Ceftolozane/tazobactam heteroresistance in cystic fibrosis-related Pseudomonas aeruginosa infections.

Objectives: Cystic fibrosis (CF) patients are often colonized with Pseudomonas aeruginosa. During treatment, P. aeruginosa can develop subpopulations exhibiting variable in vitro antimicrobial (ABX) susceptibility patterns. Heteroresistance (HR) may underlie reported discrepancies between in vitro susceptibility results and clinical responses to various ABXs. Here, we sought to examine the presence and nature of P. aeruginosa polyclonal HR (PHR) and monoclonal HR (MHR) to ceftolozane/tazobactam in isolates originating from CF pulmonary exacerbations. Methods: This was a single-centre, non-controlled study. Two hundred and forty-six P. aeruginosa isolates from 26 adult CF patients were included. PHR was defined as the presence of different ceftolozane/tazobactam minimum inhibitory concentration (MIC) values among P. aeruginosa isolates originating from a single patient specimen. Population analysis profiles (PAPs) were performed to assess the presence of MHR, defined as ≥4-fold change in the ceftolozane/tazobactam MIC from a single P. aeruginosa colony. Results: Sixteen of 26 patient specimens (62%) contained PHR P. aeruginosa populations. Of these 16 patients, 6 (23%) had specimens in which PHR P. aeruginosa isolates exhibited ceftolozane/tazobactam MICs with categorical differences (i.e. susceptible versus resistant) compared to results reported as part of routine care. One isolate, PSA 1311, demonstrated MHR. Canonical ceftolozane/tazobactam resistance genes were not found in the MHR isolates (MHR PSA 1311 or PHR PSA 6130). Conclusions: Ceftolozane/tazobactam PHR exists among P. aeruginosa isolates in this work, and approximately a quarter of these populations contained isolates with ceftolozane/tazobactam susceptibiilty interpretations different from what was reported clinically, supporting concerns surrounding the utility of traditional susceptibility testing methodology in the setting of CF specimens. Genome sequencing of isolates with acquired MHR to ceftolozane/tazobactam revealed variants of unknown significance. Future work will be centred on determining the significance of these mutations to better understand these data in clinical context.

A case-control study evaluating the unnecessary use of intravenous broad-spectrum antibiotics in presumed sepsis and septic-shock patients in the emergency department.

Objectives: Recognition of sepsis frequently occurs in emergency departments. To evaluate the appropriateness of empiric antibiotic use in the setting of suspected sepsis in emergency department, the percentages of bacterial infection and antibiotic-related adverse drug effects were quantified in an emergency department at an academic medical center. Methods: We retrospectively reviewed electronic medical records of adults who presented to the emergency department between January 2018 and June 2018 with suspected sepsis (defined as having ≥2 systemic inflammatory response syndrome [SIRS] criteria) and received ≥1 dose of intravenous broad-spectrum antibiotic. Results: In total, 218 patients were included in the final analysis. Moreover, 19.3% of these patients had confirmed bacterial infections; 44.5% had suspected bacterial infections; and 35.9% did not have bacterial infection. Elevated SIRS score (ie, ≥2) and Quick Sequential Organ Failure Assessment (qSOFA) score (ie, ≥2) were not associated with the presence of bacterial infections. We identified 90-day Clostridioides difficile infections in 7 patients and drug-resistant organism infections in 6 patients, regardless of the presence of bacterial infections. Conclusions: A high number of patients received intravenous broad-spectrum antibiotics in the emergency department without confirmed or suspected bacterial infections that were supported by microbiologic cultures, radiographic imaging, or other symptoms of infections. Most patients who were initially admitted to the emergency department with suspected sepsis were discharged home after receiving 1 dose of intravenous antibiotic. Patients who were initially screened using SIRS score and who received broad-spectrum antibiotics in the emergency department were without confirmed or suspected bacterial infection.

Clinically undetected polyclonal heteroresistance among Pseudomonas aeruginosa isolated from cystic fibrosis respiratory specimens.

BACKGROUND: Pseudomonas aeruginosa infection is the leading cause of death among patients with cystic fibrosis (CF) and a common cause of difficult-to-treat hospital-acquired infections. P. aeruginosa uses several mechanisms to resist different antibiotic classes and an individual CF patient can harbour multiple resistance phenotypes. OBJECTIVES: To determine the rates and distribution of polyclonal heteroresistance (PHR) in P. aeruginosa by random, prospective evaluation of respiratory cultures from CF patients at a large referral centre over a 1 year period. METHODS: We obtained 28 unique sputum samples from 19 CF patients and took multiple isolates from each, even when morphologically similar, yielding 280 unique isolates. We performed antimicrobial susceptibility testing (AST) on all isolates and calculated PHR on the basis of variability in AST in a given sample. We then performed whole-genome sequencing on 134 isolates and used a machine-learning association model to interrogate phenotypic PHR from genomic data. RESULTS: PHR was identified in most sampled patients (n = 15/19; 79%). Importantly, resistant phenotypes were not detected by routine AST in 26% of patients (n = 5/19). The machine-learning model, using the extended sampling, identified at least one genetic variant associated with phenotypic resistance in 94.3% of isolates (n = 1392/1476). CONCLUSION: PHR is common among P. aeruginosa in the CF lung. While traditional microbiological methods often fail to detect resistant subpopulations, extended sampling of isolates and conventional AST identified PHR in most patients. A machine-learning tool successfully identified at least one resistance variant in almost all resistant isolates by leveraging this extended sampling and conventional AST.

Ceftaroline versus vancomycin for treatment of acute pulmonary exacerbations of cystic fibrosis in adults.

OBJECTIVES: Vancomycin remains a first-line treatment for methicillin-resistant Staphylococcus aureus (MRSA)-mediated acute pulmonary exacerbations (APEs) in adult cystic fibrosis (CF) patients; however, optimal alternatives remain poorly defined. The aim of this study was to determine the safety and efficacy of ceftaroline for MRSA-mediated APEs of CF in adults. METHODS: We conducted a retrospective, observational cohort study comparing ceftaroline with vancomycin for the treatment of MRSA-mediated APEs in adult CF patients. The primary endpoint was the return to at least 90% of baseline lung function measured by discharge FEV1% predicted in comparison with baseline FEV1% predicted. RESULTS: A total of 55 patients were included in the analysis (22 receiving ceftaroline and 33 receiving vancomycin). Of the patients included in the analysis, 13 patients (59%) in the ceftaroline group and 24 patients (73%) in the vancomycin group met the primary outcome (P = 0.38). FEV1 measurements at baseline, admission and discharge were not different between treatments. Secondary outcomes including 30-day re-admission rate, 30-day mortality, treatment duration and adverse events (neutropenia, Clostridioides difficile infection and acute kidney injury) were similar between groups. CONCLUSION: Our small cohort study supports ceftaroline as an alternative treatment option for MRSA-mediated APE of CF in adults.

A Large-Scale Retrospective Study on Thrombocytopenia Associated with Beta-Lactam Antibiotics.

While the ability for beta-lactams (BL) to induce thrombocytopenia (TCP) is well understood, their association is not well quantified in the general population. Despite this, when platelets drop in the clinical setting, BL are frequently substituted for alternative antibiotics, leading to suboptimal outcomes. Here, we present a large-scale, retrospective study on the association of TCP and BL when compared to alternative non beta-lactam (nBL) therapy. All adult inpatients who received at least one antibiotic between 2008 and 2021 were included. Incidence of TCP in the 30 days following antibiotic administration was compared across patients receiving exclusively BLs vs nBLs as well as with each antibiotic subclass permutation following propensity score matching. There is a mild, though statistically significant increase in TCP risk for BL when compared to alternative nBL therapy. Risks and benefits should be considered prior to switching off BL therapy if clinically indicated.

The role of tazobactam-based combinations for the management of infections due to extended-spectrum ß-lactamase-producing Enterobacterales: Insights from the Society of Infectious Diseases Pharmacists.

Extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales are a global threat to public health due to their antimicrobial resistance profile and, consequently, their limited available treatment options. Tazobactam is a sulfone ß-lactamase inhibitor with in vitro inhibitory activity against common ESBLs in Enterobacterales, including CTX-M. However, the role of tazobactam-based combinations in treating infections caused by ESBL-producing Enterobacterales remains unclear. In the United States, two tazobactam-based combinations are available, piperacillin-tazobactam and ceftolozane-tazobactam. We evaluated and compared the roles of tazobactam-based combinations against ESBL-producing organisms with emphasis on pharmacokinetic/pharmacodynamic exposures in relation to MIC distributions and established breakpoints, clinical outcomes data specific to infection site, and considerations for downstream effects with these agents regarding antimicrobial resistance development. While limited data with ceftolozane-tazobactam are encouraging for its potential role in infections due to ESBL-producing Enterobacterales, further evidence is needed to determine its place in therapy. Conversely, currently available microbiologic, pharmacokinetic, pharmacodynamic, and clinical data do not suggest a role for piperacillin-tazobactam, and we caution clinicians against its usage for these infections.

Bronchoalveolar Lavage Gram Stains for Early Bacterial Identification in Pneumonia: Should They Stay or Should They Go?

OBJECTIVES: The primary endpoint was to determine the sensitivity and specificity of the bronchoalveolar lavage Gram stain in predicting culture results. Secondary endpoints included determining the proportion of Gram stains from bronchoalveolar lavages that accurately identify culture isolates and the duration of antibiotic treatment before bronchoalveolar lavage collection. DESIGN: Retrospective, observational study. SETTING: Four ICUs at a single academic medical center. SUBJECTS: Patients at least 18 years old admitted to an ICU with a diagnosis of pneumonia, collection of a bronchoalveolar lavage sample, and receipt of antibiotics. MEASUREMENTS AND MAIN RESULTS: Two-hundred five isolates were included. Gram stains for Gram-positive and Gram-negative isolates showed high specificity, 97.3% and 100%, respectively, but lower sensitivity at 61.9% and 54.2%, respectively. The positive predictive value and negative predictive value were 77.2% and 95.7% for Gram-positive isolates and 100% and 84.4% for Gram-negative isolates, respectively. Gram stains correctly identified isolates on the bronchoalveolar lavage culture in 61.9% of Gram-positive organisms and in 54.2% of Gram-negative organisms. CONCLUSIONS: Gram stains accurately identified causative organisms in a limited number of patients making the utility of the Gram stain an uncertain modality for predicting causative respiratory pathogens from bronchoalveolar lavage samples.

Tedizolid vs Linezolid for the Treatment of Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients.

BACKGROUND: Treatment options for nontuberculous mycobacteria (NTM) infections are limited by the pathogen's intrinsic resistance profile and toxicities. Tedizolid and linezolid display in vitro activity against NTM species. However, safety data and treatment outcomes are limited in the solid organ transplant (SOT) population. METHODS: This was a single-center retrospective cohort study of adult SOT recipients receiving linezolid or tedizolid for an NTM infection from January 1, 2010, to August 31, 2019. The primary outcome compared the hematologic safety profiles of tedizolid vs linezolid. We also described nonhematological adverse drug events (ADEs) and therapy discontinuation rates. In an exploratory analysis, we assessed symptomatic microbiologic and clinical outcomes in those receiving tedizolid or linezolid for at least 4 weeks. RESULTS: Twenty-four patients were included (15 tedizolid, 9 linezolid). No differences were identified comparing the effects of tedizolid vs linezolid on platelet counts, absolute neutrophil counts (ANCs), and hemoglobin over 7 weeks using mixed-effects analysis of variance models. ANC was significantly decreased in both groups after 7 weeks of therapy (P = .04). Approximately 20% of patients in each arm discontinued therapy due to an ADE. Seven of 12 (58%) and 2 of 3 (67%) patients were cured or clinically cured with tedizolid- and linezolid-containing regimens, respectively. CONCLUSIONS: This study suggests no significant safety benefit of tedizolid over linezolid for the treatment of NTM infections in SOT recipients. Tedizolid or linezolid-containing regimens demonstrated a potential benefit in symptomatic and microbiologic improvement. Larger cohorts are needed to further delineate the comparative role of linezolid and tedizolid for the treatment of NTM infections in SOT recipients.

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review.

IMPORTANCE: The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. OBSERVATIONS: No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. CONCLUSIONS AND RELEVANCE: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

Minimal Cerebrospinal Fluid Concentration of Miltefosine despite Therapeutic Plasma Levels during the Treatment of Amebic Encephalitis.

Miltefosine is an alkylphosphocholine compound that is used primarily for treatment of leishmaniasis and demonstrates in vitro and in vivo antiamebic activity against Acanthamoeba species. Recommendations for treatment of amebic encephalitis generally include miltefosine therapy. Data indicate that treatment with an amebicidal concentration of at least 16 µg/ml of miltefosine is required for most Acanthamoeba species. Although there is a high level of mortality associated with amebic encephalitis, a paucity of data regarding miltefosine levels in plasma and cerebrospinal fluid in vivo exists in the literature. We found that despite aggressive dosing (oral miltefosine 50 mg every 6 h) and therapeutic plasma levels, the miltefosine concentration in cerebrospinal fluid was negligible in a patient with AIDS and Acanthamoeba encephalitis.

Pharmacokinetics-pharmacodynamics of ß-lactamase inhibitors: are we missing the target?

Introduction: ß-lactamase production in Gram-negative bacteria is a leading cause of antimicrobial resistance. ß-lactamase inhibitors are therapeutic agents used in combination with a partner antimicrobial to overcome the production of these enzymes and restore antimicrobial activity. To address the ongoing threat of multi-drug resistant bacteria, a recent wave of ß-lactamase inhibitor development has occurred. Emphasis on the pharmacokinetics and pharmacodynamics of these agents is needed to optimize their clinical impact. Areas covered: This review will describe methods currently used to define the pharmacokinetics/pharmacodynamics of ß-lactamase inhibitors. Minimal focus will be on the structure and mechanism of ß-lactamase inhibitors. Emphasis will be placed on the use of specific thresholds to normalize ß-lactamase inhibitor exposure. In vitro and in vivo pharmacokinetic/pharmacodynamic data specific to FDA approved and pipeline ß-lactamase inhibitors will be explored. Expert opinion: Describing the exposure-response relationship of ß-lactamase inhibitors is an ongoing challenge due to the dynamic relationship of the ß-lactamase inhibitor with the active partner compound. Pharmacokinetic/pharmacodynamic indices and target exposures lack generalizability, as they are often specific to the infecting organism and/or ß-lactamase, rather than ß-lactamase inhibitor class. Selected dosage regimens of new agents should be validated via the use of population target attainment analyses.

In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Multidrug-Resistant Pseudomonas aeruginosa in the Neutropenic Murine Thigh Infection Model.

We describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against multidrug-resistant Pseudomonas aeruginosa (meropenem MICs 8 to >256 µg/ml) in a neutropenic murine thigh infection model. WCK 5222 MICs ranged from 4 to 32 µg/ml. Substantial in vivo WCK 5222 activity was observed against all isolates, further enhancing the efficacy of zidebactam alone in 11/16 isolates (WCK 5222 mean reduction, -1.62 ± 0.58 log10 CFU/thigh), and a lack of activity was observed with cefepime monotherapy.

Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model.

Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 µg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 µg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.

In Vivo Efficacy of Meropenem with a Novel Non-ß-Lactam-ß-Lactamase Inhibitor, Nacubactam, against Gram-Negative Organisms Exhibiting Various Resistance Mechanisms in a Murine Complicated Urinary Tract Infection Model.

Urinary tract infections (UTIs) are a tremendous burden on the health care system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multidrug-resistant (MDR) organisms, limiting the availability of effective antimicrobials. Nacubactam is a novel non-ß-lactam-ß-lactamase inhibitor with in vitro activity against class A and class C ß-lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common ß-lactamases. Here, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of meropenem-nacubactam compared with meropenem or nacubactam alone against 10 Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM enzyme-producing isolates. Selected isolates had meropenem-nacubactam MICs between 1 and 8 µg/ml. Meropenem-nacubactam demonstrated the greatest in vivo efficacy against 9 of 10 isolates, achieving a ≥3 log reduction from the 48-h control in all isolates tested, including isolates prepared as high inoculums. Nacubactam alone confirmed antibacterial properties, achieving a >1 log reduction against the majority of isolates. The combination of meropenem-nacubactam further enhanced the activity of either agent alone, notably against meropenem-resistant isolates. Against ceftazidime-avibactam-resistant isolates, meropenem-nacubactam demonstrated increased antibacterial kill upwards of 6 log10 CFU in comparison to the 48-h control. Our data support the potential clinical utility of meropenem-nacubactam for cUTI in humans against MDR Enterobacteriaceae, although further clinical data supporting meropenem-nacubactam efficacy are needed.

Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia.

BACKGROUND: Anti-staphylococcal penicillins have long been the first-line treatment option for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Recent retrospective data comparing nafcillin and cefazolin report similar clinical efficacy despite concerns about high inoculum MSSA infections. METHODS: This was a retrospective, non-inferiority, cohort study comparing treatment failure rates between nafcillin and cefazolin in patients with MSSA bacteremia from any source, other than meningitis. Multiple logistic regression was used to adjust for confounding variables. RESULTS: A total of 142 patients were included in the study. The overall treatment failure rate among patients receiving cefazolin was non-inferior to nafcillin (11.3% versus 8.5%; 90% confidence interval -5.2% to 10.8%). Rates of adverse drug events were significantly higher in the nafcillin arm (19.7% versus 7%; p=0.046). After adjustment for confounding variables, no difference between treatment groups was found in treatment failure (adjusted odds ratio (OR)=1.2; 95% CI, 0.3-4.5), but nafcillin was associated with significantly higher nephrotoxicity (adjusted odds ratio (OR)=5.4; 95% CI, 1.1-26.8). CONCLUSION: Cefazolin was associated with lower nephrotoxicity and similar treatment failure rates compared to nafcillin suggesting that cefazolin is an appealing first line agent for most MSSA bloodstream infections.

Humanized Exposures of a ß-Lactam-ß-Lactamase Inhibitor, Tazobactam, versus Non-ß-Lactam-ß-Lactamase Inhibitor, Avibactam, with or without Colistin, against Acinetobacter baumannii in Murine Thigh and Lung Infection Models.

ß-lactam-ß-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including ß-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models. In vitro, colistin and tazobactam MICs were 1 and 16 µg/mL against AB 25-49 (CS) and 1 and 128 µg/mL against AB 5075 (MDR) respectively. In the lung model, tazobactam alone and in combination with colistin achieved a 1-log reduction in CFU, while colistin alone was not active against AB 25-49. No activity was observed against AB 5075. In the thigh model, tazobactam with and without colistin was bacteriostatic against AB 25-49 but did not demonstrate any activity against AB 5075. Avibactam and colistin alone and in combination were not active against either isolate. No synergy was observed; however, we found tazobactam activity against A. baumannii. This activity was not observed for the non-ß-lactam-BLI, avibactam. This suggests that binding to penicillin-binding proteins of the ß-lactam molecule is required for tazobactam activity against A. baumannii. These data point to an added role of ß-lactam-BLIs beyond their primary purpose of ß-lactamase inhibition in the treatment of MDR A. baumannii infections by enhancing the activity of peptide antibiotics, a property that is not shared by the novel non-ß-lactam-BLIs. Future studies are needed to define tazobactam and colistin activity in an A. baumannii infection model.

Humanized Exposures of Cefiderocol, a Siderophore Cephalosporin, Display Sustained in vivo Activity against Siderophore-Resistant Pseudomonas aeruginosa.

We evaluated the in vivo efficacy of humanized exposures of cefiderocol, a novel siderophore cephalosporin, against a test panel of P. aeruginosa (PSA) previously shown to develop resistance to 2 preclinical candidate siderophores (MB-1 and SMC-3176). In the thigh infection model, the PSA bacterial density in untreated controls grew from 5.54 ± 0.23 to 8.68 ± 0.57 log10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log10 CFU reduction in all 8 isolates, while MB-1 and SMC-3176 exhibited variable activity similar to that previously reported. Humanized exposures of cefepime and levofloxacin, acting as positive antimicrobial controls displayed activity consistent with that of the bacterial phenotypic susceptibility profiles. Cefiderocol manifested in vivo efficacy against all PSA isolates including those resistant to cefepime and levofloxacin in contrast to its predecessor siderophore compounds. These preclinical data are supportive of further evaluation of cefiderocol in the treatment of P. aeruginosa.

Assessment of in vivo efficacy of eravacycline against Enterobacteriaceae exhibiting various resistance mechanisms: a dose-ranging study and pharmacokinetic/pharmacodynamic analysis.

After the pharmacokinetic (PK) profile of eravacycline, a novel fluorocycline, was defined, understanding its pharmacodynamic (PD) profile became essential. This study aimed to assess the correlation of the PK/PD index fAUC/MIC (ratio of area under the free drug concentration-time curve to MIC) and its magnitude with eravacycline's efficacy against Enterobacteriaceae using an immunocompetent murine thigh infection model to resemble the immunocompetent environment in eravacycline's clinical trials. Eight Enterobacteriaceae isolates with various resistance mechanisms were tested. Eravacycline doses ranged from 1-10 mg/kg/day and were given either once daily (q24h) or divided into doses every 12 h (q12h) over the 24-h treatment period. Antibacterial efficacy was measured as the change in log10CFU at 24 h compared with 0 h controls. Composite data were modelled using a sigmoid Emax model. Eravacycline MICs ranged from 0.125-0.5 µg/mL. The mean fAUC/MIC magnitudes required for stasis and 1-log reduction for the eight isolates were 2.9 ± 3.1 and 5.6 ± 5.0, respectively. Whilst the humanised eravacycline regimen (2.5 mg/kg q12h) pharmacokinetically achieves an fAUC0-24 that is higher than the fAUC0-24 achieved with the 5 mg/kg q24h dose, the latter was associated with greater efficacy, raising a suggestive correlation of the peak free drug concentration to MIC (fCmax/MIC) ratio with eravacycline's efficacy. This study showed that the magnitudes associated with eravacycline's efficacy in an immunocompetent murine thigh model appear to be close to achievable targets in human. These data support further development of eravacycline for treatment of infections caused by drug-resistant Enterobacteriaceae.

Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model.

Cefiderocol is a siderophore cephalosporin that displays potent in vitro activity against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to describe the pharmacokinetics, pharmacodynamics and 24-h efficacy of cefiderocol using dose-ranging methods in a neutropenic murine thigh infection model. Infection was established in neutropenic mice (administered cyclophosphamide 150 mg/kg and 100 mg/kg at 4 days and 1 day prior to inoculation, respectively) with eight Pseudomonas aeruginosa isolates [minimum inhibitory concentration (MIC) range 0.063-0.5 µg/mL] that displayed variable in vivo activity against previously tested ß-lactams with siderophore moieties. Renal excretion was controlled by administration of 5 mg/kg uranyl nitrate 3 days prior to inoculation. Cefiderocol was administered subcutaneously in eight escalating doses [4.2-166.7 mg/kg every 8 h (q8h)]. In pharmacokinetic studies, cefiderocol manifested similar pharmacokinetics across tested doses (4, 100 and 250 mg/kg) with a mean half-life of 0.86 h. In pharmacodynamic studies, the change in CFU after 24 h from the initial inoculum ranged from +3.4 to -3.1 log10 with doses of 4.2-166.7 mg/kg q8h. Dose-response curves for the eight isolates assumed the characteristic sigmoidal shape, with greater CFU reductions as the dose increased. Focusing on the previously defined efficacy parameter of fT>MIC (time that the free drug concentration exceeds the MIC) for this compound, targets for stasis and 1 log10 and 2 log10 reductions ranged from 44.4-94.7, 50.2-97.5 and 62.1-100, respectively. Cefiderocol displayed sustained antibacterial effects against these MDR P. aeruginosa isolates. These data support the cefiderocol dose selected for clinical trials.