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Objectives: Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients., Methods: A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam., Results: The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable., Conclusions: This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Bacterial keratitis (BK) is a serious ocular infection that can lead to vision impairment or blindness if not treated promptly. Herein, we report the development of a versatile composite hydrogel consisting of silk fibroin and sodium alginate, reinforced by antibiotic-loaded mesoporous silica nanoparticles (MSNs) for the treatment of BK. The drug delivery system is constructed by incorporating vancomycin- and ceftazidime-loaded MSNs into the hydrogel network. The synthesized MSNs were found to be spherical in shape with an average size of about 95 nm. The loading capacities of both drugs were approximately 45% and 43%, for vancomycin and ceftazidime respectively. Moreover, the formulation exhibited a sustained release profile, with 92% of vancomycin and 90% of ceftazidime released over a 24 h period. The cytocompatibility of the drug carrier was also confirmed by MTT assay results. In addition, we performed molecular dynamics (MD) simulations to better reflect the drug-drug and drug-MSN interactions. The results obtained from RMSD, number of contacts, and MSD analyses perfectly corroborated the experimental findings. In brief, the designed drug-MSN@hydrogel could mark an intriguing new chapter in the treatment of BK., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The spread of multidrug-resistant Gram-negative bacterial infections is a significant issue for worldwide public health. Gram-negative organisms regularly develop resistance to antibiotics, especially to β-lactam antimicrobials, which can drastically restrict the number of therapies. A third-generation cephalosporin and the non-β-lactam β-lactamase inhibitor avibactam, which exhibits broad-spectrum β-lactamase inhibition in vitro , are combined to form ceftazidime-avibactam (CAZ-AVI). In this narrative review, we summarize data on pharmacokinetic (PK) parameters for CAZ-AVI in both animal and human models of pneumonia, as well as in healthy individuals. We assessed current literature performing an extensive search of the literature, using as search words 'CAZ-AVI', 'pharmacokinetics', 'pneumonia', 'lung', and 'epithelial lining fluid'. Overall, lung exposure studies of CAZ-AVI revealed that the epithelial lining fluid penetration ranges between 30% and 35% of plasma concentration. Despite the fair lung penetration of CAZ-AVI, this antimicrobial agent has a pivotal role in managing patients with multi-drug resistant Gram-negative pneumonia, however further studies are needed to better assess its PK profile.

Rationale: Shewanella algae are Gram-negative bacteria that are widely found in aquatic habitats and rarely cause lung infections in inland areas., Patient Concerns: Cough with light-yellow phlegm for 2 weeks., Diagnoses: The final diagnosis was bacterial pneumonia., Interventions: The patient was treated with ceftazidime (2 g, every 12 h) for 1 week., Outcomes: The patient's lung infection improved and he was discharged., Lessons: This case highlights a rare occurrence of lung infection caused by Shewanella algae in elderly Tibetan men residing in non-marine environments., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Vancomycin and tobramycin have traditionally been used in antibiotic spacers. In 2020, our institution replaced tobramycin with ceftazidime. We hypothesized that the use of ceftazidime/vancomycin (CV) in antibiotic spacers would not lead to an increase in treatment failure compared to tobramycin/vancomycin (TV)., Methods: From 2014 to 2022, we identified 243 patients who underwent a stage I revision for periprosthetic joint infection. The primary outcome was a recurrent infection requiring antibiotic spacer exchange. We were adequately powered to detect a 10% difference in recurrent infection. Patients who had a prior failed stage I or two-stage revision for infection, acute kidney injury prior to surgery, or end-stage renal disease were excluded. Given no other changes to our spacer constructs, we estimated cost differences attributable to the antibiotic change. Chi-square and t-tests were used to compare the two groups. Multivariable logistic regressions were utilized for the outcomes., Results: The combination of TV was used in 127 patients; CV was used in 116 patients. Within one year of stage I, 9.8% of the TV group had a recurrence of infection versus 7.8% of the CV group (P = .60). By final follow-up, results were similar (12.6 versus 8.6%, respectively, P = .32). Adjusting for potential risk factors did not alter the results. Cost savings for ceftazidime versus tobramycin are estimated to be $68,550 per one hundred patients treated., Conclusions: Replacing tobramycin with ceftazidime in antibiotic spacers yielded similar periprosthetic joint infection eradication success at a lower cost. While larger studies are warranted to confirm these efficacy and cost-saving results, our data justifies the continued investigation and use of ceftazidime as an alternative to tobramycin in antibiotic spacers., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Multidrug-resistant Gram-negative bacteria (MDR-GNB) are becoming increasingly common around the world, with carbapenems frequently serving as a last resort but being threatened by the growing incidence of carbapenemase-producing bacteria. Ceftazidime-avibactam (CAZ/AVI) is a potential agent against MDR-GNB but with limited clinical experience, particularly in critically ill immunosuppressed children., Methods: This study analyzed the use of CAZ/AVI as salvage treatment in severely infected immunosuppressed children from September 2019 to July 2022. Patients with confirmed GNB infection who received CAZ/AVI were matched with patients who received other antibiotics., Results: Twenty-five critically ill immunosuppressed children treated with CAZ/AVI were included. The majority had hematologic diseases. All patients presented with sepsis in all 30 courses. Septic shock presented in 36.7% of these courses. The primary sites of infection included bloodstream infection (20.0%), skin and skin structure infection (20.0%), intra-abdominal infection (13.3%) and hospital-acquired pneumonia (10.0%). Twelve of the 25 (48.0%) patients had positive microbiological cultures, mainly Pseudomonas aeruginosa and Klebsiella pneumoniae , including 5 carbapenem-resistant GNB-infected cases. Fifteen (50.0%) courses presented clinical improvement. For the initial course of each patient, the clinical response rate of the GNB recovered group was significantly higher than that of the group without GNB recovery (66.7% vs 23.1%, P = 0.047). The 14-day and 30-day mortality rates were 24.0% and 28.0%, respectively, which were significantly correlated with the absence of GNB recovery ( P = 0.004 and 0.024, respectively) and hospital-acquired pneumonia as the primary site of infection ( P = 0.001 and 0.006, respectively). There was no significant difference in major outcomes between patients who received CAZ/AVI and matched patients who received other antibiotics., Conclusion: CAZ/AVI could be considered a salvage strategy for immunosuppressed children with confirmed GNB infection. Caution should be taken when CAZ/AVI is applied to these patients in the absence of GNB recovery., Competing Interests: All authors declared no conflicts of interest in this work., (© 2024 Zhu et al.)

Objective: To present and evaluate the treatment of ciprofloxacin-resistant Pseudomonas mastoid cavity otorrhea with a ceftazidime thermosensitive poloxamer gel., Study Design: A retrospective clinical capsule report., Patients: Three patients diagnosed with ciprofloxacin-resistant Pseudomonas otorrhea in the setting of a previous canal-wall-down mastoidectomy between March 2019 and June 2023 visiting our tertiary care institution were retrospectively reviewed., Intervention: Application of a 2% ceftazidime thermosensitive poloxamer gel to mastoid cavity., Main Outcome Measures: No evidence of disease during microscopic inspection of the ear within a month of initial treatment or bacterial eradication on subsequent culture., Results: Two patients had complete resolution of symptoms and achieved a safe and dry ear after topical application of the hydrogel. The second patient had pseudomonal eradication on culture, but persistent otorrhea due to other multidrug-resistant bacteria and an anatomically unfavorable mastoid cavity, which ultimately resolved after revision surgery., Conclusions: This small case series suggests that topical treatment of mastoid cavity otorrhea with a 2% ceftazidime poloxomer gel is a potential therapeutic avenue in patients with ciprofloxacin-resistant Pseudomonas ., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

A man in his 40s with type 2 diabetes mellitus had persistent right-sided watery nasal discharge for 6 months following cerebrospinal fluid (CSF) leak repair at another hospital, prompting his visit to us due to recurring symptoms. Imaging revealed a CSF leak from the mid-clivus for which revision endoscopic CSF leak repair was done. Regrettably, he developed postoperative meningitis caused by multidrug-resistant (MDR) Klebsiella pneumoniae Managing this complex case was a challenging task due to the pathogen's resistance to conventional drugs and the scarcity of scientific evidence. We initiated a culture-guided combination regimen with ceftazidime, avibactam, aztreonam and tigecycline. This decision stemmed from meticulous literature review and observed antibiotic synergy while testing for this organism.After 4 weeks of vigilant treatment, the patient's symptoms improved significantly, and CSF cultures were sterile. We present our approach to effectively confront and manage a challenging instance of postoperative MDR bacterial meningitis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We report a fatal case of New Delhi metallo-β-lactamase (NDM)-producing Escherichia coli in a bacteremic patient with sequential failure of aztreonam plus ceftazidime-avibactam followed by cefiderocol. Acquired resistance was documented phenotypically and mediated through preexisting and acquired mutations. This case highlights the need to rethink optimal treatment for NDM-producing organisms., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Multidrug-resistant (MDR) infections are challenging to treat due to underlying patient conditions, pathogen characteristics, and high antibiotic resistance rates. As newer antibiotic therapies come to market, limited data exist about their real-world utilization., Methods: This was a national retrospective cohort study of ceftazidime/avibactam (approved in 2015) utilization among inpatients from the Veterans Affairs (VA) Healthcare System, from 2015 through 2021. Joinpoint regression was used to estimate time trends in utilization., Results: Ceftazidime/avibactam use increased by 52.3% each year (days of therapy per 1,000 bed days; 95% confidence interval, 12.4%-106.4%). We identified 1,048 unique predominantly male (98.3%) and white (66.2%; Black, 27.7%) patients treated with ceftazidime/avibactam, with a mean (SD) age of 71.5 (11.9) years. The most commonly isolated organisms were Pseudomonas aeruginosa (36.3%; carbapenem resistant, 80.6%; MDR, 65.0%) and Klebsiella species (34.1%; carbapenem resistant, 78.4%; extended-spectrum cephalosporin resistant, 90.7%). Common comorbid conditions included hypertension (74.8%), nervous system disorders (60.2%), diabetes mellitus (48.7%), and cancer (45.1%). Median time to ceftazidime/avibactam initiation from admission was 6 days, with a median of 3 changes in therapy before ceftazidime/avibactam initiation and a subsequent median length of inpatient stay of 14 days (median of 8 days of ceftazidime/avibactam therapy). Treatment heterogeneity was high, both before ceftazidime/avibactam initiation (89.6%) and during ceftazidime/avibactam treatment (85.6%), and common concomitant antibiotics included vancomycin (41.4%), meropenem (24.1%), cefepime (15.2%), and piperacillin/tazobactam (15.2%). The inpatient mortality rate was 23.6%, and 20.8% of patients had a subsequent admission with ceftazidime/avibactam treatment., Conclusion: Utilization of ceftazidime/avibactam increased from 2015 to 2021 in the national VA Healthcare System. Ceftazidime/avibactam was utilized in complex, difficult-to-treat patients, with substantial treatment heterogeneity and variation in the causative organism and culture sites., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Penicillin allergy is the most common drug allergy among hospitalized patients. Traditionally, aztreonam is recommended for patients labeled with penicillin allergy (PLWPA) in our institutional empirical antibiotic guidelines. Due to a global aztreonam shortage in December 2022, the antimicrobial stewardship unit recommended ceftazidime as a substitute. There is a paucity of real-world data on the safety profile of ceftazidime in PLWPA. Hence, we evaluated tolerability outcomes of ceftazidime use in PLWPA., Methods: This retrospective cohort study compared PLWPA in Singapore General Hospital who received aztreonam (October 2022-December 2022) or ceftazidime (December 2022-February 2023). Patients were stratified according to their risk of allergic reaction (AR) based on history of penicillin allergy. The severity of AR was based on the Delphi study grading system. The primary outcome was development of AR after initiation of aztreonam or ceftazidime. The secondary tolerability outcomes include hepatotoxicity and neurotoxicity., Findings: There were 168 patients in the study; 69 were men (41.1%) and the median age was 69 years (interquartile range: 59-76 years). Incidence of AR was statistically similar in both arms: 1 of 102 patients (0.98%) in the aztreonam arm vs 2 of 66 patients (3.03%) in the ceftazidime arm (P = 0.33). The patient in the aztreonam arm was deemed at medium risk of having an AR and developed localized rashes (grade 1). Both patients in the ceftazidime arm were deemed at high risk of AR and developed localized skin reaction (grade 1). Hepatotoxicity was observed in 1 patient prescribed aztreonam. No patients in the ceftazidime arm developed adverse events., Implications: Ceftazidime appears to be better tolerated and cheaper compared with aztreonam in PLWPA, and serves as an antimicrobial stewardship strategy to conserve broader-spectrum antibiotics use., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intrastromal antibiotic injections are a type of treatment that can be very useful in bacterial keratitis refractory to topical antibiotics. We present the case of a 44-year-old woman with an infiltrate in a laser in situ keratomiuleusis (LASIK) flap and growth of Achromobacter xylosoxidans, who was treated with topical ceftazidime for 1 month. However, after discontinuation of the antibiotic, there was a worsening with growth of the same germ. Topical treatment was reintroduced and, due to suspicion of germ reservoir, it was decided to give three cycles of intrastromal ceftazidime injections, the last one also with moxifloxacin, with good results. After 4 months asymptomatic and without treatment at the moment, no signs of recurrence have been observed. This case supports the usefulness of intraestromal injections in refractory cases to the topical medication., (Copyright © 2024 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Serratia marcescens, as a Gram-negative opportunistic pathogen, is a rare cause of peritonitis and has worse clinical outcomes than Gram-positive peritonitis. In this case report, we describe a case of Serratia marcescens associated peritonitis that was successfully cured without catheter removal. A 40-year-old male patient with peritoneal dialysis who worked in the catering industry was admitted to the hospital for 16 hours after the discovery of cloudy peritoneal dialysate and abdominal pain. Ceftazidime and cefazolin sodium were immediately given intravenously as an empirical antibiotic regimen. After detecting Serratia marcescens in the peritoneal diasate culture, the treatment was switched to ceftazidime and levofloxacin. The routine examination of peritoneal dialysate showed a significant decrease in white blood cells, the peritoneal dialysate became clear, and the peritoneal dialysis catheter was retained. The patient was treated for 2 weeks and treated with oral antibiotics for 1 week. It is necessary to further strengthen the hygiene of work environment to prevent Serratia marcescens infection in peritoneal dialysis patients. We recommend that patients with Serratia marcescens associated peritonitis should be treated with a combination of antibiotics as early as possible empirically, and at the same time, the peritoneal dialysis fluid culture should be improved, and the antibiotic regimen should be timely adjusted according to the drug sensitivity results. For patients with clinical symptoms for more than 3 days, considering the strong virulence of Serratia marcescens, whether to use meropenem directly or not can provide a reference for clinical decision-making. Further clinical studies are needed to achieve more precise anti-infective treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xie, Ling, Huang, Qin, Bao and Qin.)

Objectives: The use of extracorporeal membrane oxygenation (ECMO) may alter blood levels of several drugs, including antibiotics, leading to under dosing of these drugs and thus to potential treatment failure. No data exist on pharmacokinetics of new antimicrobial, in particular ceftazidime/avibactam. We therefore perform this study to evaluate ceftazidime/avibactam blood levels in ECMO patients and find factors associated with underdosing., Methods: Retrospective observational study of patients on ECMO having received ceftazidime/avibactam and in whom trough blood levels of ceftazidime and avibactam were available. Main outcome measurement was the number of patients with ceftazidime and avibactam blood levels above predefined cut-off values, derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa, namely 8 mg/L for ceftazidime and 4 mg/L for avibactam, and explored factors associated with underdosing., Results: Twenty-three ceftazidime/avibactam trough levels were available in 14 ECMO patients, all of them having received veno-venous ECMO for SARS-CoV-2-associated pneumonia. Although ceftazidime levels were above 8 mg/L in all except one patient, nine (39%) of the avibactam dosages were below 4 mg/L. Increased renal clearance (creatinine clearance > 130 mL/min) was the main factor associated with under dosing, since 7 out of the 10 dosages below the predefined cut-offs were measured in patients with this condition., Conclusions: In ECMO patients receiving ceftazidime/avibactam, ceftazidime and avibactam serum levels are above EUCAST breakpoints in most cases, justifying the use of normal dosing in ECMO patients. Increased renal clearance may lead to ceftazidime and avibactam under dosing., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Carbapenem-resistant Enterobacterales (CRE) due to Metallo-β-lactamase (MBL) production are treated with either polymyxins or the novel combination of ceftazidime-avibactam and aztreonam (AA). This study aims to evaluate the 30-day mortality of AA in patients with BSI caused by MBL-CRE infections., Methodology: In this systematic review and meta-analysis, all articles up to June 2023 were screened using search terms like 'CRE', 'MBL', 'AA' and 'polymyxins'. The risk ratio for AA vs polymyxins was pooled using a random-effect model, and the results were represented by a point estimate with a 95% confidence interval., Results: After removing the duplicates, the titles and abstracts of 455 articles were screened, followed by a full-text screening of 50 articles. A total of 24 articles were included for systematic review, and four comparative studies were included in the meta-analysis. All four studies had a moderate or serious risk of bias. The pooled risk ratio for 30-day mortality for AA vs. polymyxins was 0.51 (95%CI: 0.34-0.76), p  < 0.001. There was no significant heterogeneity., Conclusion: The meta-analysis from studies with a high risk of bias shows that AA is associated with lesser 30-day mortality when compared to polymyxins in patients with MBL-producing CRE BSI. Registration with PROSPERO- CRD42023433608.

Objective: To evaluate and compare the pharmacokinetic parameters of SC ceftazidime administered at 20 and 40 mg/kg to red-eared sliders., Animals: 8 adult red-eared sliders (Trachemys scripta elegans)., Methods: In a sequential, 2-period study with a 3-week washout period between treatments, ceftazidime was administered SC to turtles at 20 and 40 mg/kg. Blood samples were collected from the subcarapacial sinus at 0, 24, 48, 72, 96, and 120 hours after ceftazidime administration. Plasma ceftazidime concentrations were quantified using reversed-phase HPLC., Results: Mean plasma half-life after 20- and 40-mg/kg dosing was 39.75 ± 8.0 hours and 33.03 ± 6.56 hours, respectively. Mean maximum plasma concentration after 20- and 40-mg/kg dosing was 71.0 ± 15.93 µg/mL and 120.0 ± 30.62 µg/mL, respectively. Mean plasma ceftazidime concentrations remained ≥ 8 µg/mL, the theoretical MIC for various reptile pathogens for all time points., Clinical Relevance: Results indicate that ceftazidime dosed at either 20 or 40 mg/kg produces plasma concentrations exceeding the theoretical MIC of various reptile pathogens for at least 120 hours. An ideal dosing interval could not be determined, as all plasma concentrations remained above the threshold of interest for all time points. Follow-up studies should focus on establishing a dosing interval and more rigorous monitoring for potential adverse effects.

Objectives: The objective of this study was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) in patients with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) pulmonary infections., Methods: A total of 70 KPC-Kp strains were isolated from sputum and bronchoalveolar lavage samples of patients with pulmonary infections in three hospitals in northern China from April 2015 to October 2015. Monte Carlo simulation (MCS) was performed using population pharmacokinetic parameters of CZA combined with the minimum inhibitory concentration (MIC) distributions gained from antimicrobial susceptibility testing to predict the efficacy of different dosing regimens. Various CZA dosing regimens were modelled using MCS., Results: The in vitro study showed potent activity of CZA against KPC-Kp strains with MIC 50/90 values of 1/2 mg/L, with a susceptibility rate of 95.7%. The values of cumulative fraction of response (CFR) for bactericidal (50%fT>5 × MIC) target were as follows: for patients with creatinine clearance (CL Cr ) >51 mL/min, the CFR was 96.01% for 2.5 g CZA every 12 h (q12h) and 97.14% for 2.5 g CZA every 8 h (q8h); and for patients with moderate renal impairment (CL Cr >30 to ≤50 mL/min), the CFR was 95.75% for 1.25 g CZA q12h and 97.09% for 1.25 g CZA q8h., Conclusion: This study indicated that the recommended dose of CZA can provide adequate pharmacodynamic exposure for treating KPC-Kp pneumonia., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

To provide direction for clinical application and pharmaceutical exploitation, the in vitro activity of sulbactam compounds and PIP/TAZ 8 : 1 against clinical isolates of Gram-negative bacteria (GNB, n = 976) was evaluated according to Clinical and Laboratory Standards Institute (CLSI) 2019. By minimal inhibitory concentrations (MICs), the resistance rate of all GNB to AMP/SBT 2 : 1 (56.9-100%) was significantly higher than other drugs, except the resistance rate of Acinetobacter baumannii ( Aba , n = 204) to piperacillin/tazobactam (PIP/TAZ 8 : 1, 78.4%) which was close to it (76.5%). Additionally, the resistance rate of Aba to other compounds except AMP/SBT 2 : 1 differed greatly, but that of Klebsiella pneumonia ( Kpn , n = 205) varied rarely. In addition, Escherichia coli ( Eco , n = 204) and Kpn demonstrated low and high resistance rates, respectively. Compared with cefoperazone/sulbactam (CPZ/SBT 2 : 1), PIP/TAZ 8 : 1 had advantage in anti- Eco (RR = 0.5and OR = 2.17) and anti- Kpn activity (RR = 0.88and OR = 1.27), while its activity against Pseudomonas aeruginosa ( Pae : n = 194, RR = 0.91, and OR = 1.12), Aba (RR = 1.31 and OR = 0.41), and other Enterobacteriaceae (other Ebc : n = 169, RR = 1.40, and OR = 0.62) was not better than CPZ/SBT 2 : 1. Although it had advantage against Eco (RR = 0.60 and OR = 1.78), Pae (RR = 0.67 and OR = 1.63), and Aba (RR = 0.70 and OR = 2.05), the inhibition effect of piperacillin/sulbactam (PIP/SBT 2 : 1) against Kpn (RR = 0.94 and OR = 1.12) and other Ebc was just similar with CPZ/SBT 2 : 1 (RR = 0.93 and OR = 1.10). Furthermore, the anti- Eco (RR = 0.70 and OR = 1.50), anti- Kpn (RR = 0.89 and OR = 1.24), and anti- Pae (RR = 0.74 and OR = 1.46) activities of ceftazidime/sulbactam (CAZ/SBT 1 : 1) had a weak advantage, while its activity against Aba (RR = 0.94 and OR = 1.15) and other Ebc (RR = 0.79 and OR = 1.36) was just close to CPZ/SBT 2 : 1. Moreover, the inhibitory effect of PIP/SBT 1 : 1 against all tested clinical species was more active than CPZ/SBT 2 : 1, while that of CAZ/SBT 2 : 1 against all species of bacteria analyzed was weaker than the controls., Competing Interests: The authors declared no conflict of interest., (Copyright © 2021 Shunian Xiao et al.)

Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

The post-antibiotic effect (PAE) of ceftazidime-avibactam in vivo was evaluated using models of thigh- and lung-infection with Pseudomonas aeruginosa in neutropenic mice. In thigh-infected mice, the PAE was negative (-2.18 to -0.11 h) for three of four strains: caused by a 'burst' of rapid bacterial growth after the drug concentrations had fallen below their pre-specified target values. With lung infection, PAE was positive, and longer for target drug concentrations in ELF (>2 h) than plasma (1.69-1.88 h). The time to the start of regrowth was quantified as a new parameter, PAE R , which was positive (0.35-1.00 h) in both thigh- and lung-infected mice. In the context that measurements of the PAE of β-lactam/β-lactamase inhibitor combinations in vivo have not previously been reported, it is noted that the negative values were consistent with previous measurements of the PAE of ceftazidime-avibactam in vitro and of ceftazidime alone in vivo .

Purpose: MBL and OXA-48 genes in carbapenem-resistant Enterobacterales (CRE) have emerged as a major public health problem worldwide, including Thailand. Due to the lack of susceptibility data and dosing regimens of ceftazidime-avibactam (CZA) against CRE in Thailand, especially in colistin-resistant era, we aimed to demonstrate in vitro susceptibility data of CZA and optimal dose based on Monte Carlo simulation of CZA to expand the treatment options., Patients and Methods: We collected 49 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients at Phramongkutklao Hospital (June-October 2020). CZA disk diffusion and E-test testing were performed to obtain minimum inhibitory concentration (MIC). Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR)., Results: The most common genotypes of CRKP were bla OXA-48 (53.1%) and bla OXA-48 + bla NDM (42.8%). CZA showed 47.7% and 90.5% susceptible rate against all genotypes of carbapenemases and OXA-48 type CRKP isolates. The MIC 50 and MIC 90 of CZA against CRKP were 2 and >256 µg/mL. The categorical agreement (CA) between disk diffusion and E-test testing of CZA against CRKP was 95.4%. The CZA dosing regimens of 2.5 g infused 2-3 h every 8 h achieved ≥90% of the target of free ceftazidime plasma concentration over MIC (% f Time >MIC) ≥50% and 100% against isolates MICs of ≤8 and ≤8 µg/mL, respectively. The avibactam regimens also provided 100% f Time at 0.5 µg/mL. Based on CFR ≥90%, no CZA regimens were effective against all of the studied CRKP isolates except CRKP carrying OXA-48., Conclusion: CZA exhibited a fairly susceptible rate among the OXA-48-positive isolates in Thailand. The current suggested dose of CZA with prolonged infusion appears appropriate to achieve the pharmacokinetic/pharmacodynamic targets of ceftazidime and avibactam against CRKP carrying bla OXA-48 ., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Nasomsong et al.)

Purpose: To evaluate the administration regimen of ceftazidime/avibactam (CZA) for bloodstream infections caused by Enterobacteriaceae and Pseudomonas aeruginosa ., Methods: The minimal inhibitory concentrations (MICs) of CZA against Enterobacteriaceae and P. aeruginosa isolated from blood cultures at member hospitals in BRICS (Blood Bacterial Resistant Investigation Collaborative System) in 2019 were determined by broth micro-dilution methodology. A 10,000-patient Monte Carlo simulation (MCS) was used to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different CZA dosage regimens to evaluate their efficacies and optimize the best initial dosage regimen., Results: Altogether, 6487 Enterobacteriaceae and P. aeruginosa strains were isolated from the blood cultures. The overall CZA resistance rate was 2.31%, of which the Enterobacteriaceae and P. aeruginosa rates were 1.57% and 14.29%, respectively. The MCS showed that the greater the MIC value, the worse the therapeutic effect. When the CZA MIC was ≤8 mg/L, the standard dose (2.5g iv q8h) achieved 90% PTA in the subset of patients with creatinine clearance (CrCl) values from 51 to 120 mL/min. Although the high-dose regimen (3.75g iv q8h) achieved 90% PTA in patients with CrCl values from 121 to 190 mL/min, implementing the low-dose regimen (1.25g iv q8h) was also effective for patients in the 51-89 mL/min CrCl range. Generally, the high-dose regimen (3.75g iv q8h) reached 90% CFR against all of the strains. Conversely, in patients with CrCl values of 121-190 mL/min, the standard dose (2.5g iv q8h) failed to reach 90% CFR against some Enterobacteriaceae members and P. aeruginosa . When the dose was reduced to the low-dose regimen (1.25g iv q8h), no patients reached 90% CFR against some Enterobacteriaceae members and P. aeruginosa., Conclusion: CZA has good antibacterial activity against Enterobacteriaceae and P. aeruginosa in bloodstream infections. Clinicians could make individualized treatment regimens in accordance with the sensitivity of the strains and the level of renal function in their patients to best predict the drug-related clinical responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2021 Dai et al.)

Pandrug-resistant (PDR) K. pneumoniae refractory to conventional treatment has been reported worldwide, causing a huge burden on the healthcare system, patient safety and the economy. K. pneumoniae is a prominent opportunistic pathogen causing hospital-acquired and community-acquired infections, but is rarely associated with infective endocarditis. Currently, there are sparse data guiding the optimal regimen when commonly used antibiotics fail, notably for the treatment of endocarditis infections. Here we report our experience in treating a 40-year-old female with PDR K. pneumoniae infection of cardiovascular implantable electronic device (CIED) and right-sided infective endocarditis. Initial susceptibility testing of the incriminated pathogen showed an apparent susceptibility to colistin but the prolonged course of colistin, gentamicin and meropenem did not resolve the infection. However, the synergistic combinations of aztreonam with ceftazidime-avibactam was able to overcome resistance and clear the infection rapidly. Genome sequencing showed that the PDR K. pneumoniae isolate belongs to the international high-risk clone ST14. The isolate harbored genes encoding NDM-1, OXA-48, CTX-M-14b, SHV-28 and OXA-1, explaining resistance to all β-lactams, including carbapenems. It carried the armA gene conferring resistance to all clinically important aminoglycosides and had alterations in GyrA, ParC and MgrB, explaining resistance to ciprofloxacin and colistin.

Population pharmacokinetics utilizing sparse sampling were used to determine pharmacokinetics of ceftazidime in eastern hellbenders ( Cryptobranchus alleganiensis alleganiensis ) due to their slow growth rate and the limited number of appropriately sized individuals in the zoo-housed population. Twenty-five eastern hellbenders received a single subcutaneous injection of ceftazidime at 20 mg/kg. Each animal had blood samples collected up to four times between 0 and 192 hr postinjection. Plasma samples were analyzed by high-pressure liquid chromatography. A nonlinear mixed-effects model was fitted to the data to determine typical values for population parameters, an ideal method due to the sampling limitation of each hellbender. Results indicate an elimination half-life of 36.63 hr and volume of distribution of 0.31 L/kg. Antibiotic concentrations were above a minimum inhibitory concentration (MIC) value of 8 µg/ml for 120 hr. Prior to antibiotic administration, six hellbenders had oral and six other individuals had cloacal swabs taken for aerobic culture. Fifty-five bacterial isolates were obtained (24 cloacal, 31 oral) with 10/12 (83%) individuals growing three or more different isolates and 11/12 (92%) growing Shewanella putrefaciens . Twelve isolates had susceptibility testing performed and all were susceptible to ceftazidime. These results indicate that ceftazidime is an appropriate choice of antibiotic in hellbenders and when given at a dosage of 20 mg/kg subcutaneously, maintains concentrations above the MIC of susceptible bacteria for up to 5 days.

Background: Meropenem monotherapy vs ceftazidime plus amikacin have been approved for use against febrile neutropenia. To assess the effectiveness and safety of them for empirical treatment of cancer patients with febrile neutropenia, we conducted a meta-analysis of randomized controlled trial., Methods: Randomized controlled trials on ceftazidime plus amikacin, or/and monotherapy with meropenem for the treatment of cancer patients with febrile neutropenia were identified by searching Cochrane Library, PubMed, Science Direct, Wiley Online, Science Citation Index, Google (scholar), National Center for Biotechnology Information, and China National Knowledge Infrastructure. Data on interventions, participants' characteristics and the outcomes of therapy, were extracted for statistical analysis. Seven trials fulfilled the inclusion criteria., Result: The treatment with ceftazidime plus amikacin was more effective than meropenem (OR = 1.17; 95% CI 0.93-1.46; 1270 participants). However, the treatment effects of the 2 therapy methods were almost parallel in adults (OR = 1.15; 95% CI 0.91-1.46; 1130 participants older than 16). Drug-related adverse effects afflicted more patients treated with ceftazidime plus amikacin (OR = 0.78; 95% CI 0.52-1.15; 1445 participants). The common responses were nausea, diarrhea, rash, and increased in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin., Conclusion: Ceftazidime plus amikacin should be the first choice for empirical treatment of cancer patients with febrile neutropenia, and meropenem may be chosen as a last defense against pathogenic bacteria., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The pharmacokinetics/pharmacodynamics of continuous infusion (CI) beta-lactams for Pseudomonas aeruginosa biofilm infections has not been defined. This study evaluated the efficacy of several dosage regimens of CI ceftazidime, with or without colistin, an antibiotic with a potential antibiofilm effect, against biofilm-embedded P. aeruginosa., Methods: Mature biofilms of the reference strain PAO1 and the clinical isolate HUB8 (both ceftazidime- and colistin-susceptible) were investigated over 54h using a dynamic CDC biofilm reactor. CI dosage regimens were ceftazidime monotherapy (4, 10, 20 and 40 mg/L), colistin monotherapy (3.50 mg/L), and combinations of colistin and ceftazidime (4 or 40 mg/L). Efficacy was evaluated by changes in log 10 colony-forming units (cfu)/mL and confocal microscopy., Results: At 54 h, the antibiofilm activity of ceftazidime monotherapies was slightly higher for ceftazidime 20 mg/L (-2.84 log 10 cfu/mL) and 40 mg/L (-3.05) against PAO1, but no differences were seen against HUB8. Ceftazidime-resistant colonies emerged with 4 mg/L regimens in both strains and with other regimens in PAO1. Colistin monotherapy had significant antibiofilm activity against HUB8 (-3.07), but lower activity against PAO1 (-1.12), and colistin-resistant strains emerged. Combinations of ceftazidime and colistin had higher antibiofilm activity at 54 h compared with each monotherapy, and prevented the emergence of resistance to both antibiotics; higher antibiofilm activity was observed with ceftazidime 40 mg/L plus colistin compared with ceftazidime 4 mg/L plus colistin (-4.19 vs. -3.10 PAO1; -4.71 vs. -3.44 HUB8)., Conclusions: This study demonstrated that, with %T>MIC=100%, CI ceftazidime displayed concentration-dependent antibiofilm activity against P. aeruginosa biofilm, particularly in combination with colistin. These results support the use of high-dosage regimens of CI ceftazidime with colistin against biofilm-associated infections with ceftazidime-susceptible P. aeruginosa., (Copyright © 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Objectives: Antimicrobial resistance is a major threat to public health. New drugs such as Ceftazidime/avibactam have been developed for the treatment of Multi-Drug resistant (MDR) pathogens. Susceptibility can be variable and inappropriate use can add a financial strain on the National Health Service (NHS). There is a pressing need to ensure these new and invaluable antimicrobials are preserved and used effectively., Methods: We undertook a retrospective observational study to assess the use of Ceftazidime/avibactam and evaluated prescribing against applied standards., Results: Between August 2017 and January 2019, 28 patients received 31 courses of Ceftazidime/avibactam. Prescribing according to the approved indications was observed for 68% of prescriptions (p < 0.0001). Duration of therapy was often prolonged but improved with Antimicrobial stewardship interventions. We observed 56% susceptibility (15/27 isolates) of MDR organisms ( Pseudomonas, Klebsiella, Burkholderia, Enterobacter aerogenes, Achromobacter) . We also report first in vivo experience to treat pulmonary disease caused by Non-tuberculous mycobacteria (NTM). Ceftazidime/avibactam was well tolerated, with no evidence of development of resistance at 6-months follow-up., Conclusions: Our study showed that Antimicrobial stewardship interventions led to a more appropriate use of Ceftazidime/avibactam (as measured by duration of therapy), preserving it as a treatment option for MDR infections.

The American Academy of Orthopaedic Surgeons Clinical Practice Guideline "Diagnosis and Prevention of Periprosthetic Joint Infections (PJI)" is a summary of the available literature designed to help guide surgeons and other qualified physicians in the management of PJI. Obesity and intra-articular joint injections are associated with an increased risk of PJI according to this Clinical Practice Guideline. Serum erythrocyte sedimentation rate, C-reactive protein, and/or interleukin-6 should be obtained when diagnosing PJI. Synovial fluid leukocyte count, neutrophil percentage, aerobic and anaerobic bacterial cultures, leukocyte esterase, alpha-defensin, C-reactive protein, and nucleic acid amplification testing may assist with the diagnosis of PJI. Antibiotics should be held for 2 weeks before obtaining samples. Intraoperatively, Gram stains do not help with PJI diagnosis, whereas histopathology samples are helpful. These guidelines may help clinicians with the prevention and diagnosis of PJI.

The objective of this study was to compare the release of endotoxin and pro-inflammatory cytokines as well as pregnancy outcomes after antibiotic exposure in healthy and bacterial infected pregnant rats. Thirty female Wistar pregnant rats were divided into five groups. Group A considered as control and received intraperitoneal saline 0.9% on 17th day of gestation or DG) and groups B and C treated with 20 mg/kg/day intravenous ceftriaxone and ceftazidime, respectively (DG: 18-20). Groups D and E received intraperitoneal E. coli and LPS on 17th DG respectively. Also, groups F and G received the same treatment as group D but they treated with the exact antibiotics mentioned for groups B and C (same dose and duration). Pregnancy outcomes as well as maternal sera levels of endotoxin, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 were assessed using enzyme-linked immunosorbent assay. It was shown that group B had a higher IL-1β (P = 0.003) and TNF-α (P = 0.003) levels compared to the controls (CTC). Group C expressed a lower gestational duration (P = 0.007) as well as higher IL-6 (P = 0.025) and TNF-α (P < 0.001) levels CTC. Interestingly, both group B (P = 0.021) and C (P < 0.001) had a higher rate of endotoxin release CTC. Moreover, in group C, IL-6 (P < 0.0001 and r = -0.941) had a significant correlation with gestational duration. As the results showed, antibiotic administration in non-indication condition seems to be associated with significantly higher production of endotoxin and inflammatory cytokines which increase the risk of poor pregnancy outcomes., (Copyright © 2020. Published by Elsevier B.V.)

Background: Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO., Methods: Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints., Results: The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem., Conclusions: ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.

Resolution is an active process that protects the host damage from inflammation responses induced by infections. Simultaneously resolving inflammation and eliminating pathogens may be effective to treat infectious diseases, but it is required to deliver therapeutics to infectious sites. Here, we proposed a strategy to incorporate RvD1 and an antibiotic (ceftazidime) in human neutrophil-membrane derived nanovesicles that can specifically target inflamed vasculature for treatment of lung infection caused by P. aeruginosa. Using the nitrogen cavitation method, we generated liposome-like nanovesicles from human neutrophil membrane. The results showed that nanovesicles loaded with RvD1 decreased cytokine levels and neutrophil lung infiltration, thus shortening the resolution intervals of lung inflammation. When RvD1 and ceftazidime were co-loaded in nanovesicles, they alleviated both inflammation and bacterial growth in the mouse lung. The studies reveal a new strategy to treat infectious diseases by designing nanoparticles to simultanesouly target host inflammatory pathways and pathogens.

Introduction: Treatment of recurrent Urinary tract infections (UTIs) has become challenging because of the dramatic increase in the rates of recurrent infection andof multidrug-resistant (MDR) infections., Areas Covered: The authors review recurrent UTIs(rUTI) management in women., Expert Opinion: Continuous or post-coital prophylaxis with low-dose antimicrobials or intermittent self-treatment has all been demonstrated to be effective in managing rUTIs in women. Intravaginal estrogen therapy , shows potential toward preventing rUTI. Oral vaccine Uro-Vaxom seems to reduce the number of UTIs. There is evidence that other therapies (e.g. cranberry, Methenamine hippurate, oral D-mannose) may decrease the number of symptomatic UTIs. The treatment of CRE-UTIs is focused on a colistin backbone. Carbapenems are considered first-line agents for UTIs caused by ESBL, but their use is associated with increased MDR. The usage of non-carbapenem for the treatment of ESBL UTIs is necessary. Cefepime, Piperacillin-Tazobactam, Ceftolozane-Tazobactam, and Ceftazidime-Avibactam are justified options. Oral therapy with Pivmecillinam, Fosfomycin, and Nitrofurantoin can be used against uncomplicated UTIs due to ESBL infection.

Bloodstream infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) is a severe and challenging complication in the early post-transplantation period. Pulmonary infection secondary to sepsis caused by CRKP has been reported only rarely in kidney transplant recipients. Here we report an interesting and complicated case in which CRKP was initially isolated in a culture of renal graft preservation solution, yet was not detected in the daily cultures from collection of surgical drainage. Prophylactic tigecycline was terminated at post-transplantation day 10 because of the occurrence of acute pancreatitis. Five days later, the patient suddenly developed a multisite infection with CRKP involving the bloodstream, urinary tract, and lungs, indicating probable transmission from the donor. Fortunately, the infection was controlled quickly and effectively with a combination therapy consisting of ceftazidime-avibactam (CZA) and carbapenem, which was suggested by the results of disc diffusion susceptibility testing. However, the CRKP infection reappeared in the bloodstream and urinary tract soon after the treatment of acute rejection. The combination regimen was continued for another 15 days, and the patient ultimately recovered. During the following 15 months of observation, the patient's renal graft function remained stable, without recurrence of the CRKP infection. In conclusion, the combined use of CZA and carbapenem was safe and produced an optimal therapeutic effect on the severe multisite infection caused by CRKP in a renal transplant recipient, thus providing a reference case for treating such patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa., Methods: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10., Findings: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group., Interpretation: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis., Funding: National Institute for Health Research Health Technology Assessment Programme., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration., Methods: Ceftazidime-avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate., Findings: Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime-avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments., Implications: Ceftazidime-avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Ceftazidime-avibactam combines the established anti-pseudomonal cephalosporin, ceftazidime, with the novel non-β-lactam β-lactamase inhibitor, avibactam., Objectives: The aim of this study was to evaluate the safety of ceftazidime-avibactam in adults using pooled data from two phase II (NCT00690378, NCT00752219) and five phase III (NCT01499290, NCT01726023, NCT01644643, NCT01808093 and NCT01595438/NCT01599806) clinical studies., Methods: Safety data from seven multicentre, randomised, active-comparator studies were pooled by study group at the patient level for descriptive analyses, comprising patients with complicated urinary tract infection (cUTI), including pyelonephritis, complicated intra-abdominal infection (cIAI), or nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), treated with ceftazidime-avibactam ± metronidazole or comparator., Results: In total, 4050 patients (ceftazidime-avibactam ± metronidazole, n = 2024; comparator, n = 2026) were included in the pooled analysis. Adverse events (AEs) up to the last study visit occurred in 996 (49.2%) and 965 (47.6%) patients treated with ceftazidime-avibactam ± metronidazole and comparator, respectively. The most common AEs across treatment groups were diarrhoea, nausea, headache, vomiting and pyrexia. There were few discontinuations due to AEs (2.5% and 1.7% for ceftazidime-avibactam ± metronidazole and comparators, respectively). Overall rates of serious AEs were 8.7% for ceftazidime-avibactam ± metronidazole and 7.2% for comparators; respective rates of AEs with an outcome of death were 2.0% and 1.8%. AEs considered causally related to the study drug or procedures occurred in 10.7% and 9.6% of patients treated with ceftazidime-avibactam ± metronidazole and comparators; the most common drug-related AEs in both groups were diarrhoea, headache, nausea and increased alanine aminotransferase. No impact to the safety profile of ceftazidime-avibactam ± metronidazole was found with regard to intrinsic factors, such as age or renal function at baseline, or extrinsic factors, such as geographical origin. Potentially clinically significant changes in laboratory parameters were infrequent with no trends or safety concerns identified., Conclusion: The observed safety profile of ceftazidime-avibactam across infection types is consistent with the established safety profile of ceftazidime monotherapy and no new safety findings were identified. This analysis supports the use of ceftazidime-avibactam as a treatment option in adults with cUTI, cIAI and NP, including VAP.

To report long-term outcomes of intravitreal ceftazidime injection in patients with endogenous Klebsiella pneumoniae endophthalmitis (EKPE).This was a retrospective observational case study, including 7 eyes from 6 patients with EKPE. The medical records from January 2010 to December 2018 were reviewed.Diagnosis of EKPE was made based on the finding of endophthalmitis with concurrent systemic infection and positive blood culture result. All patients received tap and intravitreal ceftazidime injection base on the results of antibiotics sensitivity test. Visual acuity ranged from no light perception to 20/60 at initial visit, and the final visual acuity was 20/20. Two eyes underwent evisceration after intravitreal injection.Intravitreal ceftazidime injection showed favorable results in patients with EKPE.

Background: Intraperitoneal (IP) cefazolin and ceftazidime during the short-dwell (≤ 2 h) automated exchange has been shown to provide adequate dialysate and plasma concentrations for up to 24 h in peritoneal dialysis (PD) patients without peritonitis. This study aimed to evaluate plasma and dialysate concentration of this novel IP cefazolin and ceftazidime regimen during the first 24 h in PD patients with peritonitis., Methods: Cefazolin and ceftazidime (2500 mg each) were added to in to a 5-L bag containing 2.5% of dextrose PD fluid which was placed on the warmer of PD cycling machine. Patients underwent five exchanges of 2-L PD fluid over 10 h by the PD cycling machine without last fill or additional dwell. Plasma samples and dialysate samples were collected over 24 h. Cefazolin and ceftazidime concentrations in plasma and dialysate were determined by high-performance liquid chromatography., Results: Seven PD patients with peritonitis participated in this study. Plasma cefazolin and ceftazidime levels increased substantially within the first few hours, peaked around 6-10 h, and sustained well above the target plasma concentrations (10 mg L -1 for cefazolin and 16 mg L -1 for ceftazidime) until 24 h. Dialysate cefazolin and ceftazidime levels were sustained above the target peritoneal concentrations (2 mg L -1 for cefazolin and 8 mg L -1 for ceftazidime) throughout the PD session except in some samples which the antibiotics levels were unusually low, probably from beta-lactamase activity., Conclusions: IP cefazolin and ceftazidime during the short-dwell automated exchange could provide adequate dialysate and plasma concentrations in peritonitis patients. This novel regimen is a promising regimen for peritonitis in PD patients.

Purpose: Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination recently approved in Europe and the USA for the treatment of adults with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), among other indications. In the phase III REPROVE trial (NCT01808092), ceftazidime-avibactam demonstrated non-inferiority to meropenem for the treatment of patients with nosocomial pneumonia (NP), including VAP. As ceftazidime-avibactam was not studied in patients with NP prior to REPROVE, selecting an appropriate dosage regimen in the "perfect storm" of NP required careful consideration of potential determinants and confounders of response specific to the NP patient population., Methods: This review describes the series of preclinical studies and pharmacokinetic/pharmacodynamic (PK/PD) analyses that supported ceftazidime-avibactam dosage selection for patients with NP/VAP (2000/500 mg by 2-h intravenous infusion every 8 h, adjusted for renal function). In parallel, important considerations for antibiotic dosage selection in patients with NP are highlighted, including adequate drug penetration into the lungs, the suitability of murine-derived plasma PK/PD targets, evaluation of MIC distributions against clinical bacterial isolates from patients with NP, and consideration of PK in patients with NP, who are often critically ill. These analyses also supported the European approval of ceftazidime-avibactam for adults with HAP, including VAP, before the completion of REPROVE., Conclusions: This work serves as a successful practical example of dosage design for a new antibacterial drug therapy in the indication of NP, including VAP, where previous drug therapies have failed, possibly as a result of evaluation of too few variables, thereby limiting the accuracy of pharmacodynamic predictions.

Monte Carlo simulations (MCSs) are used in antibiotic development to predict the probability of pharmacodynamic target attainment (PTA) for a dosing regimen. However, for β-lactam/β-lactamase inhibitor combinations (BL-BLICs), methods for linking simulated concentration profiles of the β-lactam (BL) and β-lactamase inhibitor (BLI) components are rarely described. Using a previously defined pharmacokinetic model of ceftazidime/avibactam from critically ill patients, we performed four 5000-patient MCSs using different methods of increasing complexity to couple the BL and BLI components and compared PTA for ceftazidime and avibactam targets of >70% fT>MIC and >70% fT>1 mg/L, respectively, at MICs from 1 to 128 mg/L. Method A ignored all covariates and correlations, whereas methods B, C, and D enhanced associations by adding (B) pharmacokinetic parameter correlation within each drug only; (C) pharmacokinetic parameter correlation within each drug and creatinine clearance (CRCL); and (D) pharmacokinetic parameter correlation within each drug, CRCL, and pharmacokinetic parameter correlation between drugs. Method D produced a simulated patient population that best recapitulated the observed relationships between pharmacokinetic parameters in actual patients. Ceftazidime/avibactam PTA at MIC 8 mg/L (the susceptibility break point) and 16 mg/L ranged from 92.4% to 98.3% and 80.2% to 88.4%, respectively. PTA was lowest with method A, whereas PTA estimates were similar for all other methods. Compared with ignoring all pharmacokinetic parameter associations, the inclusion of covariate relationships and parameter correlation between both components of ceftazidime/avibactam leads to fewer patients with discordant pharmacokinetic parameters and results in higher PTA. Consideration of these methodologies should guide future MCS analyses for BL-BLIC., (© 2019, The American College of Clinical Pharmacology.)