Immunogenicity and safety in rabbits of a Clostridioides difficile vaccine combining novel toxoids and a novel adjuvant.

Clostridioides difficile infection (CDI) is a serious healthcare-associated disease, causing symptoms such as diarrhea and pseudomembranous colitis. The major virulence factors responsible for the disease symptoms are two secreted cytotoxic proteins, TcdA and TcdB. A parenteral vaccine based on formaldehyde-inactivated TcdA and TcdB supplemented with alum adjuvant, has previously been investigated in humans but resulted in an insufficient immune response. In search for an improved response, we investigated a novel toxin inactivation method and a novel, potent adjuvant. Inactivation of toxins by metal-catalyzed oxidation (MCO) was previously shown to preserve neutralizing epitopes and to annihilate reversion to toxicity. The immunogenicity and safety of TcdA and TcdB inactivated by MCO and combined with a novel carbohydrate fatty acid monosulphate ester-based (CMS) adjuvant were investigated in rabbits. Two or three intramuscular immunizations generated high serum IgG and neutralizing antibody titers against both toxins. The CMS adjuvant increased antibody responses to both toxins while an alum adjuvant control was effective only against TcdA. Systemic safety was evaluated by monitoring body weight, body temperature, and analysis of red and white blood cell counts shortly after immunization. Local safety was assessed by histopathologic examination of the injection site at the end of the study. Body weight gain was constant in all groups. Body temperature increased up to 1 ˚C one day after the first immunization but less after the second or third immunization. White blood cell counts, and percentage of neutrophils increased one day after immunization with CMS-adjuvanted vaccines, but not with alum. Histopathology of the injection sites 42 days after the last injection did not reveal any abnormal tissue reactions. From this study, we conclude that TcdA and TcdB inactivated by MCO and combined with CMS adjuvant demonstrated promising immunogenicity and safety in rabbits and could be a candidate for a vaccine against CDI.

Cefepime versus carbapenems for treatment of AmpC beta-lactamase-producing Enterobacterales bloodstream infections.

PURPOSE: Cefepime is recommended for treating infections caused by AmpC beta-lactamase-producing Enterobacterales (AmpC-PE), though supporting evidence is limited. Therefore, this study compared outcomes associated with cefepime versus carbapenem therapy for bloodstream infections (BSIs) caused by AmpC-PE after phenotypic exclusion of ESBL-co-producing isolates. METHODS: This retrospective cohort study compared definite cefepime versus carbapenem treatment for AmpC-PE BSI in hospitalized patients of the University Hospital Basel, Switzerland, between 01/2015 and 07/2020. Primary outcomes included in-hospital death, renal impairment and neurologic adverse events; secondary outcomes included length of hospital stay and recurrent infection. RESULTS: Two hundred and seventy episodes of AmpC-PE BSI were included, 162, 77 and 31 were treated with a carbapenem, cefepime and other antibiotics, respectively. Patients treated with carbapenems were more likely to be transferred to the ICU on admission and more frequently had central venous catheter as a source of infection. In uni- and multivariable analyses, primary and secondary outcomes did not differ between the two treatment groups, except for more frequent occurrence of neurological adverse events among patients treated with carbapenems and shorter length of hospital stay among survivors treated with cefepime. CONCLUSION: After excluding isolates with phenotypic ESBL-co-production, cefepime was not associated with adverse outcomes compared to carbapenems when used to treat BSIs caused by AmpC-PE. Our study provides evidence to support the use of cefepime as a safe treatment strategy for AmpC-PE BSI, particularly in clinically stable patients without initial renal impairment or increased susceptibility to neurological adverse events.

Multidrug-resistant Gram-negative clinical isolates with reduced susceptibility/resistance to cefiderocol: which are the best present and future therapeutic alternatives?

PURPOSE: To evaluate the different present and future therapeutic ß-lactam/ß-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam, meropenem-vaborbactam, cefepime-zidebactam, cefepime-taniborbactam, meropenem-nacubactam, and sulbactam-durlobactam against clinical isolates showing reduced susceptibility or resistance to cefiderocol in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa. METHODS: MIC values of aztreonam, aztreonam-avibactam, cefepime, cefepime-taniborbactam, cefepime-zidebactam, imipenem, imipenem-relebactam, meropenem, meropenem-vaborbactam, meropenem-nacubactam, sulbactam-durlobactam, and cefiderocol combined with a BLI were determined for 67, 9, and 11 clinical Enterobacterales, P. aeruginosa or A. baumannii isolates, respectively, showing MIC values of cefiderocol being ≥1 mg/L. If unavailable, the respective ß-lactam breakpoints according to EUCAST were used for BL/BLI combinations. RESULTS: For Enterobacterales, the susceptibility rates for aztreonam, cefepime, imipenem, and meropenem were 7.5%, 0%, 10.4%, and 10.4%, respectively, while they were much higher for cefepime-zidebactam (91%), cefiderocol-zidebactam (91%), meropenem-nacubactam (71.6%), cefiderocol-nacubactam (74.6%), and cefiderocol-taniborbactam (76.1%), as expected. For P. aeruginosa isolates, the higher susceptibility rates were observed for imipenem-relebactam, cefiderocol-zidebactam, and meropenem-vaborbactam (56% for all combinations). For A. baumannii isolates, lower susceptibility rates were observed with commercially or under development BL/BLI combos; however, a high susceptibility rate (70%) was found for sulbactam-durlobactam and when cefiderocol was associated to some BLIs. CONCLUSIONS: Zidebactam- and nacubactam-containing combinations showed a significant in vitro activity against multidrug-resistant Enterobacterales clinical isolates with reduced susceptibility to cefiderocol. On the other hand, imipenem-relebactam and meropenem-vaborbactam showed the highest susceptibility rates against P. aeruginosa isolates. Finally, sulbactam-durlobactam and cefiderocol combined with a BLI were the only effective options against A. baumannii tested isolates.

The emergence of cefiderocol resistance in Pseudomonas aeruginosa from a heteroresistant isolate during prolonged therapy.

Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility has been associated with mutations in the chromosomal cephalosporinase (PDC) along with mutations in the PirA and PiuA/D TonB-dependent receptor pathways. Here, we report a clinical case of cefiderocol-resistant P. aeruginosa that emerged in a patient during treatment. This resistance was associated with mutations not previously reported, suggesting potential novel pathways to cefiderocol resistance.

Cefiderocol: Clinical application and emergence of resistance.

Antibacterial drug resistance of gram-negative bacteria (GNB) results in high morbidity and mortality of GNB infection, seriously threaten human health globally. Developing new antibiotics has become the critical need for dealing with drug-resistant bacterial infections. Cefiderocol is an iron carrier cephalosporin that achieves drug accumulation through a unique "Trojan horse" strategy into the bacterial periplasm. It shows high antibacterial activity against multidrug-resistant (MDR) Enterobacteriaceae and MDR non-fermentative bacteria. The application of cefiderocol offers new hope for treating clinical drug-resistant bacterial infections. However, limited clinical data and uncertainties about its resistance mechanisms constrain the choice of its therapeutic use. This review aimed to summarize the clinical applications, drug resistance mechanisms, and co-administration of cefiderocol.

Treatment guidelines for multidrug-resistant Gram-negative microorganisms.

In recent years, new antimicrobials have been introduced in therapeutics, including new beta-lactam-beta-lactamase inhibitor combinations and cefiderocol in response to therapeutic needs in the face of increasing resistance. There are also different treatment guidelines for infections caused by these microorganisms that have been approved by different professional societies, including those of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Disease Society of America (IDSA) and the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). All of them are based on scientific evidence, but with differences in the weight of expert opinion in their recommendations. Both ESCMID and IDSA include recommendations for the treatment of extended-spectrum beta-lactamase-producing microorganisms. The IDSA is the only one including AmpC producers, all address the treatment of infections caused by carbapenem-resistant Enterobacterales and Acinetobacter baumannii and multidrug-resistant or difficult-to-treat Pseudomonas aeruginosa, and the IDSA and SEIMC include recommendations on the treatment of Stenotrophomonas maltophilia. Future guidelines should integrate new antimicrobials and new innovative management options not covered by current guidelines.

Antibiotic therapy for nonfermenting Gram-negative bacilli infections: future perspectives.

PURPOSE OF REVIEW: Serious infections caused by nonfermenting Gram-negative bacteria (NF-GNB) pose a significant challenge for clinicians due to the limited treatment options available, which are frequently associated with issues of toxicity and unfavourable pharmacokinetic profiles. The aim of this review is to provide a brief overview of the existing data concerning the ongoing development of antiinfective agents targeting NF-GNB. RECENT FINDINGS: Several agents exhibiting efficacy against NF-GNB are under clinical investigation. Durlobactam-sulbactam and cefepime-taniborbactam emerge as promising therapeutic avenues against carbapenem-resistant Acinetobacter baumanii . Cefepime-zidebactam may serve as a suitable treatment option for urinary tract infections caused by a wide range of NF-GNB. Cefepime-enmetazobactam demonstrates potent in vitro activity against various NF-GNB strains; however, its role as an anti- Pseudomonal agent is inadequately substantiated by available data. Xeruborbactam is a wide ß-lactamase inhibitor that can be associated with a range of agents, enhancing in-vitro activity of these against many NF-GNB, including those resistant to newer, broader spectrum options. Lastly, murepavadin appears to be a potential pathogen-specific solution for severe Pseudomonas infections; however, additional investigation is necessary to establish the safety profile of this compound. SUMMARY: Each of the novel molecules reviewed possesses an interesting range of in-vitro activity against NF-GNB. In addition, some of them have already been proved effective in vivo, underscoring their potential as future treatment options.

Characterization of Pseudomonas aeruginosa resistance to ceftolozane-tazobactam due to ampC and/or ampD mutations observed during treatment using semi-mechanistic PKPD modeling.

A double ampC (AmpCG183D) and ampD (AmpDH157Y) genes mutations have been identified by whole genome sequencing in a Pseudomonas aeruginosa (PaS) that became resistant (PaR) in a patient treated by ceftolozane/tazobactam (C/T). To precisely characterize the respective contributions of these mutations on the decreased susceptibility to C/T and on the parallel increased susceptibility to imipenem (IMI), mutants were generated by homologous recombination in PAO1 reference strain (PAO1- AmpCG183D, PAO1-AmpDH157Y, PAO1-AmpCG183D/AmpDH157Y) and in PaR (PaR-AmpCPaS/AmpDPaS). Sequential time-kill curve experiments were conducted on all strains and analyzed by semi-mechanistic PKPD modeling. A PKPD model with adaptation successfully described the data, allowing discrimination between initial and time-related (adaptive resistance) effects of mutations. With PAO1 and mutant-derived strains, initial EC50 values increased by 1.4, 4.1, and 29-fold after AmpCG183D , AmpDH157Y and AmpCG183D/AmpDH157Y mutations, respectively. EC50 values were increased by 320, 12.4, and 55-fold at the end of the 2 nd experiment. EC50 of PAO1-AmpCG183D/AmpDH157Y was higher than that of single mutants at any time of the experiments. Within the PaR clinical background, reversal of AmpCG183D, and AmpDH157Y mutations led to an important decrease of EC50 value, from 80.5 mg/L to 6.77 mg/L for PaR and PaR-AmpCPaS/AmpDPaS, respectively. The effect of mutations on IMI susceptibility mainly showed that the AmpCG183D mutation prevented the emergence of adaptive resistance. The model successfully described the separate and combined effect of AmpCG183D and AmpDH157Y mutations against C/T and IMI, allowing discrimination and quantification of the initial and time-related effects of mutations. This method could be reproduced in clinical strains to decipher complex resistance mechanisms.

Antibiotic resistance trends for common bacterial aetiologies of childhood diarrhoea in low- and middle-income countries: A systematic review.

Background: Diarrhoea is the second most common cause of death among children under the age of five worldwide. The World Health Organization (WHO) recommends treating diarrhoea with oral rehydration therapy, intravenous fluids for severe dehydration, and zinc supplements. Antibiotics are only recommended to treat acute, invasive diarrhoea. Rising antibiotic resistance has led to a decrease in the effectiveness of treatments for diarrhoea. Methods: A systematic literature review in PubMed, Web of Science, and EMBASE was conducted to identify articles relevant to antibiotic-resistant childhood diarrhoea. Articles in English published between 1990 to 2020 that described antibiotic resistance patterns of common pathogens causing childhood diarrhoea in low- and middle-income countries were included. The studies were limited to papers that categorized children as 0-5 years or 0-10 years old. The proportion of isolates with resistance to major classes of antibiotics stratified by major WHO global regions and time was determined. Results: Quantitative data were extracted from 44 articles that met screening criteria; most focused on children under five years. Escherichia coli isolates had relatively high resistance rates to ampicillin and tetracycline in the African (AFR), American (AMR), and Eastern Mediterranean Regions (EMR). There was moderate to high resistance to ampicillin and third generation cephalosporins among Salmonella spp in the AFR, EMR, and the Western Pacific Region (WPR). Resistance rates for ampicillin, co-trimoxazole, and chloramphenicol for Shigella in the AFR started at an alarmingly high rate ( ~ 90%) in 2006 and fluctuated over time. There were limited antibiotic resistance data for Aeromonas, Yersinia, and V. cholerae. The 161 isolates of Campylobacter analysed showed initially low rates of fluoroquinolone resistance with high rates of resistance in recent years, especially in the Southeast Asian Region. Conclusions: Resistance to inexpensive antibiotics for treatment of invasive diarrhoea in children under ten years is widespread (although data on 6- to 10-year-old children are limited), and resistance rates to fluoroquinolones and later-generation cephalosporins are increasing. A strong regional surveillance system is needed to carefully monitor trends in antibiotic resistance, future studies should include school-aged children, and interventions are needed to reduce inappropriate use of antibiotics for the treatment of community-acquired, non-invasive diarrhoea. Registration: This systematic review was registered in Prospero (registration number CRD42020204004) in August 2020.

Ceftolozane-Tazobactam Versus Ceftazidime-Avibactam for the Treatment of Infections Caused by Multidrug-Resistant Pseudomonas aeruginosa: a Multicenter Cohort Study.

Ceftolozane-tazobactam (C-T) and ceftazidime-avibactam (CAZ-AVI) are two novel antimicrobials that retain activity against resistant Pseudomonas aeruginosa. The comparative effectiveness and safety of C-T versus CAZ-AVI remain unknown. A retrospective, multicenter cohort study was performed in six tertiary centers in Saudi Arabia and included patients who received either C-T or CAZ-AVI for infections due to multidrug-resistant (MDR) P. aeruginosa. Overall in-hospital mortality, 30-day mortality, and clinical cure were the main study outcomes. Safety outcomes were also evaluated. A multivariate analysis using logistic regression was used to determine the independent impact of treatment on the main outcomes of interest. We enrolled 200 patients in the study (100 in each treatment arm). A total of 56% were in the intensive care unit, 48% were mechanically ventilated, and 37% were in septic shock. Approximately 19% of patients had bacteremia. Combination therapy was administered to 41% of the patients. The differences between the C-T and CAZ-AVI groups did not reach statistical significance in the overall in-hospital mortality (44% versus 37%; P = 0.314; OR, 1.34; 95% CI, 0.76 to 2.36), 30-day mortality (27% versus 23%; P = 0.514; OR, 1.24; 95% CI, 0.65 to 2.35), clinical cure (61% versus 66%; P = 0.463; OR, 0.81; 95% CI, 0.43 to 1.49), or acute kidney injury (23% versus 17%; P = 0.289; OR, 1.46; 95% CI, 0.69 to 3.14), even after adjusting for differences between the two groups. C-T and CAZ-AVI did not significantly differ in terms of safety and effectiveness, and they serve as potential options for the treatment of infections caused by MDR P. aeruginosa.

Compassionate use of a novel ß-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM-expressing Pseudomonas aeruginosa infection in an intra-abdominal infection-induced sepsis patient: a case report.

Infections in critically-ill patients caused by extensively-drug-resistant (XDR)-Pseudomonas aeruginosa are challenging to manage due to paucity of effective treatment options. Cefepime/zidebactam, which is currently in global Phase 3 clinical development (Clinical Trials Identifier: NCT04979806, registered on July 28, 2021) is a novel mechanism of action based ß-lactam/ ß-lactam-enhancer combination with a promising activity against a broad-range of Gram-negative pathogens including XDR P. aeruginosa. We present a case report of an intra-abdominal infection-induced sepsis patient infected with XDR P. aeruginosa and successfully treated with cefepime/zidebactam under compassionate use. The 50 year old female patient with past-history of bariatric surgery and recent elective abdominoplasty and liposuction developed secondary pneumonia and failed a prolonged course of polymyxins. The organism repeatedly isolated from the patient was a New-Delhi metallo ß-lactamase-producing XDR P. aeruginosa resistant to ceftazidime/avibactam, imipenem/relebactam and ceftolozane/tazobactam, susceptible only to cefepime/zidebactam. As polymyxins failed to rescue the patient, cefepime/zidebactam was administered under compassionate grounds leading to discharge of patient in stable condition. The present case highlights the prevailing precarious scenario of antimicrobial resistance and the need for novel antibiotics to tackle infections caused by XDR phenotype pathogens.

Successful Use of Cefepime-Zidebactam (WCK 5222) as a Salvage Therapy for the Treatment of Disseminated Extensively Drug-Resistant New Delhi Metallo-ß-Lactamase-Producing Pseudomonas aeruginosa Infection in an Adult Patient with Acute T-Cell Leukemia.

With limited and often toxic treatment options, carbapenem-resistant Gram-negative infections are associated with significant mortality. Cefepime-zidebactam is a promising antibiotic option undergoing a phase 3 trial that has activity against diverse antibiotic-resistant mechanisms in Gram-negative pathogens due to its ß-lactam enhancer mechanism, mediating multiple PBP binding. We report a case of disseminated infection caused by a New Delhi metallo-ß-lactamase-producing, extensively drug-resistant Pseudomonas aeruginosa isolate in a patient with acute T-cell leukemia, successfully managed with cefepime-zidebactam as a salvage therapy.

Cefiderocol Treatment for Patients with Multidrug- and Carbapenem-Resistant Pseudomonas aeruginosa Infections in the Compassionate Use Program.

Cefiderocol is an option for infections caused by multidrug-resistant Pseudomonas aeruginosa, but its in vitro activity against these isolates and its clinical effectiveness for isolates with MICs of >1 µg/mL is unclear. We investigated the in vitro activity of cefiderocol against P. aeruginosa isolates collected from patients treated with cefiderocol through the compassionate use program and assessed physician-reported clinical response and 28-day all-cause mortality by cefiderocol MIC values. P. aeruginosa isolates underwent susceptibility testing to cefiderocol and comparator agents by using reference broth microdilution. U.S. Food and Drug Administration (FDA; susceptible, ≤1 µg/mL) and Clinical and Laboratory Standards Institute (CLSI; susceptible, ≤4 µg/mL) cefiderocol breakpoints were applied. Additionally, molecular characterization of ß-lactamase genes was performed. Clinical response and vital status were reported by treating physicians. Forty-six patients with P. aeruginosa infections were evaluated. Twenty-nine (63%) and 42 (91%) isolates were susceptible to cefiderocol using FDA and CLSI breakpoints, respectively. Thirty-seven (80%) and 32 (70%) isolates were not susceptible to ceftolozane-tazobactam and ceftazidime-avibactam, respectively. The clinical response rate was 69% (20/29) with a cefiderocol MIC of ≤1 µg/mL, 69% (9/13) with a cefiderocol MIC of 2 to 4 µg/mL, and 100% (4/4) with an MIC of ≥8 µg/mL, while day 28 all-cause mortality rates were 23% (6/26; MIC ≤ 1 µg/mL), 33% (4/12; MIC, 2 to 4 µg/mL), and 0% (0/4; MIC ≥8 µg/mL), respectively. Cefiderocol was active in vitro against most P. aeruginosa isolated from patients with limited or no alternative therapies. Patients with cefiderocol MICs of 2 to 4 µg/mL did not have significantly worse outcomes than those with MICs of ≤1 µg/mL.

A Selective Culture Medium for Screening Cefiderocol Resistance in Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Cefiderocol (FDC) is a siderophore cephalosporin with a broad spectrum of activity against many multidrug-resistant Gram-negative bacteria. Acquired resistance to FDC has been already reported among Gram-negative isolates, thus highlighting the need for rapid and accurate identification of such resistant pathogens, in order to control their spread. Therefore, the SuperFDC medium was developed to screen FDC-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. After testing several culture conditions, a selective medium was set up by supplementing an iron-depleted agar medium with 8 µg/mL of FDC and evaluated with a collection of 68 FDC-susceptible and 33 FDC-resistant Gram-negative isolates exhibiting a variety of ß-lactam resistance mechanisms. The sensitivity and specificity of detection of this medium were evaluated at 97% and 100%, respectively. In comparison with the reference broth microdilution method, only 3% very major errors were found. In addition, excellent detection performances were obtained by testing spiked stools with a lower limit of detection ranging between 100 and 103 CFU/mL. The SuperFDC medium allows detection of FDC-resistant Gram-negative isolates regardless of their corresponding resistance mechanisms.

Global antimicrobial-resistance drivers: an ecological country-level study at the human-animal interface.

BACKGROUND: Antimicrobial resistance (AMR) is a pressing, holistic, and multisectoral challenge facing contemporary global health. In this study we assessed the associations between socioeconomic, anthropogenic, and environmental indicators and country-level rates of AMR in humans and food-producing animals. METHODS: In this modelling study, we obtained data on Carbapenem-resistant Acinetobacter baumanii and Pseudomonas aeruginosa, third generation cephalosporins-resistant Escherichia coli and Klebsiella pneumoniae, oxacillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium AMR in humans and food-producing animals from publicly available sources, including WHO, World Bank, and Center for Disease Dynamics Economics and Policy. AMR in food-producing animals presented a combined prevalence of AMR exposure in cattle, pigs, and chickens. We used multivariable ß regression models to determine the adjusted association between human and food-producing animal AMR rates and an array of ecological country-level indicators. Human AMR rates were classified according to the WHO priority pathogens list and antibiotic-bacterium pairs. FINDINGS: Significant associations were identified between animal antimicrobial consumption and AMR in food-producing animals (OR 1·05 [95% CI 1·01-1·10]; p=0·013), and between human antimicrobial consumption and AMR specifically in WHO critical priority (1·06 [1·00-1·12]; p=0·035) and high priority (1·22 [1·09-1·37]; p<0·0001) pathogens. Bidirectional associations were also found: animal antibiotic consumption was positively linked with resistance in critical priority human pathogens (1·07 [1·01-1·13]; p=0·020) and human antibiotic consumption was positively linked with animal AMR (1·05 [1·01-1·09]; p=0·010). Carbapenem-resistant Acinetobacter baumanii, third generation cephalosporins-resistant Escherichia coli, and oxacillin-resistant Staphylococcus aureus all had significant associations with animal antibiotic consumption. Analyses also suggested significant roles of socioeconomics, including governance on AMR rates in humans and animals. INTERPRETATION: Reduced rates of antibiotic consumption alone will not be sufficient to combat the rising worldwide prevalence of AMR. Control methods should focus on poverty reduction and aim to prevent AMR transmission across different One Health domains while accounting for domain-specific risk factors. The levelling up of livestock surveillance systems to better match those reporting on human AMR, and, strengthening all surveillance efforts, particularly in low-income and middle-income countries, are pressing priorities. FUNDING: None.

Ceftobiprole medocaril for the treatment of pneumonia.

INTRODUCTION: Ceftobiprole, a fifth-generation cephalosporin, exhibits a broad-spectrum activity against common pathogens causing pneumonia, including multidrug-resistant organisms (MDROs), such as penicillin-resistant S. pneumoniae (PRSP) and methicillin-resistant Staphylococcus aureus (MRSA) and non-extended-spectrum ß -lactamase (non-ESBL) producing Enterobacterales strains. Therefore, ceftobiprole should be considered as a potential alternative for the empirical treatment of pneumonia in patients with high risk for MDROs. AREA COVERED: In this review, we discussed the role of ceftobiprole in the treatment of patients with pneumonia. EXPERT OPINION: Ceftobiprole has several advantages in the treatment of pneumonia. First, ceftobiprole exerts its bactericidal activity by inhibiting transpeptidases, especially showing strong affinities to penicillin-binding protein (PBP) 2a, PBP2× and PBP3. Second, its plasma protein binding is minimal, allowing it to penetrate lung tissue and achieve high concentrations in epithelial lung fluid. Third, ceftobiprole exhibits potent in vitro activity against a wide range of susceptible pathogens, including S. aureus, S. pneumoniae, Viridans streptococci, H. influenzae, M. catarrhalis, Enterobacterales, and particularly, MRSA and P. aeruginosa. Finally, several randomized controlled trials have demonstrated the clinical efficacy and safety of ceftobiprole in the treatment of pediatric and adult patients with community-acquired pneumonia and hospital-acquired pneumonia (excluding ventilator-associated pneumonia).

Simultaneous and divergent evolution of resistance to cephalosporin/ß-lactamase inhibitor combinations and imipenem/relebactam following ceftazidime/avibactam treatment of MDR Pseudomonas aeruginosa infections.

OBJECTIVES: To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection. METHODS: One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on ß-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays. RESULTS: Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC ß-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility. CONCLUSIONS: We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new ß-lactam/ß-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.

Off-label use versus formal recommendations of conventional and novel antibiotics for the treatment of infections caused by multidrug-resistant bacteria.

The infections caused by multidrug- and extensively drug-resistant (MDR, XDR) bacteria, including Gram-positive cocci (GPC, including methicillin-resistant Staphylococcus aureus, MDR-Streptococcus pneumoniae and vancomycin-resistant enterococci) and Gram-negative bacilli (GNB, including carbapenem-resistant [CR] Enterobacterales, CR-Pseudomonas aeruginosa and XDR/CR-Acinetobacter baumannii complex) can be quite challenging for physicians with respect to treatment decisions. Apart from complicated urinary tract and intra-abdominal infections (cUTIs, cIAIs), bloodstream infections and pneumonia, these difficult-to-treat bacteria also cause infections at miscellaneous sites (bones, joints, native/prosthetic valves and skin structures, etc.). Antibiotics like dalbavancin, oritavancin, telavancin and daptomycin are currently approved for the treatment of acute bacterial skin and skin structural infections (ABSSSIs) caused by GPC. Additionally, ceftaroline, linezolid and tigecycline have been formally approved for the treatment of community-acquired pneumonia and ABSSSI. Cefiderocol and meropenem-vaborbactam are currently approved for the treatment of cUTIs caused by XDR-GNB. The spectra of ceftazidime-avibactam and imipenem/cilastatin-relebactam are broader than that of ceftolozane-tazobactam, but these three antibiotics are currently approved for the treatment of hospital-acquired pneumonia, cIAIs and cUTIs caused by MDR-GNB. Clinical investigations of other novel antibiotics (including cefepime-zidebactam, aztreonam-avibactam and sulbactam-durlobactam) for the treatment of various infections are ongoing. Nevertheless, evidence for adequate antibiotic regimens against osteomyelitis, arthritis and infective endocarditis due to several GPC and MDR-GNB is still mostly lacking. A comprehensive review of PubMed publications was undertaken and the formal indications and off-label use of important conventional and novel antibiotics against MDR/XDR-GPC and GNB isolates cultured from miscellaneous sites are presented in this paper.