Clinical efficacy of cefiderocol-based regimens in patients with carbapenem-resistant Acinetobacter baumannii infections: A systematic review with meta-analysis.

OBJECTIVES: To perform a systematic review with meta-analysis to assess the clinical efficacy of cefiderocol-based regimens for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) infections. METHODS: Two authors independently searched PubMed-MEDLINE, Scopus, and Cochrane databases, from inception to 02 July 2023, for randomised controlled trials (RCTs) or observational studies comparing clinical efficacy of cefiderocol-based vs. non-cefiderocol-based regimens in patients with CRAB infections. Data were extracted by the two authors independently, and the quality of included studies was independently assessed using ROB 2.0 or ROBINS-I tools. Primary outcome was mortality rate. Meta-analysis was performed by pooling odds ratios (ORs) retrieved from studies providing adjustment for confounders using a random-effects model with the inverse variance method. Multiple subgroups and sensitivity analyses were conducted to investigate the source of heterogeneity. RESULTS: A total of 530 articles were screened, and 6 studies (1 RCT and 5 observational; N=561; 247 cefiderocol-based vs. 314 non-cefiderocol-based regimens) were included. Cefiderocol did not significantly reduce in-hospital mortality compared to alternative therapies (predominantly colistin-based), but the confidence intervals around the effect estimate included clinically important benefit (N=5; OR 0.64; 95%CI 0.40-1.04; I2=57.5%). When only observational studies providing adjustment for confounders were considered, a lower risk of mortality was found in patients treated with cefiderocol-based regimens (N=4; OR 0.53; 95%CI 0.39-0.71; I2=0.0%). CONCLUSIONS: Cefiderocol-based regimens were associated with a significantly lower risk of mortality in patients with CRAB infections in observational studies providing proper adjustment for confounders.

Therapeutic drug monitoring of ceftazidime/avibactam: why one leg is not enough to run.

BACKGROUND: Therapeutic drug monitoring (TDM) is becoming an increasingly recommended approach for assessing optimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ceftazidime/avibactam. Some authors hypothesized that the PK/PD target attainment of ceftazidime/avibactam could be assessed by means of the TDM of solely ceftazidime, since avibactam concentrations might be extrapolated based on the fixed 4:1 ceftazidime-to-avibactam ratio present in the vial. The reliability of this hypothesis could be called into question if a wide interindividual variability in the ceftazidime-to-avibactam ratio would exist among patients. This study aimed to assess the distribution of the individual ceftazidime-to-avibactam ratios in relation to renal function in a cohort of adult patients who were treated with continuous infusion ceftazidime/avibactam and underwent TDM of both ceftazidime and avibactam. METHODS: Individual ceftazidime-to-avibactam ratio was calculated at each TDM assessment. Receiving operating characteristics (ROC) curve analysis was performed for testing the potential impact of renal function on ceftazidime-to-avibactam ratio variability. RESULTS: A total of 188 TDM assessments were collected from 107 patients. The ceftazidime-to-avibactam ratios ranged from 1.29:1 to 13.46:1. Seventy-seven out of 188 ceftazidime-to-avibactam ratios (41.0%) were >5:1, and 36 (19.1%) were >6:1. Patients without renal dysfunction had significantly higher proportions of ceftazidime-to-avibactam ratio >5:1 (59.3% versus 23.8%; P < 0.001) and >6:1 (32.1% versus 6.3%; P < 0.001) compared with those with mild-to-severe renal dysfunction. CONCLUSIONS: The findings may strengthen the contention that for properly assessing the PK/PD target attainment of ceftazidime/avibactam, both ceftazidime and avibactam concentrations should be measured, given the unpredictability of the ceftazidime-to-avibactam ratio occurring among patients.

Could an optimized joint pharmacokinetic/pharmacodynamic target attainment of continuous infusion ceftazidime-avibactam be a way to avoid the need for combo therapy in the targeted treatment of deep-seated DTR Gram-negative infections?

The objective of this study was to assess the relationship between joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome of documented difficult-to-treat resistant (DTR) Gram-negative infections. A 2-year retrospective cohort study was performed in patients receiving CI ceftazidime-avibactam mono- or combo therapy for documented DTR Gram-negative infections and undergoing therapeutic drug monitoring of both ceftazidime and avibactam. The free fractions of steady-state concentrations (fCss) of ceftazidime and avibactam were calculated. The joint PK/PD target was considered optimal when both the fCss/MIC ratio for ceftazidime ≥4 (equivalent to 100% fT>4xMIC) and the fCss/CT ratio for avibactam >1 (equivalent to 100% fT >CT of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two and suboptimal if neither of the two was achieved). Multivariate logistic regression analysis was applied for testing potential variables associated with microbiological failure. Fifty-eight patients were treated with CI ceftazidime-avibactam mono- (36) or combo therapy (22) for documented DTR Gram-negative infections [74.2% for primary or secondary bloodstream infections (BSIs)]. Combo therapy was administered more frequently to intensive care unit (ICU) patients (P = 0.023) or for pneumonia (P = 0.001) and less frequently for intra-abdominal infections and BSIs (P = 0.04). Microbiological failure occurred in five cases (8.6%, three in mono- and two in combo therapy). In the multivariate analysis, the suboptimal/quasi-optimal joint PK/PD target emerged as the only independent predictor of microbiological failure (odds ratio [OR] 11.11; 95% confidence interval [CI] 1.31-93.98; P = 0.023), whereas monotherapy was not (P = 0.99). Optimized joint PK/PD target attainment of CI ceftazidime-avibactam monotherapy could represent a way forward for allowing microbiological eradication of DTR Gram-negative infections and could render unnecessary combo therapy.

Invasive Candida infection: epidemiology, clinical and therapeutic aspects of an evolving disease and the role of rezafungin.

INTRODUCTION: Invasive Candida Infections (ICIs) have undergone a series of significant epidemiological, pathophysiological, and clinical changes during the last decades, with a shift toward non-albicans species, an increase in the rate of exogenous infections and clinical manifestations ranging from candidemia to an array of highly invasive and life-threatening clinical syndromes. The long-acting echinocandin rezafungin exhibits potent in-vitro activity against most wild-type and azole-resistant Candida spp. including C.auris. AREAS COVERED: The following topics regarding candidemia only and ICIs were reviewed and addressed: i) pathogenesis; ii) epidemiology and temporal evolution of Candida species; iii) clinical approach; iv) potential role of the novel long-acting rezafungin in the treatment of ICIs. EXPERT OPINION: Authors' expert opinion focused on considering the potential role of rezafungin in the evolving context of ICIs. Rezafungin, which combines a potent in-vitro activity against Candida species, including azole-resistant strains and C.auris, with a low likelihood of drug-drug interactions and a good safety profile, may revolutionize the treatment of candidemia/ICI. Indeed, it may shorten the length of hospital stays when clinical conditions allow and extend outpatient access to treatment of invasive candidiasis, especially when prolonged treatment duration is expected.

A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam for treating DTR gram-negative infections in a case series of critically ill patients undergoing continuous veno-venous haemodiafiltration (CVVHDF).

PURPOSE: To explore pharmacokinetic/pharmacodynamic (PK/PD) profile of continuous infusion (CI) ceftazidime-avibactam for treating difficult-to-treat resistant Gram-negative (DTR-GN) infections in critical patients undergoing continuous venovenous haemodiafiltration (CVVHDF). MATERIALS AND METHODS: Patients treated with CI ceftazidime-avibactam for DTR-GN infections during CVVHDF were retrospectively assessed. Ceftazidime and avibactam concentrations were measured at steady-state and the free fraction (fCss) was calculated. Total clearance (CLtot) of both agents were calculated and the impact of CVVHDF intensity was assessed by linear regression. The joint PK/PD target of ceftazidime-avibactam was defined as optimal when both fCss/MIC≥4 for ceftazidime and fCss/CT > 1 for avibactam were achieved. Relationship between ceftazidime-avibactam PK/PD targets and microbiological outcome was assessed. RESULTS: Eight patients with DTR-GN infections were retrieved. Median fCss were 84.5 (73.7-87.7 mg/L) for ceftazidime and 24.8 mg/L (20.7-25.8 mg/L) for avibactam. Median CLtot was 2.39 L/h (2.05-2.96 L/h) for ceftazidime and 2.56 L/h (2.12-2.98 L/h) for avibactam. Median CVVHDF dose was 38.6 mL/h/kg (35.9-40.0 mL/kg/h). CLtot were linearly correlated with CVVHDF dose (r = 0.53;p = 0.03, and r = 0.64;p = 0.006, respectively). The joint PK/PD targets were optimal granting microbiological eradication in all the assessable cases. CONCLUSION: CI administration of 1.25-2.5 g q8h ceftazidime-avibactam may allow prompt attainment and maintenance of optimal joint PK/PD targets during high-intensity CVVHDF.

A novel method to evaluate ceftazidime/avibactam therapy in patients with carbapenemase-producing Enterobactericeae (CPE) bloodstream infections.

INTRODUCTION: This study reports experience managing eight patients with bloodstream infections treated with a continuous infusion of ceftazidime-avibactam. METHODS: Patients who were treated for documented CPE BSIs susceptible to CAZ-AVI and who underwent real-time therapeutic drug monitoring were retrospectively assessed. Ceftazidime MICs were assessed in presence of increasing concentrations of avibactam by the broth microdilution method. An inhibitory sigmoid Emax model was used to characterize ceftazidime MIC reduction as a function of avibactam concentration, and the MICi was derived by conditioning the best-fit model using steady-state avibactam concentrations (Css). Ceftazidime fCss/MICi ratio was calculated for each patient and correlated to microbiological outcome. RESULTS: By adopting the innovative concept of effective MIC with an inhibitor (MICi), a trend towards higher microbiological failure and resistance development was found in patients with a lower ceftazidime fCss/MICi ratio (2/3 vs. 0/5). CONCLUSION: Assessment of changes in the ceftazidime MIC in relation to increasing avibactam concentration could represent a more robust pharmacokinetic/pharmacodynamic method for predicting microbiological failure given beta-lactam/beta-lactamase inhibitor combinations.

Colonization by ceftazidime/avibactam-resistant KPC-producing Klebsiella pneumoniae following therapy in critically ill patients.

OBJECTIVES: Ceftazidime-avibactam (CAZ-AVI)-based treatments have been associated with the emergence of resistance in KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates after antimicrobial exposure. Here, we evaluated the CAZ-AVI resistance development in KPC-Kp isolated from patients treated with CAZ-AVI-based therapy. METHODS: We enrolled adult patients treated with CAZ-AVI-based regimens between January 2020 and January 2021. Carbapenemase-producing isolates collected from clinical samples and rectal swabs were evaluated for CAZ-AVI resistance development after antimicrobial exposure. KPC-Kp developing CAZ-AVI resistance and parental susceptible strains were genomically characterized. Whole genome sequencing was performed by using the Illumina iSeq100 platform and genomes were analyzed for antimicrobial-resistance genes, plasmid and porins sequences. RESULTS: We enrolled 90 patients treated with CAZ-AVI-based therapy and 62.2% (56/90) of them were colonized by KPC-producers before CAZ-AVI-based treatment and 6.6% acquired colonization during therapy. Six (6.6%) patients developed infections because of resistant KPC-Kp after CAZ-AVI exposure and 3 (3.3%) of them developed CAZ-AVI resistance in the rectum. Development of resistance among KPC in the rectum occurred after 32 (IQR, 9-35) days of therapy and after 30 (IQR, 22-40) days in clinical specimens. Genetic analysis demonstrated that the development of CAZ-AVI resistance was associated with mutated blaKPC-3 (blaKPC-31, blaKPC-53, blaKPC-89, and blaKPC-130) and phylogenetic analysis demonstrated a close genomic relationship between KCP-Kp collected from rectum and clinical samples of the same patient. DISCUSSION: Antimicrobial exposure induce a higher incidence of CAZ-AVI resistance development in the blood and respiratory tract than in the rectum (6.7% vs. 3.3%) of CAZ-AVI-treated patients and genome analysis showed that resistance was associated with mutated blaKPC-3 variants.

Jumping into the future: overcoming pharmacokinetic/pharmacodynamic hurdles to optimize the treatment of severe difficult to treat-Gram-negative infections with novel beta-lactams.

INTRODUCTION: The choice of best therapeutic strategy for difficult-to-treat resistance (DTR) Gram-negative infections currently represents an unmet clinical need. AREAS COVERED: This review provides a critical reappraisal of real-world evidence supporting the role of pharmacokinetic/pharmacodynamic (PK/PD) optimization of novel beta-lactams in the management of DTR Gram-negative infections. The aim was to focus on prolonged and/or continuous infusion administration, penetration rates into deep-seated infections, and maximization of PK/PD targets in special renal patient populations. Retrieved findings were applied to the three most critical clinical scenarios of Gram-negative resistance phenotypes (i.e. carbapenem-resistant Enterobacterales; difficult-to-treat resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii). EXPERT OPINION: Several studies supported the role of PK/PD optimization of beta-lactams in the management of DTR Gram-negative infections for both maximizing clinical efficacy and preventing resistance emergence. Optimizing antimicrobial therapy with novel beta-lactams based on the so called 'antimicrobial therapy puzzle' PK/PD concepts may represent a definitive jump into the future toward a personalized patient management of DTR Gram negative infections. Establishing a dedicated and coordinated multidisciplinary team and implementing a real-time TDM-guided personalized antimicrobial exposure optimization of novel beta-lactams based on expert clinical pharmacological interpretation, could represent crucial cornerstones for the proper management of DTR Gram-negative infections.

An evidence-based multidisciplinary approach focused at creating algorithms for targeted therapy of infection-related ventilator associated complications (IVACs) caused by Enterobacterales in critically ill adult patients.

INTRODUCTION: Prompt implementation of appropriate targeted antibiotic therapy representsa valuable approach in improving clinical and ecological outcome in critically septic patients. Thismultidisciplinary opinion article aims to develop evidence-based algorithms for targeted antibiotictherapy of infection-related ventilator associated complications (IVACs) caused by Enterobacterales,which are among the most common pathogens associated with these conditions. AREAS COVERED: A multidisciplinary team of four experts had several rounds of assessment for developingalgorithms devoted to targeted antimicrobial therapy of IVACs caused by Enterobacterales.A literature search was performed on PubMed-MEDLINE (until March 2021) to provide evidence forsupporting therapeutic choices. Quality and strength of evidence was established according toa hierarchical scale of the study design. Six different algorithms with associated recommendations concerning therapeutic choice and dosing optimization were suggested according to the susceptibilitypattern of Enterobacterales: multi-susceptible, extended-spectrum beta-lactamase (ESBL)-producing,AmpC beta-lactamase-producing, Klebsiella pneumoniae carbapenemase (KPC)-producing, OXA-48-producing, and metallo-beta-lactamase (MBL)-producing Enterobacterales. EXPERT OPINION: The implementation of algorithms focused on prompt revision of antibiotic regimensguided by results of conventional and rapid diagnostic methodologies, appropriate place in therapy ofnovel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and PK/PD optimization of antibiotic dosing regimens is strongly suggested.

Usefulness of therapeutic drug monitoring in estimating the duration of dalbavancin optimal target attainment in staphylococcal osteoarticular infections: a proof-of-concept.

Dalbavancin is increasingly used for the treatment of staphylococcal osteoarticular infections (OIs). Some population pharmacokinetic studies suggest that a regimen of two 1500 mg doses 1 week apart could ensure effective treatment for several weeks. Here we aim to provide clinicians with a proof-of-concept of the potential role that therapeutic drug monitoring may have in giving real-time feedback of the estimated duration of optimal treatment of staphylococcal OIs with dalbavancin in each single patient.

Population pharmacokinetics of continuous infusion of piperacillin/tazobactam in very elderly hospitalized patients and considerations for target attainment against Enterobacterales and Pseudomonas aeruginosa.

Continuous infusion (CI) piperacillin/tazobactam is frequently used to treat infections in very elderly patients. This study aimed to conduct a population pharmacokinetic analysis of CI piperacillin/tazobactam, and to identify optimal dosages for safe and effective probability of target attainment (PTA) against Enterobacterales and Pseudomonas aeruginosa. Non-linear mixed-effects modelling was performed with Pmetrics. Monte Carlo simulations assessed the steady-state concentration (Css) of increasing piperacillin/tazobactam regimens (from 2.25 to 18 g daily by continuous infusion). Permissible doses were defined as those associated with <10% probability of Css >157.2 mg/L. PTA at the pharmacodynamic targets of free plasma steady-state concentration (fCss)/minimum inhibitory concentration (MIC) ≥1 and ≥4 and cumulative fraction of response (CFR) against EUCAST MIC distribution were also calculated. A total of 141 patients (median age 85 years) provided 217 plasma piperacillin Css. Most patients (55.2%) had hospital-acquired pneumonia and intra-abdominal infections. A one-compartment pharmacokinetic model with parallel linear and Michaelis-Menten elimination best described piperacillin data. Creatinine clearance (CLCR) was the covariate retained by the model. Pharmacokinetic estimates were 6.05 L/h for clearance and 3.39 mg/L for the Michaelis-Menten constant. Permissible doses were up to 4.5, 9, 11.25 and 13.5 g daily by continuous infusion for patients with CLCR of 0-19, 20-39, 40-59 and 60-79 mL/min/1.73 m2, respectively. At the clinical breakpoint of 8 mg/L, the permissible doses only achieved optimal PTA for fCss/MIC ≥1 in patients with CLCR 20-79 mL/min/1.73 m2. Optimal CFRs with the permissible doses were only attained against Escherichia coli and Proteus mirabilis. Permissible dosages and CLCR should be considered for prescribing CI piperacillin/tazobactam in very elderly patients.

Real-time TDM-based optimization of continuous-infusion meropenem for improving treatment outcome of febrile neutropenia in oncohaematological patients: results from a prospective, monocentric, interventional study.

OBJECTIVES: To assess the role that real-time therapeutic drug monitoring (TDM)-guided optimization of continuous-infusion (CI) meropenem may have in maximizing empirical treatment and in preventing breakthrough infection and/or colonization with carbapenem-resistant Enterobacteriaceae (CRE) among oncohaematological patients with febrile neutropenia (FN). METHODS: A monocentric, interventional, prospective study was conducted. The pharmacodynamic (PD) target was a steady-state meropenem concentration-to-MIC ratio (Css/MIC) of 4-8. The primary endpoint was 14 day all-cause mortality. The secondary endpoint was the prevalence of CRE colonization in rectal swabs of patients rehospitalized within 3 months. RESULTS: Among the 75 patients enrolled, most (56%) had AML, almost half (37/75, 49.3%) underwent HSCT and one-third (32%) received meropenem as monotherapy. Meropenem dosages were adjusted in 30.1% of TDM reassessments. Gram-negative infections were microbiologically documented in 20.0% of patients. All of the 12 patients having infections caused by in vitro meropenem-susceptible pathogens attained the desired PD target and were cured. Three patients had infections caused by in vitro meropenem-resistant pathogens. Two of these achieved a Css/MIC target of 1 and were cured; the other one achieved a suboptimal PD target (0.59) and died. The 14 day all-cause mortality (10.7%) was significantly associated, at multivariate regression, with HSCT (OR 0.086, 95% CI 0.008-0.936, P = 0.044) and with augmented renal clearance (OR 10.846, 95% CI 1.534-76.672, P = 0.017). None of the patients who had hospital readmissions in the 3 month follow-up (63/75) had CRE colonization in rectal swabs. CONCLUSIONS: Real-time TDM-guided CI meropenem may be a useful approach for attaining adequate exposure and preventing CRE emergence in FN oncohaematological patients.

Real-Time Therapeutic Drug Monitoring-Based Pharmacokinetic/Pharmacodynamic Optimization of Complex Antimicrobial Therapy in a Critically Ill Morbidly Obese Patient. Grand Round/A Case Study.

The authors present the case of a critically ill morbidly obese patient (body mass index, 51.2 kg/m) who suffered from methicillin-resistant Staphylococcus epidermidis, and Candida albicans bloodstream infections. Initial treatment with caspofungin and daptomycin was deemed inappropriate, because blood cultures remained positive for both isolates after 14 days. The clinical pharmacological consultant suggested adding fluconazole and ceftobiprole to the ongoing antimicrobial therapy, and starting a real-time therapeutic drug monitoring program of daptomycin, ceftobiprole, and fluconazole, aimed at optimizing plasma exposures. Punctual minimum inhibitory concentration knowledge on the clinical isolates allowed attainment of the desired pharmacodynamic efficacy targets. Within few days, the patient greatly improved, as blood cultures became negative, and the inflammatory markers decreased to near normal values. This is a proof-of-concept of the importance of a therapeutic drug monitoring-based multidisciplinary approach in the proper management of complex antimicrobial therapy in special populations.

Use of meropenem in treating carbapenem-resistant Enterobacteriaceae infections.

Introduction: The epidemiology of carbapenem-resistant Enterobacterales (CRE) is increasingly worldwide. Production of carbapenemases is the most common and efficient mechanism of carbapenem resistance, and could theoretically be overcome by optimizing the pharmacokinetic/pharmacodynamic (PK/PD) behavior of meropenem. Areas covered: This article overviews the available literature concerning the potential role that meropenem may still have in the treatment carbapenem-resistant Enterobacteriaceae infections. Clinical studies published in English language until June 2019 were searched on PubMed database. Expert commentary: High-dose continuous infusion meropenem-based combination regimens could still represent a valuable option for treating CRE infections in specific circumstances. Knowledge of the local prevalent mechanisms of carbapenem resistance, of patient clinical severity, of the site of infection, of an accurate minimum inhibitory concentration (MIC) value, coupled with the possibility of carrying-out a real-time therapeutic drug monitoring (TDM)-based PK/PD optimization of drug exposure must all be considered as fundamental for properly pursuing this goal.

Population pharmacokinetics of continuous-infusion ceftazidime in febrile neutropenic children undergoing HSCT: implications for target attainment for empirical treatment against Pseudomonas aeruginosa.

OBJECTIVES: To conduct a population pharmacokinetic analysis of continuous-infusion ceftazidime in a retrospective cohort of paediatric HSCT patients who were empirically treated for febrile neutropenia (FN) and who underwent therapeutic drug monitoring of ceftazidime steady-state plasma concentrations (Css) for optimization of drug exposure. METHODS: A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed to calculate the PTA of the pharmacodynamic determinant of efficacy (Css/MIC ≥4) against Pseudomonas aeruginosa with continuous-infusion ceftazidime dosages of 1-6 g daily. The Css safety threshold was arbitrarily placed at 100 mg/L and advisable dosages were used. RESULTS: A total of 46 patients with 70 ceftazidime Css values were included. Estimated glomerular filtration rate (eGFR) and body surface area were the covariates associated with drug clearance. At the EUCAST clinical breakpoint of 8 mg/L, simulations showed that continuous-infusion ceftazidime dosages of 4-6 g daily attained optimal PTAs (>90%) across most of 16 different clinical scenarios based on four classes of eGFR (50-145, 145.1-200, 200.1-286 and 286.1-422 mL/min/1.73 m2) and body surface area (0.30-0.64, 0.65-0.88, 0.89-1.34 and 1.35-1.84 m2). In patients with body surface area 0.30-0.64 m2 and eGFR ≤200 mL/min/1.73 m2 the advisable dose of 3 g daily allowed only suboptimal PTAs (<75%). The cumulative fraction of response against MIC distribution of P. aeruginosa was >87%. CONCLUSIONS: Continuous-infusion ceftazidime dosages ranging from 3 to 6 g daily according to different classes of eGFR and body surface area may allow optimized empirical treatment of P. aeruginosa infections in paediatric HSCT patients with FN.

Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections.

INTRODUCTION: In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach. Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included. Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram-positive infections, especially if co-infection with other pathogens is suspected. This is because of the very low MIC of the agent for Gram-positive (including MRSA) and anaerobic bacteria and because of the wide spectrum of activity against Gram-negative organisms. For these interesting microbiological and PK/PD characteristics we expect future uses of this drug in other indications such as diabetic foot infection, osteomyelitis, prosthetic joint infections, abdominal infections and central nervous system infections.

Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae.

We assessed the population pharmacokinetics of high-dose continuous-infusion (HDCI) meropenem in a cohort of patients with Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with a ≤10% to 15% likelihood of meropenem steady-state concentrations (Css) of >100 mg/liter. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100% T>1×MIC, 100% T>2×MIC, 100% T>3×MIC, and 100% T>4×MIC, where "T>MIC" represents the time during which the plasma concentration of this time-dependent antibacterial agent is maintained above the MIC for the pathogen) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 (n = 169). Ninety-seven meropenem Css were included in the analysis. The final model included creatinine clearance (CrCL) as a covariate and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages of up to 6 g/day predicted an acceptable PTA (>80%) of 100% T>1×MIC against KPC-Kp with a meropenem MIC of ≤32 mg/liter in patients with a CrCL level of <130 ml/min. Dosages of 8 g/day were needed for achieving the same target in patients with CrCL at levels of 130 to 200 ml/min. In dealing with pathogens with a meropenem MIC of 64 mg/liter, HDCI regimens using meropenem at higher than licensed levels should be considered. In these cases, real-time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

Pharmacokinetics and Dosing of Ceftobiprole Medocaril for the Treatment of Hospital- and Community-Acquired Pneumonia in Different Patient Populations.

Hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP) are among the most common infections treated in the hospital setting, and together they place a significant burden on healthcare systems. Successful management of HAP and CAP depends on rapid initiation of empirical antibiotic therapy with broad-spectrum antibiotics. Ceftobiprole is a new-generation, broad-spectrum cephalosporin antibiotic for the treatment of HAP (excluding ventilator-associated pneumonia) and CAP. It displays potent in vitro activity against a broad range of pathogens important in pneumonia. This review summarizes the pharmacokinetic profile of ceftobiprole, and considers the pharmacokinetic parameters and pharmacodynamics underlying the choice of dosing regimen. Ceftobiprole shows linear pharmacokinetics after single and multiple doses and is eliminated predominantly through the kidneys. Ceftobiprole is administered as a 500 mg intravenous infusion over 2 h every 8 h, and steady-state concentrations are reached on the first day of dosing. Dose adjustment is recommended for patients with moderate or severe renal impairment and for those with end-stage renal disease. Extending the infusion time of ceftobiprole to 4 h is recommended to optimize drug exposure in critically ill patients with augmented renal clearance. However, there is no need for dose adjustments based on age, sex or ethnicity, or for patients with severe obesity. Population pharmacokinetic modelling and Monte Carlo simulations were used to determine the optimal dosing regimen for ceftobiprole in special patient populations, including paediatric patients. Future studies of ceftobiprole in patients with HAP and CAP would be of interest.