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.

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.

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.

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.

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.

Comparative Assessment of Tedizolid Pharmacokinetics and Tissue Penetration between Diabetic Patients with Wound Infections and Healthy Volunteers via In Vivo Microdialysis.

Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200 mg every 24 h for 3 doses to achieve steady state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the third dose, 12 blood and 14 dialysate fluid samples were collected over 24 h to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± standard deviation (SD) tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were as follows: maximum concentration (Cmax), 1.5 ± 0.5 versus 2.7 ± 1.1 mg/liter (P = 0.005); time to Cmax (Tmax) (median [range]), 5.9 (1.2 to 8.0) versus 2.5 (2.0 to 3.0 h) (P = 0.003); half-life (t1/2), 9.1 ± 3.6 versus 8.9 ± 2.2 h (P = 0.932); and plasma area under the concentration-time curve for the dosing interval (AUC p ), 18.5 ± 9.7 versus 28.7 ± 9.6 mg · h/liter (P = 0.004). The tissue area under the concentration-time curve (AUC t ) for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg · h/liter (P = 0.075). Tissue penetration median (range) was 1.1 (0.3 to 1.6) versus 0.8 (0.7 to 1.0) (P = 0.351). Despite lower plasma Cmax and delayed Tmax values for patients with DFI relative to healthy volunteers, the penetration into and exposure to tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200 mg once-daily regimen are suitable for further study in treatment of DFI.

Antibacterial activity of ceftolozane/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa.

Objectives: Broad-spectrum antimicrobial resistance in Pseudomonas aeruginosa (PSA) isolates is a growing concern as our therapeutic options have become significantly limited. Although ceftolozane/tazobactam (C/T) has been shown to be highly active against MDR PSA pathogens, combination regimens are often employed in real-world settings. To assist the clinical decision-making process regarding the selection of combination antibiotics and dosages for this pathogen, we performed time-kill studies assessing clinical free peak and trough C/T concentrations alone and in combination with eight anti-pseudomonal agents against four clinical MDR PSA isolates. Methods: Time-kill analyses were performed over 24 h in duplicate using C/T concentrations reflective of the free peak concentrations of a 3 g dose every 8 h (q8h; 120/25.2 mg/L) and the peak and trough of a 1.5 g q8h dose (60/12.6 and 7.5/1.6 mg/L) in humans. The activity of C/T 120, 60 and 7.5 mg/L alone and C/T 7.5 mg/L in combination with free peak and trough concentrations of clinical doses for cefepime, ciprofloxacin, colistin, aztreonam, meropenem, piperacillin/tazobactam, fosfomycin and amikacin was tested for all isolates. Results: C/T 3 and 1.5 g q8h peak concentrations demonstrated killing against the MDR PSA. Colistin and fosfomycin were synergistic with C/T as dual therapy and triple therapy regimens. Conclusions: As a result of escalating resistance, PSA is an increasingly challenging pathogen in the clinical setting. Our findings aid in the identification of novel treatment options using achievable drug exposures for the treatment of MDR PSA.

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.

Translational Efficacy of Humanized Exposures of Cefepime, Ertapenem, and Levofloxacin against Extended-Spectrum-ß-Lactamase-Producing Escherichia coli in a Murine Model of Complicated Urinary Tract Infection.

Validated animal models are required as bridging tools to assess the utility of novel therapies and potential microbiologic outcomes. Herein, we utilized uropathogenic extended-spectrum-ß-lactamase (ESBL)-producing and non-ESBL-producing Escherichia coli in the neutropenic murine complicated urinary tract infection (cUTI) model with humanized exposures of cefepime, ertapenem, and levofloxacin to assess its translational value to human outcomes. Our data support the translational utility of this murine model to cUTI in humans as humanized exposures produced microbiologic outcomes consistent with the phenotypic profiles of the organisms.

Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model.

Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 µg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 µg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 µg/ml, whereas isolates with MICs of ≥8 µg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers.

Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients (n = 10) with DFI were compared with those in healthy volunteers (n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (Cmax), 55.2 µg/ml (range, 40.9 to 169.3 µg/ml); half-life (t1/2), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC0-8), 191.6 µg · h/ml (range, 147.1 to 286.6 µg · h/ml). The median AUC for tissue (AUCtissue; where AUCtissue was the AUC0-8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (fAUCplasma) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 µg/ml (the Pseudomonas aeruginosa susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: Cmax, 14.2 µg/ml (range, 7.6 to 64.2 µg/ml); t1/2, 2.0 h (range, 0.7 to 2.4 h); and AUC0-8, 27.1 µg · h/ml (range, 15.0 to 70.0 µg · h/ml). The AUCtissue (where AUCtissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/fAUCplasma for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: Cmax, 91.5 µg/ml (range, 65.7 to 110.7 µg/ml); t1/2, 1.9 h (range, 1.6 to 2.1 h); and AUC0-8, 191.3 µg · h/ml (range, 118.1 to 274.3 µg · h/ml). The median AUCtissue/fAUCplasma was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 µg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: Cmax, 17.5 µg/ml (range, 15.4 to 27.3 µg/ml); t1/2, 0.7 h (range, 0.6 to 0.8 h); and AUC0-8, 22.2 µg · h/ml (range, 19.2 to 36.4 µg · h/ml). The AUCtissue/fAUCplasma for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.).

Eravacycline Pharmacokinetics and Challenges in Defining Humanized Exposure In Vivo.

We assessed the pharmacokinetic profile of eravacycline, a novel antibiotic of the tetracycline class, and determined the dose in an immunocompetent murine thigh infection model that would provide free-drug exposure similar to that observed in humans after the administration of 1 mg/kg intravenously (i.v.) every 12 h (q12h). Eravacycline demonstrated a nonlinear protein-binding profile. The 2.5-mg/kg i.v. q12h dose in mice resulted in an area under the concentration-time curve for the free, unbound fraction of the drug of 1.64 mg · h/liter, which closely resembles the human exposure level.

Antibacterial Efficacy of Eravacycline In Vivo against Gram-Positive and Gram-Negative Organisms.

Members of the tetracycline class are frequently classified as bacteriostatic. However, recent findings have demonstrated an improved antibacterial killing profile, often achieving ≥3 log10 bacterial count reduction, when such antibiotics have been given for periods longer than 24 h. We aimed to study this effect with eravacycline, a novel fluorocycline, given in an immunocompetent murine thigh infection model over 72 h against two methicillin-resistant Staphylococcus aureus (MRSA) isolates (eravacycline MICs = 0.03 and 0.25 µg/ml) and three Enterobacteriaceae isolates (eravacycline MICs = 0.125 to 0.25 µg/ml). A humanized eravacycline regimen, 2.5 mg/kg of body weight given intravenously (i.v.) every 12 h (q12h), demonstrated progressively enhanced activity over the 72-h study period. A cumulative dose response in which bacterial density was reduced by more than 3 log10 CFU at 72 h was noted over the study period in the two Gram-positive isolates, and eravacycline performed similarly to comparator antibiotics (tigecycline, linezolid, and vancomycin). A cumulative dose response with eravacycline and comparators (tigecycline and meropenem) over the study period was also observed in the Gram-negative isolates, although more variability in bacterial killing was observed for all antibacterial agents. Overall, a bacterial count reduction of ≥3 log was achieved in one of the three isolates with both eravacycline and tigecycline, while meropenem achieved a similar endpoint against two of the three isolates. Bactericidal activity is typically defined in vitro over 24 h; however, extended regimen studies in vivo may demonstrate an improved correlation with clinical outcomes by better identification of antimicrobial effects.

Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation.

Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 µg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.).

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 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.

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.

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.