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Introduction: Intra-abdominal infections are becoming increasingly common and can lead to significant morbidity and mortality. The incidence of these infections due to resistant gram-negative organisms is also increasing. Given this resistance, new antibiotic combinations are being developed, often utilizing older antibiotics and newer β-lactamase inhibitors. Aztreonam/avibactam (ATM-AVI) is one of the combination antibiotics, which combines aztreonam, a monobactam, with avibactam, a broad-spectrum β-lactamase inhibitor for the treatment of complicated intra-abdominal infections in combination with metronidazole., Areas Covered: In this drug evaluation manuscript, we provide an overview of intra-abdominal infections and an overview of currently available antimicrobial agents used to treat these infections. ATM-AVI is introduced, including chemistry, pharmacodynamics, pharmacokinetics and clinical studies of this compound., Expert Opinion: There are limited treatment options for complicated intra-abdominal infections due to resistant gram-negative organisms, especially those with metallo-β-lactamases. One treatment option for these infections is ATM-AVI, which was recently approved in Europe, in addition to metronidazole. These bacteria are difficult to treat, and this new compound is a safe and effective option for empiric treatment in places with a high incidence of infections due to these bacteria, and also treatment for infections when these resistant bacteria are isolated in culture.

Carbapenem-resistant Enterobacterales are being reported increasingly and cause nosocomial infections, which may include postoperative mediastinitis. This paper reports a case of postoperative mediastinitis caused by an Escherichia coli NDM-1 carbapenemase producer in a 13-month-old boy with DiGeorge syndrome. The infection was managed with surgical debridement and antibiotherapy with aztreonam, ceftazidime-avibactam and IV fosfomycin for 6 weeks. The evolution was favourable, without relapse over 10 weeks of follow-up., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Amongst all etiologic hospital-acquired infection factors, K. pneumoniae strains producing New Delhi metallo-β-lactamase (KP-NDM) belong to pathogens with the most effective antibiotic resistance mechanisms. Clinical guidelines recommend using ceftazidime/avibactam with aztreonam (CZA + AT) as the preferred option for NDM-producing Enterobacterales. However, the number of observations on such treatment regimen is limited. This retrospective study reports the clinical and microbiological outcomes of 23 patients with KP-NDM hospital-acquired infection treated with CZA + AT at a single center in Poland., Methods: The isolates were derived from the urine, lungs, blood, peritoneal cavity, wounds, and peritonsillar abscess. In microbiological analysis, mass spectrometry for pathogen identification, polymerase chain reaction, or an immunochromatographic assay for detection of carbapenemase, as well as VITEK-2 system, broth microdilution, and microdilution in agar method for antimicrobial susceptibility tests were used, depending of the pathogens' nature. CZA was administered intravenously (IV) at 2.5 g every eight hours in patients with normal kidney function, and aztreonam was administered at 2 g every eight hours IV. Such dosage was modified when renal function was reduced., Results: KP-NDM was eradicated in all cases. Four patients (17.4%) died: three of them had a neoplastic disease, and one - a COVID-19 infection., Conclusion: The combination of CZA + AT is a safe and effective therapy for infections caused by KP-NDM, both at the clinical and microbiological levels. The synergistic action of all compounds resulted in a good agreement between the clinical efficacy of CZA + AT and the results of in vitro susceptibility testing., (© 2024. The Author(s).)

Purpose: Enterobacteriaceae carrying mcr-9, in particularly those also co-containing metallo-β-lactamase (MBL) and TEM type β-lactamase, present potential transmission risks and lack adequate clinical response methods, thereby posing a major threat to global public health. The aim of this study was to assess the antimicrobial efficacy of a combined ceftazidime/avibactam (CZA) and aztreonam (ATM) regimen against carbapenem-resistant Enterobacter cloacae complex (CRECC) co-producing mcr-9, MBL and TEM., Methods: The in vitro antibacterial activity of CZA plus ATM was evaluated using a time-kill curve assay. Furthermore, the in vivo interaction between CZA plus ATM was confirmed using a Galleria mellonella (G. mellonella) infection model., Results: All eight clinical strains of CRECC, co-carrying mcr-9, MBL and TEM, exhibited high resistance to CZA and ATM. In vitro time-kill curve analysis demonstrated that the combination therapy of CZA + ATM exerted significant bactericidal activity against mcr-9, MBL and TEM-co-producing Enterobacter cloacae complex (ECC) isolates with a 100% synergy rate observed in our study. Furthermore, in vivo survival assay using Galleria mellonella larvae infected with CRECC strains co-harboring mcr-9, MBL and TEM revealed that the CZA + ATM combination significantly improved the survival rate compared to the drug-treatment alone and untreated control groups., Conclusion: To our knowledge, this study represents the first report on the in vitro and in vivo antibacterial activity of CZA plus ATM against CRECC isolates co-harboring mcr-9, MBL and TEM. Our findings suggest that the combination regimen of CZA + ATM provides a valuable reference for clinicians to address the increasingly complex antibiotic resistance situation observed in clinical microorganisms., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.)

Pseudomonas aeruginosa harboring Verona Integron-encoded metallo-β-lactamase enzymes (VIM-CRPA) have been associated with infection outbreaks in several parts of the world. In the US, however, VIM-CRPA remain rare. Starting in December 2018, we identified a cluster of cases in our institution. Herein, we present our epidemiological investigation and strategies to control/manage these challenging infections. This study was conducted in a large academic healthcare system in Miami, FL, between December 2018 and January 2022. Patients were prospectively identified via rapid molecular diagnostics when cultures revealed carbapenem-resistant P. aeruginosa . Alerts were received in real time by the antimicrobial stewardship program and infection prevention teams. Upon alert recognition, a series of interventions were performed as a coordinated effort. A retrospective chart review was conducted to collect patient demographics, antimicrobial therapy, and clinical outcomes. Thirty-nine VIM-CRPA isolates led to infection in 21 patients. The majority were male (76.2%); the median age was 52 years. The majority were mechanically ventilated ( n = 15/21; 71.4%); 47.6% ( n = 10/21) received renal replacement therapy at the time of index culture. Respiratory ( n = 20/39; 51.3%) or bloodstream ( n = 13/39; 33.3%) were the most common sources. Most infections ( n = 23/37; 62.2%) were treated with an aztreonam-avibactam regimen. Six patients (28.6%) expired within 30 days of index VIM-CRPA infection. Fourteen isolates were selected for whole genome sequencing. Most of them belonged to ST111 (12/14), and they all carried bla VIM-2 chromosomally. This report describes the clinical experience treating serious VIM-CRPA infections with either aztreonam-ceftazidime/avibactam or cefiderocol in combination with other agents. The importance of implementing infection prevention strategies to curb VIM-CRPA outbreaks is also demonstrated., Competing Interests: The authors declare no conflict of interest.

Carbapenemase-producing Enterobacterales (CPEs) are one of the top priority antimicrobial-resistant pathogens. Among CPEs, those producing acquired metallo-β-lactamases (MBLs) are considered particularly problematic as few agents are active against them. Imipenemase (IMP) is the most frequently encountered acquired MBL in Japan, but comprehensive assessment of clinical and microbiological features of IMP-producing Enterobacterales infection remains scarce. Here, we retrospectively evaluated 62 patients who were hospitalized at a university hospital in Japan and had IMP-producing Enterobacterales from a clinical culture. The isolates were either Enterobacter cloacae complex or Klebsiella pneumoniae , and most of them were isolated from sputum. The majority of K. pneumoniae, but not E. cloacae complex isolates, were susceptible to aztreonam. Sequence type (ST) 78 and ST517 were prevalent for E. cloacae complex and K. pneumoniae , respectively, and all isolates carried bla IMP-1 . Twenty-four of the patients were deemed infected with IMP-producing Enterobacterales . Among the infected patients, therapy varied and largely consisted of conventional β-lactam agents, fluoroquinolones, or combinations. Three (13%), five (21%), and nine (38%) of them died by days 14, 30, and 90, respectively. While incremental mortality over 90 days was observed in association with underlying comorbidities, active conventional treatment options were available for most patients with IMP-producing Enterobacterales infections, distinguishing them from more multidrug-resistant CPE infections associated with globally common MBLs, such as New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase (VIM)., Competing Interests: The authors declare no conflict of interest.

Introduction: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections commonly cause hospital-acquired infections. The study aimed to compare the outcomes of CRKP infections between patients receiving ceftazidime avibactam +/- aztreonam and polymyxins in a hospital setting with a high prevalence of New Delhi Metallo Beta Lactamase production., Methods: We conducted a retrospective cohort study from January 2020 to September 2022 in critically ill adult patients admitted to a non-COVID-19 medical intensive care unit with CRKP infection. The patients were followed up for a total of 30 days or death, whichever was later., Results: Of a total of 106 patients included in the study, 65 patients received polymyxins and 41 patients received ceftazidime-avibactam +/- aztreonam. Higher 30-day mortality was noted in the polymyxin group (56.9% vs. 29.2%, P = 0.005). The mean time to event (mortality) in ceftazidime-avibactam +/- aztreonam was 23.9 + 1.5 days which was significantly higher compared to polymyxins (17.9 + 1.2 days, p = 0.006). On Cox regression analysis, after adjusting for the covariates, the hazard ratio for time to event with the use of polymyxin was 2.02 (95% CI: 1.03-3.9)., Conclusion: Ceftazidime-avibactam + aztreonam is possibly associated with better clinical outcomes in patients infected with CRKP., (© 2023. The Author(s).)

Purpose: The choice of antibiotics for treatment of Carbapenem-Resistant Enterobacterales (CRE) is increasing becoming limited due to co-expression of Metallo-beta-lactamases (MBL) along with other carbapenemases in these isolates. The study aimed to investigate the occurrence of CRE and to determine the in-vitro synergy and clinical outcomes of Ceftazidime-Avibactam and Aztreonam combination in CRE infections in adult Intensive Care Units (ICUs)., Methods: 79 CRE isolates recovered from adult ICUs during January to March 2023 were tested by O.K.N.V.I. RESIST-5, a lateral flow multiplex assay for rapid detection of OXA-48-like, NDM, IMP, VIM, and KPC carbapenemases. Ceftazidime-Avibactam MIC was determined by microbroth dilution method and in vitro synergy between Ceftazidime-Avibactam and Aztreonam was assessed by Modified E-test/disc diffusion method for these isolates., Results: The study revealed 7.5 % occurrence of CRE in our hospital, with high occurrence of NDM (n = 42, 53.1 %) and OXA-48-like (n = 63, 79.7 %) carbapenemase. Production of more than one type of carbapenemases was found in 44 isolates. A total of 57 isolates (72 %) had Ceftazidime-Avibactam resistance and 44 of them displayed Ceftazidime-Avibactam and Aztreonam in-vitro synergy. Successful clinical outcome was observed in two patients who received Ceftazidime-Avibactam and Aztreonam combination therapy for 7 days or more., Conclusions: Despite the preponderance of Ceftazidime-Avibactam resistant CRE expressing NDM and OXA-48-like carbapenemase in our hospital, 77.2 % of them displayed in-vitro synergy of Ceftazidime-Avibactam with Aztreonam. It emphasizes the potential therapeutic utility of this combination in CRE strains showing coproduction of MBL and serine carbapenemases. Greater therapeutic potential of Ceftazidime-Avibactam and Aztreonam combination was observed with extended duration of therapy. However, further clinical evidence is needed to establish the efficacy of this combination and consider other factors that influence treatment outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.Kalaivani reports financial support and administrative support were provided by Mahatma Gandhi Medical College and Research Institute. R.Kalaivani reports a relationship with Mahatma Gandhi Medical College and Research Institute that includes: employment. No conflicts of interest., (Copyright © 2024 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Importance: To our knowledge, this is the first study to report the in vitro activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA), toward carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKP) strains. Our in vitro activity study revealed that only few antibacterial agents (including several novel agents) exhibit high antimicrobial activity toward carbapenem-resistant Klebsiella pneumoniae (CRKP) and CR-hvKP isolates. IMR and AZA may be promising therapeutic agents for the treatment of infections caused by CRKP and CR-hvKP isolates., Competing Interests: The authors declare no conflict of interest.

Purpose of Review: This review focuses on the management of severe Pseudomonas aeruginosa infections in critically ill patients., Recent Findings: Pseudomonas aeruginosa is the most common pathogen in intensive care; the main related infections are nosocomial pneumonias, then bloodstream infections. Antimicrobial resistance is common; despite new antibiotics, it is associated with increased mortality, and can lead to a therapeutic deadlock., Summary: Carbapenem resistance in difficult-to-treat P. aeruginosa (DTR-PA) strains is primarily mediated by loss or reduction of the OprD porin, overexpression of the cephalosporinase AmpC, and/or overexpression of efflux pumps. However, the role of carbapenemases, particularly metallo-β-lactamases, has become more important. Ceftolozane-tazobactam, ceftazidime-avibactam and imipenem-relebactam are useful against DTR phenotypes (noncarbapenemase producers). Other new agents, such as aztreonam-ceftazidime-avibactam or cefiderocol, or colistin, might be effective for carbapenemase producers. Regarding nonantibiotic agents, only phages might be considered, pending further clinical trials. Combination therapy does not reduce mortality, but may be necessary for empirical treatment. Short-term treatment of severe P. aeruginosa infections should be preferred when it is expected that the clinical situation resolves rapidly., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus ., Methods: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed., Results: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole., Conclusions: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.)., (Copyright © 2023 Massachusetts Medical Society.)

Introduction: Stenotrophomonas maltophilia is a Gram-negative, opportunistic pathogen associated with a high morbidity and mortality rate. We report our clinical experience in treating a patient with infected pancreatic necrosis caused by multidrug-resistant (MDR) S. maltophilia with a novel drug combination., Case Report: A 65-year-old male with history of type II diabetes was admitted with acute pancreatitis, voluminous ascites, and signs of sepsis after undergoing an echo-endoscopy procedure with pancreas biopsy to investigate a Wirsung duct dilatation. Retroperitoneal fluid culture revealed S. maltophilia resistant to colistin and with intermediate susceptibility to trimethoprim-sulfamethoxazole and levofloxacin. The synergy between aztreonam (ATM) and ceftazidime/avibactam (CZA) was demonstrated using the combined disk pre-diffusion test., Conclusions: There are sparse data providing guidance on the optimal regimen against MDR S. maltophilia infections. Although in this case a surgical excision was essential, combination of ATM and CZA provided effective synergistic antimicrobial treatment with clinical cure of severe acute pancreatitis infected with S. maltophilia. The combined disk pre-diffusion test with ATM and CZA requires no special equipment and can be routinely performed in clinical microbiology labs. Combination of ATM with CZA should be considered for cases of MDR S. maltophilia infections with limited treatment options., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2023 Natália de Almeida Torres, Ronaldo Morales Junior, Luis Fernando Bueno Lopes, Rogério Zeigler, David Everson Uip.)

The rapid acquisition of antibiotic resistance of Pseudomonas aeruginosa has been a complex problem in clinics. Two meropenem-resistant P. aeruginosa isolates were collected from the same patient on May 24, 2021, and June 4, 2021, respectively. The first was susceptible to aztreonam, while the second displayed resistance. This study aimed to identify the genetic differences between two P. aeruginosa isolates and uncover alterations formed by the within-host bacterial evolution leading to aztreonam resistance during therapy. Strains were subjected to antimicrobial susceptibility testing using the broth microdilution method. Genomic DNAs were obtained to identify their genetic differences. The relative mRNA levels of β-lactam-resistance genes were determined by real-time PCR. Both isolates belonged to ST 773 high-risk clones with the same antibiotic resistance genes, eliminating the possibility of horizontally obtaining resistance genes. Reverse transcription (RT)-PCR results showed that the bla PDC-16 mRNA level in the second one was about 1,500 times higher than that in the first one. When 3-aminophenyl boronic acid was added, the second strain recovered its susceptibility to aztreonam, which confirmed that the overexpression of bla PDC-16 was the main reason for the isolate's resistance to aztreonam. Compared to the first strain, the second showed a single amino acid substitution in AmpR located upstream of bla PDC-16 , which may contribute to the upregulation of bla PDC-16 and lead to aztreonam resistance. AmpR plays an essential role in regulating antibiotic resistance in P. aeruginosa, and there is a need to be alert to clinical treatment failures associated with mutations in ampR . IMPORTANCE Pseudomonas aeruginosa is notorious for being highly resistant to antimicrobial agents. In this study, two P. aeruginosa strains isolated from the same patient with different susceptibility to aztreonam were used to illustrate the within-host resistance evolution process of P. aeruginosa. Both isolates, which belonged to a ST773 high-risk clone, had the same β-lactam resistance genes ( bla PDC-16 , bla IMP-45 , bla OXA-1 , and bla OXA-395 ), which means the second isolate might have been derived from the first isolate by gaining aztreonam resistance via mutations associated with aztreonam resistance relative genes. Subsequently, we found that mutation in ampR may be the cause of aztreonam resistance in the second isolate. Mutation in ampR leads to its loss of control over bla PDC-16 , allowing overexpression of bla PDC-16 and further resistance to aztreonam. This study revealed that ampR plays an essential role in regulating antibiotic resistance in P. aeruginosa. There is a need to be alert to clinical treatment failures associated with mutations in ampR ., Competing Interests: The authors declare no conflict of interest.

Cefiderocol and aztreonam-avibactam (ATM-AVI) both had activity against carbapenem-resistant Gram-negative bacilli, including those that produce metallo-β-lactamases (MBLs). We compared the in vitro activities and inoculum effects of these antibiotics against carbapenemase-producing Enterobacteriaceae (CPE), especially MBL-producing isolates. The MICs of cefiderocol and ATM-AVI were determined using broth microdilution method for a 2016 to 2021 collection of Enterobacteriaceae isolates which produced MBL, KPC, or OXA-48-like carbapenemases. MICs with high bacteria inoculum were also evaluated for susceptible isolates. A total of 195 CPE were tested, including 143 MBL- (74 NDM, 42 IMP, and 27 VIM), 38 KPC-, and 14 OXA-48-like-producing isolates. The susceptible rates of MBL-, KPC-, and OXA-48-like producers to cefiderocol were 86.0%, 92.1%, and 92.9%, respectively, and that to ATM-AVI were 95.8%, 100%, and 100%, respectively. NDM producers displayed lower susceptibility and higher MIC 50 s/MIC 90 s of cefiderocol (78.4%, 2/16 mg/L) than IMP (92.9%, 0.375/4 mg/L) and VIM (96.3%, 1/4 mg/L) producers. NDM- and VIM-producing Escherichia coli showed lower susceptibility to ATM-AVI (77.3% and 75.0%, respectively) compared to MBL-CPE of other species (100% susceptible). Inoculum effects for cefiderocol and ATM-AVI were observed among 95.9% and 95.2% of susceptible CPE, respectively. A switch from susceptible to resistant category was observed in 83.6% (143/171) of isolates for cefiderocol and 94.7% (179/189) for ATM-AVI. Our results revealed that NDM-producing Enterobacteriaceae had lower susceptibility to cefiderocol and ATM-AVI. Prominent inoculum effects on both antibiotics were observed for CPE, which suggested a risk of microbiological failure when they were used for CPE infections with high bacteria burden. IMPORTANCE The prevalence of infections caused by carbapenem-resistant Enterobacteriaceae is increasing worldwide. Currently, therapeutic options for metallo-β-lactamase (MBL)-producing Enterobacteriaceae remain limited. We demonstrated that clinical metallo-β-lactamase (MBL)-producing Enterobacteriaceae isolates were highly susceptible to cefiderocol (86.0%) and aztreonam-avibactam (ATM-AVI) (95.8%). However, inoculum effects on cefiderocol and ATM-AVI were observed for over 90% of susceptible carbapenemase-producing Enterobacteriaceae (CPE) isolates. Our findings highlight a potential risk of microbiological failure when using monotherapy with cefiderocol or ATM-AVI to treat severe CPE infection., Competing Interests: The authors declare no conflict of interest.

Aztreonam-avibactam, eravacycline, and cefoselis are three novel antimicrobial agents for the treatment of serious infections caused by Gram-negative bacteria. We evaluated the in vitro activities of the above-mentioned three antimicrobial agents against clinical Enterobacterales isolates. A total of 1,202 Enterobacterales isolates, including 10 genera or species, were collected from 26 hospitals that cover seven regions of China. The susceptibilities of the 30 antimicrobial agents were interpreted based on the combination of U.S. Food and Drug Administration and Clinical and Laboratory Standards Institute guidelines. The results indicated that all Enterobacterales isolates showed high susceptibility to aztreonam-avibactam (98.25%), eravacycline (85.69%), and cefoselis (62.73%). The first two antimicrobial agents also demonstrated potent activities against multidrug-resistant and carbapenem-resistant Enterobacterales independent of antimicrobial resistance mechanisms. The rates of susceptibility to aztreonam-avibactam, eravacycline, and cefoselis were lowest in Morganella spp. (84.42%), Proteus spp. (33.65%), and Escherichia coli (40.14%), respectively. In general, the lower rates of susceptibility to eravacycline and cefoselis were in the older inpatient group. The strains isolated from urinary tract exhibited the lowest rate of susceptibility (78.97%) to eravacycline, and the lowest rate of susceptibility (45.83%) to cefoselis was observed in nervous system specimens. The strains isolated from intensive care unit (ICU) wards showed significantly reduced susceptibility to cefoselis compared with those isolated from non-ICU wards. The MIC values of aztreonam-avibactam and ceftazidime-avibactam have poor consistency (weighted kappa = 0.243), as did eravacycline and tigecycline (weighted kappa = 0.478). Cefoselis and cefepime showed highly similar activities against Enterobacterales (weighted kappa = 0.801). Our results support the clinical development of aztreonam-avibactam, eravacycline, and cefoselis to treat infections caused by Enterobacterales . IMPORTANCE Infections caused by multidrug-resistant (MDR) Enterobacterales , especially carbapenem-resistant Enterobacterales (CRE), have been a challenging clinical problem due to the limited therapeutic options. Therefore, the need to develop novel antimicrobial agents and evaluate their activities against Enterobacterales in vitro is urgent. Our results show that the novel antimicrobial agents aztreonam-avibactam and eravacycline retain activities against MDR and CRE isolates, including carbapenemase producers and non-carbapenemase producers. Further analysis combined with clinical information on the strains tested revealed that no significant differences were observed in susceptibility rates of strains with different demographic parameters to aztreonam-avibactam. Age, specimen source, and department were associated with the susceptibility of strains to eravacycline and cefoselis ( P ≤ 0.01). Compared with ceftazidime-avibactam, aztreonam-avibactam has its advantages and limitations against Enterobacterales . The potent activity of eravacycline against Enterobacterales was higher than that of tigecycline. Cefoselis and cefepime showed a highly consistent activity against Enterobacterales ., Competing Interests: The authors declare no conflict of interest.

Collateral sensitivity (CS) is an evolutionary trade-off by which acquisition of resistance to an antibiotic leads to increased susceptibility to another. This Achilles' heel of antibiotic resistance could be exploited to design evolution-based strategies for treating bacterial infections. To date, most studies in the field have focused on the identification of CS patterns in model strains. However, one of the main requirements for the clinical application of this trade-off is that it must be robust and has to emerge in different genomic backgrounds, including preexisting drug-resistant isolates, since infections are frequently caused by pathogens already resistant to antibiotics. Here, we report the first analysis of CS robustness in clinical strains of Pseudomonas aeruginosa presenting different ab initio mutational resistomes. We identified a robust CS pattern associated with short-term evolution in the presence of ciprofloxacin of clinical P. aeruginosa isolates, including representatives of high-risk epidemic clones belonging to sequence type (ST) 111, ST175, and ST244. We observed the acquisition of different ciprofloxacin resistance mutations in strains presenting varied STs and different preexisting mutational resistomes. Importantly, despite these genetic differences, the use of ciprofloxacin led to a robust CS to aztreonam and tobramycin. In addition, we describe the possible application of this evolutionary trade-off to drive P. aeruginosa infections to extinction by using the combination of ciprofloxacin-tobramycin or ciprofloxacin-aztreonam. Our results support the notion that the identification of robust patterns of CS may establish the basis for developing evolution-informed treatment strategies to tackle bacterial infections, including those due to antibiotic-resistant pathogens. IMPORTANCE Collateral sensitivity (CS) is a trade-off of antibiotic resistance evolution that could be exploited to design strategies for treating bacterial infections. Clinical application of CS requires it to robustly emerge in different genomic backgrounds. In this study, we performed an analysis to identify robust patterns of CS associated with the use of ciprofloxacin in clinical isolates of P. aeruginosa presenting different mutational resistomes and including high-risk epidemic clones (ST111, ST175, and ST244). We demonstrate the robustness of CS to tobramycin and aztreonam and the potential application of this evolutionary observation to drive P. aeruginosa infections to extinction. Our results support the notion that the identification of robust CS patterns may establish the basis for developing evolutionary strategies to tackle bacterial infections, including those due to antibiotic-resistant pathogens.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects ( n  = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [ C max ] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.

Background: Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review., Objectives: To evaluate the effects of long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug-sensitivity reactions and survival)., Search Methods: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries. Date of last search: 28 June 2022., Selection Criteria: We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic)., Data Collection and Analysis: Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system., Main Results: The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials. Inhaled antibiotics compared to placebo We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates. Different antibiotics or regimens compared Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEV 1 ) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high., Authors' Conclusions: Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a pathogen of global concern due to the fact that therapeutic drugs are limited. Metallo-β-lactamase (MBL)-producing P. aeruginosa has become a critical part of CRPA. Alcaligenes faecalis metallo-β-lactamase (AFM) is a newly identified subclass B1b MBL. In this study, 487 P. aeruginosa strains isolated from patients and the environment in an intensive care unit were screened for AFM alleles. Five AFM-producing strains were identified, including four AFM-2-producing strains (ST262) and one AFM-4-producing strain (ST671). AFM-2-producing strains were isolated from rectal and throat swabs, and AFM-4-producing strains were isolated from the water sink. The bla AFM-2 carrying plasmids belonged to the IncP-2 type, while the bla AFM-4 carrying plasmid pAR19438 was a pSTY-like megaplasmid. Plasmid pAR19438 was acquired bla AFM-4 by the integration of the Tn 1403 -like transposon. All bla AFM genes were embedded in an IS CR29 - bla AFM unit core module flanked by class 1 integrons. The core module of bla AFM-2 was IS CR29 -Δ groL - bla AFM-2 - ble MBL -Δ trpF -ΔIS CR , while the core module of bla AFM-4 was IS CR29 -Δ groL - bla AFM-2 - ble MBL -Δ trpF -IS CR - msrB - msrA - yfcG - corA -ΔIS CR . The flanking sequences of IS CR29 - bla AFM units also differed. The expression of AFM-2 and AFM-4 in DH5α and PAO1 illustrated the same effect for the evaluation of the MICs of β-lactams, except for aztreonam. Identification of AFM-4 underscores that the quick spread and emerging development of mutants of MBLs require continuous surveillance in P. aeruginosa. IMPORTANCE Acquiring metallo-β-lactamase genes is one of the important carbapenem resistance mechanisms of P. aeruginosa. Alcaligenes faecalis metallo-β-lactamase is a newly identified metallo-β-lactamase, the prevalence and genetic context of which need to be explored. In this study, we identified AFM-producing P. aeruginosa strains among clinical isolates and found a new mutant of AFM, AFM-4. The bla AFM-4 carrying plasmid pAR19438 was a pSTY-like megaplasmid, unlike the plasmids encoding other bla AFM alleles. The genetic context of bla AFM-4 was also different. However, AFM-2 and AFM-4 had the same impacts on antibiotic susceptibility. The presence and transmission of AFM alleles in P. aeruginosa pose a challenge to clinical practice.

The evolution of bacterial antibiotic resistance is exhausting the list of currently used antibiotics and endangers those in the pipeline. The combination of antibiotics is a promising strategy that may suppress resistance development and/or achieve synergistic therapeutic effects. Eravacycline is a newly approved antibiotic that is effective against a variety of multidrug-resistant (MDR) pathogens. However, the evolution of resistance to eravacycline and strategies to suppress the evolution remain unexplored. Here, we demonstrated that a carbapenem-resistant Klebsiella pneumoniae clinical isolate quickly developed resistance to eravacycline, which is mainly caused by mutations in the gene encoding the Lon protease. The evolved resistant mutants display collateral sensitivities to β-lactam/β-lactamase inhibitor (BLBLI) combinations aztreonam/avibactam and ceftazidime-avibactam. Proteomic analysis revealed upregulation of the multidrug efflux system AcrA-AcrB-TolC and porin proteins OmpA and OmpU, which contributed to the increased resistance to eravacycline and susceptibility to BLBLIs, respectively. The combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam suppresses resistance development. We further demonstrated that eravacycline-resistant mutants evolved from an NDM-1-containing K. pneumoniae strain display collateral sensitivity to aztreonam/avibactam, and the combination of eravacycline with aztreonam/avibactam suppresses resistance development. In addition, the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam displayed synergistic therapeutic effects in a murine cutaneous abscess model. Overall, our results revealed mechanisms of resistance to eravacycline and collateral sensitivities to BLBLIs and provided promising antibiotic combinations in the treatment of multidrug-resistant K. pneumoniae infections. IMPORTANCE The increasing bacterial antibiotic resistance is a serious threat to global public health, which demands novel antimicrobial medicines and treatment strategies. Eravacycline is a newly approved antibiotic that belongs to the tetracycline antibiotics. Here, we found that a multidrug-resistant Klebsiella pneumoniae clinical isolate rapidly developed resistance to eravacycline and the evolved resistant mutants displayed collateral sensitivity to antibiotics aztreonam/avibactam and ceftazidime-avibactam. We demonstrated that the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam repressed resistance development and improved the treatment efficacies. We also elucidated the mechanisms that contribute to the increased resistance to eravacycline and susceptibility to aztreonam/avibactam and ceftazidime-avibactam. This work demonstrated the mechanisms of antibiotic resistance and collateral sensitivity and provided a new therapeutically option for effective antibiotic combinations.

This is a retrospective single-center study of 24 patients who received ceftazidime-avibactam plus aztreonam (CZA/ATM) for the treatment of VIM-type-producing Gram-negative bacillus (GNB) infections. The bacteria isolated were Enterobacterales in 22 patients and Pseudomonas aeruginosa in 2. Sixteen out of 19 isolates showed synergistic activity. Two patients presented clinical failure at day 14, and the 30-day mortality was 17% (4/24). CZA/ATM could be considered an alternative therapy for VIM-type-producing GNB infections.

Introduction: Infected diabetic foot ulcer (IDFU) is a worldwide problem associated with diabetes mellitus. It could lead from soft tissue infection to bone infection and is a leading cause of lower limb amputation. Gram-negative and Gram-positive bacteria, including anaerobic bacteria and fungi, are considered potential causes of infection. The early diagnosis of DFU infection and appropriate treatment based on the identification of the pathogens and their antimicrobial susceptibility pattern is important for good prognosis. Therefore, the purpose of this study was to isolate the bacteria that infect foot ulcers in selected Hospitals and determine their antimicrobial resistance profile., Method: An institutional-based multicenter, cross-sectional study was conducted in selected Hospitals in Addis Ababa, Ethiopia, from November 2020 to May 2021. A sterile swab was used to collect samples from the foot ulcer and a sterile needle to collect pus. Isolates were identified by culture, Gram-staining, and a series of biochemical tests. For each bacterial species identified, the antibiotic profiling was determined by the Kirby-Bauer disk diffusion method., Results: one hundred and twenty-seven pathogenic bacteria were isolated from samples taken from 130 patients with a diabetic foot ulcer. Sixty-eight percent had growth of multiple microorganisms. Two-thirds (66.7%) of the isolates were gram-negative bacteria. The predominant bacterial species were S. aureus 25.19% (32/127), Pseudomonas species 18.89% (24/127), and Escherichia coli 16.53% (21/127). Overall, 92.9% (118/127) of the isolates were identified as multi-drug resistant. Gram-positive isolates were susceptible to chloramphenicol, clindamycin, and amikacin. Gram-negative isolates were also sensitive to chloramphenicol, aztreonam, and amikacin., Conclusion: The majority of bacteria isolated from patients presenting with Diabetic foot ulcer infections were found to be multi-drug resistant in the study sites of the current study. The results demonstrate the importance of timely identification of infection of diabetic foot ulcers, proper sample collection for identification of the pathogens and for determining their antibiotic susceptibility pattern before initiating antimicrobial 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 © 2022 Atlaw, Kebede, Abdela and Woldeamanuel.)

Metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa is increasingly reported worldwide and usually causes infections with high mortality rates. Aztreonam/avibactam is a β-lactam/β-lactamase inhibitor (BLBLI) combination that is under clinical trials. The advantage of aztreonam/avibactam over the currently used BLBLIs lies in its effectiveness against MBL-producing pathogens, making it one of the few drugs that can be used to treat infections caused by MBL-producing P. aeruginosa. However, the molecular mechanisms underlying aztreonam/avibactam resistance development remain unexplored. Here, in this study, we performed an in vitro evolution assay by using a previously identified MBL-producing P. aeruginosa clinical isolate, NKPa-71, and found mutations in a novel gene, PA4292 , in the aztreonam/avibactam-resistant mutants. By mutation of PA4292 in the reference strain PA14, we verified the role of PA4292 in the resistance to aztreonam/avibactam and β-lactams. Transcriptomic analyses revealed upregulation of pyocyanin biosynthesis genes among the most overexpressed in the PA4292 mutant. We further demonstrated that pyocyanin overproduction in the PA4292 mutant increased the bacterial resistance to β-lactams by reducing drug influx. These data revealed a novel mechanism that might lead to the development of resistance to aztreonam/avibactam and β-lactams.

Background: Recent randomised clinical trials in bronchiectasis have failed to reach their primary end-points, suggesting a need to reassess how we measure treatment response. Exacerbations, quality of life (QoL) and lung function are the most common end-points evaluated in bronchiectasis clinical trials. We aimed to determine the relationship between responses in terms of reduced exacerbations, improved symptoms and lung function in bronchiectasis., Methods: We evaluated treatment response in three randomised clinical trials that evaluated mucoactive therapy (inhaled mannitol), an oral anti-inflammatory/antibiotic (azithromycin) and an inhaled antibiotic (aztreonam). Treatment response was defined by an absence of exacerbations during follow-up, an improvement of QoL above the minimum clinically important difference and an improvement in forced expiratory volume in 1 s (FEV 1 ) of ≥100 mL from baseline., Results: Cumulatively the three trials included 984 patients. Changes in FEV 1 , QoL and exacerbations were heterogeneous in all trials analysed. Improvements in QoL were not correlated to changes in FEV 1 in the azithromycin and aztreonam trials (r= -0.17, p=0.1 and r=0.04, p=0.4, respectively) and weakly correlated in the mannitol trial (r=0.22, p<0.0001). An important placebo effect was observed in all trials, especially regarding improvements in QoL. Clinical meaningful lung function improvements were rare across all trials evaluated, suggesting that FEV 1 is not a responsive measure in bronchiectasis., Conclusions: Improvements in lung function, symptoms and exacerbation frequency are dissociated in bronchiectasis. FEV 1 is poorly responsive and poorly correlated with other key outcome measures. Clinical parameters are poorly predictive of treatment response, suggesting the need to develop biomarkers to identify responders., Competing Interests: Conflict of interest: O. Sibila has nothing to disclose. Conflict of interest: E. Laserna has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose. Conflict of interest: L. Perea has nothing to disclose. Conflict of interest: D. Bilton has nothing to disclose. Conflict of interest: M.L. Crichton reports personal fees from AstraZeneca, outside the submitted work. Conflict of interest: A. De Soyza reports grants, travel support to attend international congresses and lecture fees from AstraZeneca, Bayer, Chiesi, Grifols, GlaxoSmithKline, Insmed, Pfizer, Novartis, Medimmune and Zambon, outside the submitted work. Conflict of interest: W.G. Boersma has nothing to disclose. Conflict of interest: J. Altenburg has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants and personal fees from GlaxoSmithKline, Grifols, Boehringer Ingelheim and Insmed, grants from AstraZeneca and Bayer Healthcare, personal fees from Aradigm, Pfizer and Napp, outside the submitted work., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Burkholderia cepacia complex (Bcc) in airways of patients with cystic fibrosis (CF) is associated with an increased morbidity and mortality. A huge range of intrinsic antimicrobial resistances challenges the treatment of Bcc infections. The aim was to assess the susceptibility of Bcc to ceftazidime/avibactam and standard drugs for the treatment for CF patients and to determine the respective genomic determinants of resistance. Bcc isolates ( n  = 64) from a prospective multicenter study of CF airway pathogens (2004-2020, Germany) were subjected to broth microdilution and minimal inhibitory concentrations were interpreted with European Committee on Antimicrobial Susceptibility Testing and Clinical & Laboratory Standards Institute breakpoints. A synergism between aztreonam and avibactam was tested using ceftazidime/avibactam disks with or without aztreonam. Plasmids and chromosomes of all isolates were screened for antimicrobial resistance genes. The highest susceptibility rate was detected for trimethoprim/sulfamethoxazole (83%), followed by ceftazidime/avibactam (78%), ceftazidime (53%), levofloxacin (39%) and meropenem (27%). The median inhibition zone diameters of ceftazidime-avibactam and ceftazidime/avibactam plus aztreonam were equal. This was in line with the absence of known class B metallo-β-lactamases in any of the isolates. The majority of isolates carried bla penA (98%) and bla ampC (86%). Trimethoprim/sulfamethoxazole and ceftazidime/avibactam showed high susceptibility rates. Aztreonam in combination with ceftazidime/avibactam had no synergistic effect in our Bcc isolates.

The case of a female who had an accident that caused an open fracture is reported. During hospitalisation, Verona integron-encoded metallo-β-lactamase (VIM)-producing Klebsiella pneumoniae was isolated. Antimicrobial susceptibility testing revealed resistance to β-lactam antibiotics, quinolones, trimethoprim/sulfamethoxazole, and susceptibility to tigecycline, colistin, fosfomycin and aminoglycosides. Synergistic activity of ceftazidime-avibactam and aztreonam was proved in vitro and a combined therapy with tigecycline was started. Combination with aminoglycosides was ruled out as it was not described in the literature and also in order to avoid side effects. Colistin was rejected because of its nephrotoxicity profile. The antibiotic treatment was assessed by a multidisciplinary team with a pharmacist who closely monitored adverse effects and interactions with other drugs. The total duration of this combination was 25 days, without any adverse events reported. Fourteen weeks after the accident the patient was discharged. After 2 months of follow-up neither relapses nor reinfections have been reported., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Metallo beta-lactamases-producing Gram-negative infection is often challenging and there is no defined treatment option. In recent years, the combination of aztreonam with ceftazidime-avibactam has gained much clinical attention mainly for MBL-producing Enterobacterales, while MBL-producing P. aeruginosa and A. baumannii are likely to be resistant. A consensus susceptibility testing method for this triple combination has yet to be recommended. Various methods such as broth disk elution, disk stacking, gradient strip stacking, and strip crossing have been proposed for testing this combination. Among them, broth disk elution and strip based testing methods showed good correlation with the broth micro-dilution method., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2021 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Background: The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens., Methods: TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection., Results: In total, 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles., Conclusions: TARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit., Clinical Trials Registration: NCT03137173., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Purpose: To determine if aztreonam as initial empiric treatment of adult septic shock is associated with increased mortality compared to the use of anti-pseudomonal beta-lactam agents., Methods: This was a multicenter, retrospective cohort study of 582 adult emergency department patients admitted to 12 acute care facilities within a single health system from January 2014 to December 2017 with septic shock receiving either aztreonam or an anti-pseudomonal beta-lactam for empiric treatment and discharged with an infection-related ICD-9 or ICD-10 code. The primary endpoint was in-hospital mortality., Results: Initial exposure to aztreonam was associated with increased hospital mortality compared to treatment with an anti-pseudomonal beta-lactam agent (22.7% vs. 12.9%, OR = 1.98, 95% CI: 1.27-3.11). When adjusted for APACHE II score, the treatment group effect on mortality remained statistically significant (OR = 1.74, 95% CI: 1.08-2.80). Aztreonam use was also associated with increased utilization of aminoglycosides (28.9% vs. 12.4%, p < 0.0001) and fluoroquinolones (50.5% vs. 25.8%, p < 0.01). There was no difference in hospital or intensive care unit length of stay in surviving patients between the two groups., Conclusions: Compared to anti-pseudomonal beta-lactams, empiric treatment with aztreonam is associated with increased mortality and greater antibiotic exposure among patients with acute septic shock. These findings suggest that treatment with anti-pseudomonal beta-lactams should be prioritized over allergy avoidance whenever feasible., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Serious infections caused by MBLs with or without OXA-48-like expressing Enterobacterales remain challenging to treat. Since aztreonam is stable to MBLs, it can be combined with ceftazidime/avibactam to protect against concurrently expressed ESBLs and class C β-lactamases in MBL pathogens. However, in the light of dose-limiting hepatotoxicity of aztreonam, short half life of avibactam, significant protein binding of aztreonam, appropriate dosing and method of administration to optimize PK/PD and toxicodynamics for this combination is being debated. Based on in-vitro PK/PD studies, simultaneous administration of 6/1.5 g of ceftazidime/avibactam and 8 g of aztreonam per day has been recently suggested., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Background: In vitro data support the use of combination of aztreonam (ATM) with ceftazidime-avibactam (CAZ-AVI), but clinical studies are lacking. The aim of our study was to compare the outcome of patients with bloodstream infections (BSIs) due to metallo-β-lactamase (MBL)-producing Enterobacterales treated either with CAZ-AVI plus ATM or other active antibiotics (OAAs)., Methods: This was a prospective observational study including patients admitted to 3 hospitals in Italy and Greece. The primary outcome measure was 30-day all-cause mortality. Secondary outcomes were clinical failure at day 14 and length of stay after BSI diagnosis. Cox regression analysis including a propensity score (PS) for receiving CAZ-AVI + ATM was performed to evaluate primary and secondary outcomes. A PS-based matched analysis was also performed., Results: We enrolled 102 patients with BSI; 82 had infections caused by NDM-producing (79 Klebsiella pneumoniae and 3 Escherichia coli) and 20 by VIM-producing (14 K. pneumoniae, 5 Enterobacter species, 1 Morganella morganii) strains. The 30-day mortality rate was 19.2% in the CAZ-AVI + ATM group vs 44% in the OAA group (P = .007). The PS-adjusted analysis showed that the use of CAZ-AVI + ATM was associated with lower 30-day mortality (hazard ratio [HR], 0.37 [95% confidence interval {CI}, .13-.74]; P = .01), lower clinical failure at day 14 (HR, 0.30 [95% CI, .14-.65]; P = .002), and shorter length of stay (subdistributional HR, 0.49 [95% CI, .30-.82]; P = .007). The PS-matched analysis confirmed these findings., Conclusions: The CAZ-AVI + ATM combination offers a therapeutic advantage compared to OAAs for patients with BSI due to MBL-producing Enterobacterales. Further studies are warranted., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)-aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin-and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.

Background: Neonatal sepsis is a major cause of morbidity and mortality. It is the third leading cause of neonatal mortality globally constituting 13% of overall neonatal mortality. Despite the high burden of neonatal sepsis, high-quality evidence in diagnosis and treatment is scarce. Due to the diagnostic challenges of sepsis and the relative immunosuppression of the newborn, many neonates receive antibiotics for suspected sepsis. Antibiotics have become the most used therapeutics in neonatal intensive care units, and observational studies in high-income countries suggest that 83% to 94% of newborns treated with antibiotics for suspected sepsis have negative blood cultures. The last Cochrane Review was updated in 2005. There is a need for an updated systematic review assessing the effects of different antibiotic regimens for late-onset neonatal sepsis., Objectives: To assess the beneficial and harmful effects of different antibiotic regimens for late-onset neonatal sepsis., Search Methods: We searched the following electronic databases: CENTRAL (2021, Issue 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED and Conference Proceedings Citation Index - Science on 12 March 2021. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs., Selection Criteria: We included RCTs comparing different antibiotic regimens for late-onset neonatal sepsis. We included participants older than 72 hours of life at randomisation, suspected or diagnosed with neonatal sepsis, meningitis, osteomyelitis, endocarditis, or necrotising enterocolitis. We excluded trials that assessed treatment of fungal infections., Data Collection and Analysis: Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. Our primary outcome was all-cause mortality, and our secondary outcomes were: serious adverse events, respiratory support, circulatory support, nephrotoxicity, neurological developmental impairment, necrotising enterocolitis, and ototoxicity. Our primary time point of interest was at maximum follow-up., Main Results: We included five RCTs (580 participants). All trials were at high risk of bias, and had very low-certainty evidence. The five included trials assessed five different comparisons of antibiotics. We did not conduct a meta-analysis due to lack of relevant data. Of the five included trials one trial compared cefazolin plus amikacin with vancomycin plus amikacin; one trial compared ticarcillin plus clavulanic acid with flucloxacillin plus gentamicin; one trial compared cloxacillin plus amikacin with cefotaxime plus gentamicin; one trial compared meropenem with standard care (ampicillin plus gentamicin or cefotaxime plus gentamicin); and one trial compared vancomycin plus gentamicin with vancomycin plus aztreonam. None of the five comparisons found any evidence of a difference when assessing all-cause mortality, serious adverse events, circulatory support, nephrotoxicity, neurological developmental impairment, or necrotising enterocolitis; however, none of the trials were near an information size that could contribute significantly to the evidence of the comparative benefits and risks of any particular antibiotic regimen. None of the trials assessed respiratory support or ototoxicity. The benefits and harms of different antibiotic regimens remain unclear due to the lack of well-powered trials and the high risk of systematic errors., Authors' Conclusions: Current evidence is insufficient to support any antibiotic regimen being superior to another. RCTs assessing different antibiotic regimens in late-onset neonatal sepsis with low risks of bias are warranted., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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.

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-β-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer β-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing β-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity., (© 2020 Wiley Periodicals LLC.)

Abstract: In this clinician-therapeutic drug monitoring (TDM) consultant interaction, the authors describe the use of TDM in an 11-year-old female patient with cystic fibrosis receiving ceftazidime/avibactam and aztreonam for the treatment of persistent pulmonary exacerbations caused by Stenotrophomonas pneumonia. Serum drug concentrations at a steady state confirmed inadequate antimicrobial exposure, and continuous infusions of both ceftazidime/avibactam and aztreonam were required to optimize the percentage of time when free drug remained above the minimum inhibitory concentration (MIC), known as fT > MIC. After dose adjustment, this continuous infusion strategy resulted in 100% target attainment for fT > MIC. This case illustrates the importance of TDM, and the logistical issues encountered with the use of alternative dosing strategies in pediatric patients with CF., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect the susceptibility profiles of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients. This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic P. aeruginosa infection. Sputum cultures were collected annually (2011 to 2016). The primary study endpoint was the proportion of subjects whose least susceptible P. aeruginosa isolate had an aztreonam MIC that was >8 μg/ml (parenteral breakpoint) and increased ≥4-fold compared with the least susceptible isolate from the previous year. Annualized data for pulmonary exacerbations, hospitalizations, and percent of predicted forced expiratory volume in 1 s (FEV 1 % predicted) were obtained from the CF Foundation Patient Registry and compared between subjects meeting and those not meeting the primary endpoint. A total of 510 subjects were enrolled; 334 (65%) completed the study. A consistent proportion of evaluable subjects (13 to 22%) met the primary endpoint each year, and AZLI use during the previous 12 months was not associated with meeting the primary endpoint. While the annual declines in lung function were comparable for subjects meeting and those not meeting the primary endpoint, more pulmonary exacerbations and hospitalizations were experienced by those who met it. The aztreonam susceptibility of P. aeruginosa remained consistent during the 5-year study. The relationship between P. aeruginosa isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with an accelerated decline in lung function but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01375036.)., (Copyright © 2021 Keating et al.)

Existing data support the combination of aztreonam and ceftazidime-avibactam against serine-β-lactamase (SBL)- and metallo-β-lactamase (MBL)-producing Enterobacterales, although there is a paucity of data against SBL- and MBL-producing Pseudomonas aeruginosa. In this study, 5 SBL- and MBL-producing P. aeruginosa (1 IMP, 4 VIM) were evaluated against aztreonam and ceftazidime-avibactam alone and in combination via broth microdilution and time-kill analyses. All 5 isolates were nonsusceptible to aztreonam, aztreonam-avibactam, and ceftazidime-avibactam. Combining aztreonam with ceftazidime-avibactam at subinhibitory concentrations produced synergy and restored bactericidal activity in 4/5 (80%) isolates tested. These results suggest that the combination of aztreonam and ceftazidime-avibactam may be a viable treatment option against SBL- and MBL-producing P. aeruginosa., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The threat of ceftriaxone-resistant Neisseria gonorrhoeae necessitates new gonorrhea treatment regimens. Repurposing older antibiotics not routinely used for N. gonorrhoeae may expeditiously identify new therapies. Ideally, all recommended therapies should eradicate gonorrhea at the pharynx. Between April and September 2019, we enrolled men in an open-label, one-arm clinical trial of single-dose intramuscular aztreonam (2 g). Enrollment criterion included (i) nucleic acid amplification test (NAAT)-positive pharyngeal gonorrhea for ≤14 days or (ii) Gram stain-positive gonococcal urethritis plus report of performing oral sex in ≤2 months. At enrollment, we collected cultures from NAAT-positive or screening sites, and men returned 3 to 8 days following treatment for a test of cure (TOC) by culture. The per-protocol analysis required men to be culture positive at enrollment and to return for TOC. We calculated efficacy as the number of subjects with negative culture at TOC divided by the number culture positive at enrollment by anatomic site. Thirty-two men enrolled in the study; 21 were pharyngeal NAAT positive, and 11 had gonococcal urethritis. The per-protocol analysis included 17 men, 6 with pharyngeal, 9 with urethral, and 4 with rectal gonococcal infections. Aztreonam cured 2 of 6 pharyngeal infections (33%; 95% confidence interval [CI], 4.3% to 78%) and 3 of 4 rectal infections (75%; 95% CI, 19% to 99%). All 11 men with urethritis were cured (100%; 95% CI, 66% to 100%). The aztreonam MIC 90 was 0.5 μg/ml (range, 0.06 to 2.0 μg/ml). All treatment failures occurred at a MIC of ≥0.25 μg/ml. Single-dose aztreonam is not a reliable treatment for gonorrhea at the pharynx but may be useful for men with gonococcal urethritis and beta-lactam allergy. (This study has been registered at ClinicalTrials.gov under identifier NCT03867734.)., (Copyright © 2020 American Society for Microbiology.)

Background: The SEP-1 measures have tied financial reimbursement to the treatment of patients with severe sepsis and septic shock. The purpose of this study was to assess the impact of a SEP-1 initiative on the utilization of broad-spectrum combination therapy (BSCT) in the emergency department (ED)., Methods: This was an IRB-approved, retrospective evaluation of adult patients who received vancomycin plus an antipseudomonal beta-lactam for a urinary tract infection (UTI) or skin or soft tissue infection (SSTI) in the ED. The primary outcome was the proportion of patients in which use of BSCT was considered appropriate based on clinical criteria. Secondary outcomes included door to antibiotic order time, door to administration time, proportion of patients continued on BSCT upon admission, duration of BSCT, and in-hospital mortality., Results: A total of 400 patients were included in the analysis. Following SEP-1 implementation, appropriate use of BSCT decreased by 12%, with 54% of patients in the pre-SEP-1 group meeting clinical criteria compared to 42% in the post-SEP-1 group (p = 0.028). In the subgroup of patients with a suspected UTI the appropriate use of BSCT declined by 25% (40% vs 15%, p = 0.005). The median door to first antibiotic administration time was not significantly different between groups (63 min vs 61 min, p = 0.091)., Conclusions: The implementation of the SEP-1 mandated measures was associated with an increase in the unnecessary use of BSCT. Additionally, no difference was seen in time to antibiotic administration. The results of this study demonstrate the negative impact that the SEP-1 mandate may have on antimicrobial utilization within the ED., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: We report the successful treatment of a bloodstream infection caused by Klebsiella pneumoniae harbouring NDM-1 using aztreonam-ceftazidime-avibactam in a neutropenic patient in whom colistin and meropenem therapy had previously failed., Methods: A clinical isolate was evaluated to determine the presence of NDM, TEM, SHV, CTX, and CMY, and the killing kinetics of aztreonam (ATM; 4 μg/mL), aztreonam-avibactam (ATM-AVI; 4/4 μg/mL), and colistin (2 and 4 μg/mL) were tested., Results: ATM-AVI showed in vitro activity against the Klebsiella pneumoniae harbouring NDM-1, whereas colistin allowed re-growth., Conclusions: This report supports reconsideration of use of colistin for treatment of infections caused by K. pneumoniae harbouring NDM. CZA/ATM use should be kept in mind as a treatment option, perhaps earlier than colistin., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-β-Lactamase-1 in the United States, recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Inhaled antibiotics may improve symptom scores, but it is not known which specific symptoms improve with therapy. Item-level analysis of questionnaire data may allow us to identify which specific symptoms respond best to treatment., Methods: Post hoc analysis of the AIR-BX1 studies and two trials of inhaled aztreonam versus placebo in bronchiectasis. Individual items from the quality of life bronchiectasis (QOL-B) respiratory symptom scale, were extracted as representing severity of nine distinct symptoms. Generalised linear models were used to evaluate changes in symptoms with treatment versus placebo from baseline to end of first on-treatment cycle and mixed models were used to evaluate changes across the full 16-week trial., Results: Aztreonam improved cough (difference 0.22, 95% CI 0.08-0.37; p=0.002), sputum production (0.30, 95% CI 0.15-0.44; p<0.0001) and sputum colour (0.29, 95% CI 0.15-0.43; p<0.0001) versus placebo equating to a 20% improvement in cough and 25% improvement in sputum production and colour. Similar results were observed for cough, sputum production and sputum purulence across the trial duration (all p<0.05). Patients with higher sputum production and sputum colour scores had a greater response on the overall QOL-B (difference 4.82, 95% CI 1.12-8.53; p=0.011 for sputum production and 5.02, 95% CI 1.19-8.86; p=0.01 for sputum colour). In contrast, treating patients who had lower levels of bronchitic symptoms resulted in shorter time to next exacerbation (hazard ratio 1.83, 95% CI 1.02-3.28; p=0.042)., Conclusion: Baseline bronchitic symptoms predict response to inhaled aztreonam in bronchiectasis. More sensitive tools to measure bronchitic symptoms may be useful to better identify inhaled antibiotic responders and to evaluate patient response to treatment., Competing Interests: Conflict of interest: M.L. Crichton has nothing to disclose. Conflict of interest: M. Lonergan has nothing to disclose. Conflict of interest: A.F. Barker has nothing to disclose. Conflict of interest: O. Sibila has nothing to disclose. Conflict of interest: P. Goeminne has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants from Gilead, during the conduct of the study; grants and personal fees from AstraZeneca, GlaxoSmithKline, Grifols, Insmed and Boehringer Ingelheim, personal fees from Chiesi, grants from Gilead, outside the submitted work., (Copyright ©ERS 2020.)

Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV 1 . Long-term effects are unknown. Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam. Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV 1 % predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted. Measurements and Main Results: Across 3 years, FEV 1 % predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, -1.53 versus -2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30-1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV 1 % predicted per-year decline of -0.16 versus nonusers (95% CI, -0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, -0.11 to 1.10). Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.

The preferable route for treatment of peritoneal dialysis related peritonitis remains the intraperitoneal administration of antibiotics admixed to peritoneal dialysis fluids. It is important to know whether the administered drug is compatible with the PD fluids and its container. In the present study the compatibility of aztreonam with four commercial PDFs at storing temperatures and duration representative for storing conditions in the clinical settings was investigated. Aztreonam concentrations were determined using high-performance liquid chromatography. The antimicrobial activity of aztreonam was evaluated using an E. coli diffusion disk inhibition assay and P. aeruginosa time-kill curves. In Extraneal evaluated at 6 °C, 25 °C and 37 °C aztreonam was stable over the whole study period of 14 days and 24 hours, respectively. In Physioneal and Nutrineal aztreonam was stable at 6 °C for up to 14 days. Antimicrobial activity was retained in all PD fluids over the whole study period. Aztreonam remained stable and was compatible with the PD fluids, particularly with Extraneal or Nutrineal, and no compensatory dose adjustment is needed when stored for up to 14 days at refrigeration temperature before use.