Introduction. Infections attributable to carbapenem-resistant Gram-negative bacilli are increasing globally. New antimicrobial agents are urgently needed to treat patients with these infections. Aim. To describe susceptibility to the novel carbapenem-β-lactamase inhibitor combination imipenem-relebactam and comparators of clinical isolates of non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa from intraabdominal infections (IAIs) and urinary tract infections (UTIs). Methods. Broth microdilution MICs were determined for isolates collected in 22 European countries in 2015–2017 and interpreted using EUCAST breakpoints; imipenem-relebactam MICs were interpreted using imipenem breakpoints. Results. For NPE, 98.4 % of isolates from IAIs (n=10,465) and 98.5 % of UTI isolates (n=7,446) were susceptible to imipenem-relebactam, as were 42.4 % of imipenem-nonsusceptible (n=474), 98.6 % of Klebsiella pneumoniae carbapenemase (KPC)-positive (n=138), and 93.9 % of multidrug-resistant (MDR) isolates (n=4,424) from IAIs and UTIs combined. Molecular analysis demonstrated that two-thirds of imipenem-nonsusceptible isolates rendered susceptible by relebactam carried KPCs; 96 % (261/271) of imipenem-nonsusceptible isolates of NPE that remained nonsusceptible in the presence of relebactam carried metallo-β-lactamase (MBL)-type and/or OXA-48-like carbapenemases. Among P. aeruginosa , 94.4 % of IAI (n=1,245) and 93.0 % of UTI isolates (n=714) were susceptible to imipenem-relebactam, as were 74.4 % of imipenem-nonsusceptible (n=469) and 79.8 % of MDR isolates (n=595) from IAIs and UTIs combined. Among the 120 isolates of P. aeruginosa that remained nonsusceptible to imipenem upon addition of relebactam, 72 % carried MBLs. The distribution of NPE and P. aeruginosa carrying carbapenemases varied substantially across Europe, as did resistance to imipenem and imipenem-relebactam. Conclusions. Continued surveillance of antimicrobial resistance and resistance mechanisms, including the study of imipenem-relebactam as it approaches regulatory approval, appears warranted.

Antimicrobial resistance including multidrug-resistance (MDR) is increasing especially among Gram-negative bacilli. New agents are needed to treat infections caused by these pathogens. For this report, the activity of imipenem-relebactam was assessed against Gram-negative bacilli from intraabdominal infections (IAIs) and urinary tract infections (UTIs) submitted to the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program in the United States from 2015 to 2017. Broth microdilution MICs for imipenem-relebactam and comparators were determined by a central laboratory against isolates of non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa. Imipenem-relebactam MICs were interpreted using United States Food and Drug Administration (FDA) breakpoints. 99.5% of NPE isolates collected from patients with IAIs (n = 3,633) and UTIs (n = 3,038) were susceptible to imipenem-relebactam, as were 77.9% of imipenem-nonsusceptible, 96.3% of KPC-positive, and 98.7% of MDR isolates from IAIs and UTIs combined. 96.7% of IAI isolates (n = 486) and 96.4% of UTI isolates (n = 360) of P. aeruginosa were susceptible to imipenem-relebactam, as were 85.0% of imipenem-nonsusceptible and 87.3% of MDR isolates from IAIs and UTIs combined. Percent susceptibility to imipenem-relebactam for cefepime-, ceftazidime-, and piperacillin-tazobactam-nonsusceptible isolates was 98.3-98.8% for NPE and 87.3-90.0% for P. aeruginosa. Imipenem-relebactam demonstrated potent in vitro activity against NPE and P. aeruginosa isolates from IAIs and UTIs, including against resistant subsets, and will provide important coverage for IAIs and UTIs caused by β-lactam-resistant, MDR, and KPC-positive Gram-negative bacilli.

Fosfomycin is a bactericidal agent that inhibits cell wall synthesis using a mechanism of action distinct from β-lactams or other antimicrobial agents. It is a broad-spectrum agent that is frequently active against antimicrobial-resistant bacterial pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant (MDR) Enterobacteriaceae, and some isolates of MDR Pseudomonas aeruginosa. Intravenous fosfomycin has been prescribed for a wide variety of infections in many countries for >40 years. It is most frequently used in combination with other antimicrobial agents (e.g., β-lactams, carbapenems, and aminoglycosides) and has an excellent safety profile, including in neonates and children, even with long-term administration (weeks). Fosfomycin achieves extensive tissue distribution including difficult to reach compartments such as aqueous humor, vitreous humor, abscess fluid, and CSF. Available data, to date, suggest no clinically relevant pharmacological interactions between fosfomycin and other agents, including drugs, stimulants, or food. Intravenous fosfomycin’s role in therapy in Canada is likely as an agent used alone or in combination for complicated urinary tract infections in hospitalized patients as well as hospitalized patients with MDR infections who have not responded to first-, and potentially, second-line antimicrobials or in patients who cannot tolerate (due to adverse effects) first- and second-line antimicrobials.

To determine the in vitro susceptibility of Enterobacterales (n = 5457) and Pseudomonas aeruginosa (n = 1949) isolated from hospitalized patients in Africa (three countries) and the Middle East (five countries) in 2018–20 to a panel of 11 antimicrobials and to identify β-lactamase/carbapenemase genes in isolates with meropenem-non-susceptible and/or ceftazidime/avibactam-resistant phenotypes. CLSI broth microdilution testing generated MICs that were interpreted using CLSI (2021) breakpoints. β-Lactamase/carbapenemase genes were identified using multiplex PCR assays. Enterobacterales isolates were highly susceptible to amikacin (96.7%), ceftazidime/avibactam (96.6%) and tigecycline (96.0%), and slightly less susceptible to meropenem (94.3%). In total, 337 Enterobacterales isolates (6.2% of all Enterobacterales isolates) carried one or more carbapenemase genes: 188 isolates carried a serine carbapenemase (178 OXA, 10 KPC) and 167 isolates carried an MBL (18 isolates carried both an MBL and an OXA). NDM-1 was the most common MBL identified (64.1% of NDM enzymes; 59.9% of all MBLs). OXA-48 (47.8%) and OXA-181 (38.8%) were the most common OXAs detected. P. aeruginosa isolates were most susceptible to ceftazidime/avibactam (89.1%) and amikacin (88.9%). Only 73.1% of P. aeruginosa isolates were meropenem susceptible. The majority (68.1%) of P. aeruginosa isolates tested for carbapenemase/β-lactamase genes were negative. In total, 88 isolates (4.5% of all P. aeruginosa isolates) carried one or more carbapenemase genes: 81 isolates carried an MBL and 8 carried a GES carbapenemase (1 isolate carried genes for both). Carbapenemase detection was closely associated with meropenem-non-susceptible phenotypes for Enterobacterales (89.1%) but not for P. aeruginosa (24.2%). Wide geographic variation in carbapenemase type and frequency of detection was observed.

Acute and chronic bacterial prostatitis in outpatients is commonly treated with oral fluoroquinolones; however, the worldwide dissemination of multidrug-resistant (MDR) Escherichia coli has resulted in therapeutic failures with fluoroquinolones. We reviewed the literature regarding the use of oral fosfomycin in the treatment of acute and chronic prostatitis caused by MDR E. coli. All English-language references on PubMed from 1986 to June 2017, inclusive, were reviewed from the search “fosfomycin prostatitis.” Fosfomycin demonstrates potent in vitro activity against a variety of antimicrobial-resistant E. coli genotypes/phenotypes including ciprofloxacin-resistant, trimethoprim-sulfamethoxazole-resistant, extended-spectrum β-lactamase- (ESBL-) producing, and MDR isolates. Fosfomycin attains therapeutic concentrations (≥4 μg/g) in uninflamed prostatic tissue and maintains a high prostate/plasma ratio up to 17 hours after oral administration. Oral fosfomycin’s clinical cure rates in the treatment of bacterial prostatitis caused by antimicrobial-resistant E. coli ranged from 50 to 77% with microbiological eradication rates of >50%. An oral regimen of fosfomycin tromethamine of 3 g·q 24 h for one week followed by 3 g·q 48 h for a total treatment duration of 6–12 weeks appeared to be effective. Oral fosfomycin may represent an efficacious and safe treatment for acute and chronic prostatitis caused by MDR E. coli.