population pharmacokinetic studies was employed to estimate the pharmacokinetic profiles for standard and/or prolonged infusion (PI) regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, ertapenem, imipenem, levofloxacin, meropenem, piperacillin-tazobactam, and tigecycline. Minimum inhibitory concentration data were obtained from intensive care units of 15 US hospitals participating in the 2006 MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) study for 640 Escherichia coli, 618 Klebsiella spp., and 606 Pseudomonas aeruginosa isolates. Cumulative fraction of response (CFR) was calculated using pharmacodynamic targets for each antibiotic and compared with results from the 2002 and 2004 OPTAMA studies., Results: Against E. coli, CFRs greater than 92% were maintained for all regimens except the fluoroquinolones (CFR range 69.4-72%), which showed a 7% decrease compared with 2004. The presence of Klebsiella spp. producing KPC-type carbapenemases with associated multidrug resistance resulted in a 7% or greater drop in CFR of standard regimens relative to 2004. Despite these resistant phenotypes, high-dose PI regimens (2 g every 8 hours as 3-hour PI) of cefepime and meropenem achieved CFRs of 97% and 95.8%, respectively. Excluding 3 KPC-harboring hospitals resulted in CFR increases to greater than 98% for carbapenems and cefepime and greater than 88% for all other agents tested, except tigecycline. Against P. aeruginosa, the fluoroquinolones had the lowest CFR (55.8-63.9%), followed by imipenem (74.6-80.4%). The most predictable activity was seen with cefepime 2 g every 12 hours or higher (>90%), ceftazidime 2 g every 8 hours (97.9%), and meropenem 1-2 g every 8 hours (86.7-92.6%). Use of PI for piperacillin-tazobactam and meropenem increased CFRs by 6% and 4%, respectively, over standard infusions., Conclusions: Relative to previous years, an increase in resistance was noted among gram-negative bacilli to common antibiotics, resulting in disproportionate decreases in pharmacodynamic target attainment. The use of PI for beta-lactams may help to overcome these decreases.

Although pharmacodynamic (PD) modeling is now being considered for decision support for susceptibility breakpoint determination against Gram-negative bacteria, these PD-derived breakpoints should be verified using a clinically applicable population of organisms. In this analysis, a 5000-patient Monte Carlo simulation was used to determine PD breakpoints, the highest 2-fold MIC in which the probability of bactericidal target attainment (PTA) remained > or = 90%. Percent susceptibilities for 639 Pseudomonas aeruginosa, 103 Acinetobacter baumannii, 705 Escherichia coli, and 418 Klebsiella spp. collected during the 2004 Meropenem Yearly Susceptibility Test Information Collection surveillance study were then defined according to the PD-derived breakpoint (%S(PD)) and compared with the current Clinical Laboratory Standards Institute (CLSI)-defined breakpoints (%S(CLSI)). %S(PD) and %S(CLSI) were compared with the bactericidal PTA for each pathogen population to determine the degree of agreement. Resulting PD breakpoints were drug and dose dependent; moreover, values were commonly 2 to 4 MIC dilutions lower than CLSI breakpoints. Overall, %S(PD) more closely agreed with the PTA for the tested beta-lactam and fluoroquinolone dosing regimens. In contrast, %S(CLSI) overestimated PTA for many dosing regimens, especially against Pseudomonas: piperacillin/tazobactam 4.5 g qid (+9.7%), ciprofloxacin 0.4 g bid (+13.7%) and 0.4 g tid (+9.3%), and levofloxacin 0.5 g every 24 h (+22.4%) and 0.75 g every 24 h (+9.9%). Differences were most pronounced against the nonfermenting Gram-negative bacteria and were not observed among the Enterobacteriaceae. As a result, a new method of breakpoint classification is proposed, which is dosing regimen and pathogen specific, and is designed to denote isolates as susceptible only if target bactericidal exposures are achievable with the dosing regimen selected.

Antibiotic surveillance studies lack consideration of pharmacodynamics and provide little information about optimal dosing. By using minimum inhibitory concentration (MIC) data derived from a global surveillance study and Monte Carlo simulation, the Optimizing Pharmacodynamic Target Attainment using the MYSTIC Antibiogram (OPTAMA) Program was established to impart greater understanding of the ability to attain pharmacodynamic exposure for specific dosing regimens and their relationship with percent susceptibility. Early OPTAMA studies focused on determining the cumulative fraction of response (CFR) for various antibiotics against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa regionally in Europe and the Americas. Later reports considered the prevalence of specific bacteria causing infections to estimate the CFR for empiric therapy of pneumonia, bloodstream, complicated skin/skin structure, and intra-abdominal infections. Collectively, the approach of the OPTAMA Program provides a novel tool that complements susceptibility data to help in the selection of appropriate empirical antibiotic therapy at the national, regional, and institutional level.

Background: Trimethoprim/sulfamethoxazole has historically been the treatment of choice for infection caused by Stenotrophomonas maltophilia. This study sought to define the pharmacodynamic indices and magnitude of exposure required for stasis and 1 log10 cfu reductions.Methods: Pharmacodynamic studies were conducted using the in vitro chemostat model over 24 h against three trimethoprim/sulfamethoxazole-susceptible S. maltophilia isolates with MICs from 0.25/4.75 to 2/38 mg/L. The primary endpoint was the change in cfu at 24 h relative to baseline. The log ratio of the area under the cfu curve (LR AUcfu) was a secondary endpoint. Trimethoprim and sulfamethoxazole exposures required for stasis and 1 log10 cfu/mL reduction were determined.Results: Trimethoprim/sulfamethoxazole exposures achieved stasis and 1 log10 cfu/mL reductions in 9/16 (56%) and 2/16 (13%) of experiments. Both the fAUC/MIC and fCmax/MIC were identified as equivalent pharmacodynamic drivers, with stasis achieved at an fAUC/MIC of 67.4 and 30.0 for trimethoprim and sulfamethoxazole, respectively. Clinically meaningful exposures required to achieve 1 log10 cfu/mL reductions were not quantifiable. The LR AUcfu analysis supported the lack of overall bacterial burden reduction against S. maltophilia.Conclusions: In this in vitro chemostat model, trimethoprim/sulfamethoxazole monotherapy, even at higher doses, achieved limited activity against susceptible S. maltophilia. [ABSTRACT FROM AUTHOR]

Background: Minocycline displays high susceptibility rates against Stenotrophomonas maltophilia at the current breakpoint of 4 mg/L. However, no pharmacodynamic data are available to guide dosing or justify this breakpoint.Methods: The murine neutropenic thigh infection model was utilized to determine minocycline pharmacodynamics against four S. maltophilia through dose ranging and fractionation studies. The efficacy of a human simulated regimen (HSR) of 100 mg IV q12h was tested against 17 isolates with a range of minocycline MICs. Monte Carlo simulation was employed to assess the PTA for achieving defined pharmacodynamic thresholds in critically ill patients.Results: The pharmacodynamic index best correlated with reductions in cfu was fAUC/MIC (R2 = 0.376). The composite fAUC/MIC required for stasis and 1 log10 reduction was 9.6 and 23.6, respectively. The minocycline 100 mg q12h HSR yielded no bacterial reduction at MICs ≥1 mg/L and mixed efficacy at 0.5 mg/L. Monte Carlo simulation of minocycline 200 mg IV q12h achieved the 1 log10 kill threshold with PTAs of 93% and 51.7% at MICs of 0.5 and 1 mg/L, respectively, but 0.1% at the current breakpoint of 4 mg/L.Conclusions: Clinically utilized minocycline dosing regimens fail to reach exposures predicted to be efficacious against S. maltophilia in critically ill patients at the current susceptibility breakpoint. [ABSTRACT FROM AUTHOR]

Background: Levofloxacin displays in vitro activity against Stenotrophomonas maltophilia (STM); however, current susceptibility breakpoints are supported by limited data. We employed the murine neutropenic thigh infection model to assess levofloxacin pharmacodynamics against STM.Methods: Twenty-six clinical STM were studied using the neutropenic murine thigh infection model. Human simulated regimens (HSR) of levofloxacin 750 mg q24h were administered over 24 h. Efficacy was measured as the change in log10 cfu/thigh at 24 h compared with 0 h. Composite cfu data were fitted to an Emax model to determine the fAUC/MIC needed for stasis and 1 log10 reduction at 24 h. Monte Carlo simulation was performed to determine PTA.Results: Levofloxacin MICs ranged from 0.5-8 mg/L. Mean bacterial burden at 0 h was 6.21 ± 0.20 log10 cfu/thigh. In the 24 h controls, bacterial growth was 1.64 ± 0.66 log10 cfu/thigh. In isolates with levofloxacin MICs ≤1, 2 and ≥4 mg/L, changes in bacterial density following levofloxacin HSR were -1.66 ± 0.89, 0.13 ± 0.97 and 1.54 ± 0.43 log10 cfu/thigh, respectively. The Emax model demonstrated strong agreement between fAUC/MIC and change in bacterial density (R2 = 0.82). The fAUC/MIC exposure needed for stasis and 1 log10 reduction was 39.9 and 54.9, respectively. PTAs for the 1 log10 reduction threshold were 95.8, 72.2, and 26.6% at MICs of 0.5, 1 and 2 mg/L, respectively.Conclusions: These are the first data to describe fAUC/MIC thresholds predictive of cfu reductions for levofloxacin against STM. Due to poor in vivo efficacy and PTA at MICs ≥2 mg/L, reassessment of the current susceptibility breakpoint is warranted. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) opens the door to personalized medicine, yet it is infrequently applied to β‐lactam antibiotics, one of the most commonly prescribed drug classes in the hospital setting. As we continue to understand more about β‐lactam pharmacodynamics (PD) and wide inter‐ and intra‐patient variability in pharmacokinetics (PK), the utility of TDM has become increasingly apparent. For β‐lactams, the time that free concentrations remain above the minimum inhibitory concentration (MIC) as a function of the dosing interval (%fT>MIC) has been shown to best predict antibacterial effect. Many studies have shown that β‐lactam %fT>MIC exposures are often suboptimal across a wide variety of disease states and clinical settings. A limitation to implementing this practice is the general lack of understanding on how to best operationalize this intervention and interpret the results. The instrumentation and expertise needed to quantify β‐lactams for TDM is rarely available locally, but certain laboratories advertise these services and perform them regularly. Familiarity with the modalities and nuances of antimicrobial susceptibility testing is crucial to establishing β‐lactam concentration targets that meet the relevant exposure thresholds. Evaluation of these concentrations is best accomplished using population PK software and Bayesian modeling, for which a multitude of programs are available. While TDM of β‐lactams has shown an ability to increase the rate of target attainment, there is currently limited evidence to suggest that it leads to improved clinical outcomes. Although consensus guidelines for β‐lactam TDM do not exist in the United States, guidance would help to promote this important practice and better standardize the approach across institutions. Herein, we discuss the basis for β‐lactam TDM, review supporting evidence, and provide guidance for implementation in specific patient populations. [ABSTRACT FROM AUTHOR]

Daptomycin is one of the few treatment options for infections caused by enterococci that are resistant to ampicillin and vancomycin, such as vancomycin-resistant Enterococcus faecium. The emergence and clinical significance of daptomycin-resistant enterococci and evolving microbiologic, pharmacokinetic-pharmacodynamic, and clinical data indicated that the pre-2019 Clinical and Laboratory Standards Institute (CLSI) susceptible-only breakpoint of ≤4 μg/mL for daptomycin and enterococci was no longer appropriate. After analyzing data that are outlined in this article, the CLSI Subcommittee on Antimicrobial Susceptibility Testing established new breakpoints for daptomycin and enterococci. For E. faecium , a susceptible dose-dependent (SDD) breakpoint of ≤4 μg/mL was established based on an increased dosage of 8–12 mg/kg/day (≥8 μg/mL-resistant). CLSI suggests infectious diseases consultation to guide daptomycin use for the SDD category. For Enterococcus faecalis and other enterococcal species, revised breakpoints of ≤2 μg/mL-susceptible, 4 μg/mL-intermediate, and ≥8 μg/mL-resistant were established based on a standard dosage of 6 mg/kg/day. [ABSTRACT FROM AUTHOR]

Monte Carlo simulations (MCSs) are used in antibiotic development to predict the probability of pharmacodynamic target attainment (PTA) for a dosing regimen. However, for β‐lactam/β‐lactamase inhibitor combinations (BL‐BLICs), methods for linking simulated concentration profiles of the β‐lactam (BL) and β‐lactamase inhibitor (BLI) components are rarely described. Using a previously defined pharmacokinetic model of ceftazidime/avibactam from critically ill patients, we performed four 5000‐patient MCSs using different methods of increasing complexity to couple the BL and BLI components and compared PTA for ceftazidime and avibactam targets of >70% fT>MIC and >70% fT>1 mg/L, respectively, at MICs from 1 to 128 mg/L. Method A ignored all covariates and correlations, whereas methods B, C, and D enhanced associations by adding (B) pharmacokinetic parameter correlation within each drug only; (C) pharmacokinetic parameter correlation within each drug and creatinine clearance (CRCL); and (D) pharmacokinetic parameter correlation within each drug, CRCL, and pharmacokinetic parameter correlation between drugs. Method D produced a simulated patient population that best recapitulated the observed relationships between pharmacokinetic parameters in actual patients. Ceftazidime/avibactam PTA at MIC 8 mg/L (the susceptibility break point) and 16 mg/L ranged from 92.4% to 98.3% and 80.2% to 88.4%, respectively. PTA was lowest with method A, whereas PTA estimates were similar for all other methods. Compared with ignoring all pharmacokinetic parameter associations, the inclusion of covariate relationships and parameter correlation between both components of ceftazidime/avibactam leads to fewer patients with discordant pharmacokinetic parameters and results in higher PTA. Consideration of these methodologies should guide future MCS analyses for BL‐BLIC. [ABSTRACT FROM AUTHOR]

Background Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. Methods Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a β-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. Results Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P =.006), which remained significant after adjusting for infection source and immunosuppression (P =.026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%–5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%–97.9% when the MIC was 1 mg/L. Conclusions For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients.Methods: Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid. All data were analysed simultaneously by a population approach also considering methodological aspects of microdialysis. The impact of covariates on the attainment of the pharmacokinetic/pharmacodynamic targets, AUC/MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration) and fT>MIC = 99 % (time that unbound concentrations exceed the MIC), was assessed by deterministic and Monte Carlo simulations.Results: A two-compartment pharmacokinetic model with nonlinear elimination and tissue distribution factors accounting for differences between plasma and ISF concentrations adequately predicted all measurements. Clearance (CL) was highest in septic patients (11.2 L/h vs. CLHealthy/CLCystic fibrosis/CLDiabetic = 7.67/6.87/6.35 L/h). Penetration into subcutaneous adipose ISF was lowest in diabetic patients (-34.9 % compared with healthy volunteers). Creatinine clearance and total body weight further impacted linezolid exposure. To achieve timely efficacious therapy, front-loaded dosing and continuous infusion seemed beneficial in septic patients.Conclusions: Our analysis suggests that after standard linezolid doses, particularly patients with sepsis and conserved renal function are at risk of not attaining pharmacokinetic/pharmacodynamic targets and would benefit from initial dose intensification. [ABSTRACT FROM AUTHOR]

Objectives: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children.Methods: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259.Results: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ± 0.23 L/h/kg and 0.30 ± 0.17 L/kg, respectively. Half-life was 1.11 ± 0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home.Conclusions: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule. [ABSTRACT FROM AUTHOR]

Abstract: Doripenem is not available on many automated susceptibility testing panels. We evaluated the surrogate predictive value (SPV) of meropenem and imipenem in predicting doripenem susceptibility using the different breakpoint definitions available globally. MIC data for 736 Pseudomonas aeruginosa were extracted, and categorical interpretations were performed using Clinical and Laboratory Standards Institute (CLSI) proposed 2012, European Committee on Antimicrobial Susceptibility Testing (EUCAST), and Food and Drug Administration (FDA) breakpoints. Regardless of the breakpoint applied, very major and major errors were observed in only 0.1–0.8% and 0.1–4.5% of isolates, respectively. Meropenem''s SPV was 98.6% for CLSI 2012 breakpoints, 94.0% for EUCAST, and 95.0% for FDA. Imipenem''s SPV was 98.6%, 90.9%, and 97.2%, respectively. These data indicate that meropenem and imipenem would be reliable surrogate markers of doripenem susceptibility when using CLSI 2012 and FDA breakpoints. Meropenem would be recommended over imipenem for EUCAST breakpoints. However, meropenem and imipenem nonsusceptible isolates should be directly tested against doripenem since the latter antibiotic may still retain susceptibility against these isolates. [Copyright &y& Elsevier]