Abstract Background Gram-negative pathogens with multidrug resistance (MDR) or difficult-to-treat resistance (DTR) are increasingly common, resulting in limited treatment options. These resistant pathogens are often isolated from the respiratory tract or bloodstream and can result in significant patient morbidity and mortality. Imipenem/relebactam is a combination of imipenem with relebactam, a β-lactamase inhibitor of class A and C β-lactamases. We evaluated the activity of imipenem/relebactam and comparators (imipenem, meropenem, piperacillin/tazobactam, cefepime, ceftazidime, levofloxacin, and amikacin) against gram-negative MDR and DTR isolates that were collected from patients with lower respiratory tract (RTI) or bloodstream infections (BSI) in the United States (US). Methods In 2018-2020, 24 clinical labs participated in the global SMART surveillance program in the US, and each collected up to 100 consecutive aerobic or facultative gram-negative pathogens per year from patients with RTI and 50 from BSI. MICs were determined using CLSI broth microdilution and interpreted with CLSI breakpoints. Results MDR isolates were found among 13.5% of collected P. aeruginosa (n=2018), 11.9% of E. coli (n=1952), 13.1% of K. pneumoniae (n=1080), 24.1% of E. cloacae complex (n=460), 19.7% of K. aerogenes (n=304), and 6.1% of S. marcescens isolates (n=304); DTR isolates were found among 7.1%, 0.1%, 2.4%, 1.5%, 0%, and 0.8%, respectively. Imipenem/relebactam was active against 61% of MDR P. aeruginosa, 43-53 percentage points higher than the studied comparator β-lactams, and against 49% of DTR P. aeruginosa, which were nonsusceptible to all studied commonly used β-lactams and levofloxacin (Table). Imipenem/relebactam was also active against 87-100% of MDR Enterobacterales, including against 97% of MDR K. pneumoniae, 18-96 percentage points higher than the studied comparator β-lactams, and against 85% of DTR K. pneumoniae. Conclusion Based on these in vitro data, imipenem/relebactam represents a promising treatment option in the US for patients with RTI or BSI caused by highly resistant gram-negative pathogens that pose substantial treatment challenges. Disclosures Fakhar Siddiqui, MD, MBA, Merck & Co., Inc.: employee|Merck & Co., Inc.: Stocks/Bonds Karri A Bauer, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds Charles A. DeRyke, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds.
Abstract Background The β-lactamase inhibitor, avibactam, has potent inhibitory activity against Class A, Class C, and certain Class D serine β-lactamases. This study evaluated the in vitro activity of ceftazidime-avibactam (CZA) and comparators against respiratory tract infection (RTI)-associated Pseudomonas aeruginosa isolated from presumed community-acquired (CA; cultured < 48 hours after hospital admission) and hospital-acquired (HA; cultured ≥48 hours post-admission) infections collected from 2017-2021. Methods 11,780 non-duplicate P. aeruginosa were collected from 246 sites in 54 countries as part of ATLAS 2017-2021 (excluding mainland China and North America) from respiratory tract infections for which the length of hospitalization was specified. Susceptibility testing was by broth microdilution according to CLSI guidelines and analyzed using CLSI 2023 breakpoints. Meropenem-nonsusceptible (MEM-NS) isolates were screened for the presence of β-lactamase genes. All MEM-NS isolates were screened in 2017-2020, whereas ∼25% of those collected in 2020 and 2021 were screened. Results CZA was the most active agent examined against the CA-infection isolates, inhibiting 92.3% of the population (Table). Against the HA isolates, 89.0% were susceptible to CZA, a percentage slightly lower than amikacin (89.4%). Removing MBL-producers increased the percentages susceptible to CZA for both groups by 2-3 percentage points. Approximately 68-70% of the meropenem-nonsusceptible isolates from both groups were susceptible to CZA, values similar to those demonstrated by amikacin and ceftolozane/tazobactam. Conclusion The percentage of CA and HA isolates from respiratory tract infections inhibited by CZA was approximately 15 and 20 percentage points higher, respectively, than the percentages inhibited by meropenem, and slightly higher (1-2 percentage points) than ceftolozane-tazobactam. The potent in vitro activity of CZA against HA isolates was exceeded only by amikacin, an agent discouraged as monotherapy for P. aeruginosa infections outside of the urinary tract by the CLSI. CZA remains an excellent therapeutic choice for use against P. aeruginosa, regardless of whether they’re CA or HA. Disclosures Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Gregory Stone, PhD, Pfizer: Stocks/Bonds Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
The Infectious Diseases Society of America advocates trimethoprim-sulfamethoxazole (SXT) as initial therapy for females with acute uncomplicated bacterial cystitis in settings where the prevalence of SXT resistance does not exceed 10 to 20%. To determine trends in the activities of SXT, ampicillin, ciprofloxacin, and nitrofurantoin among urine isolates of Escherichia coli from female outpatients, susceptibility testing data from The Surveillance Network (TSN) Database-USA (n 286,187) from 1995 to 2001 were analyzed. Resistance rates among E. coli isolates to ampicillin (range, 36.0 to 37.4% per year), SXT (range, 14.8 to 17.0%), ciprofloxacin (range, 0.7 to 2.5%), and nitrofurantoin (range, 0.4 to 0.8%) varied only slightly over this 7-year period. Ciprofloxacin was the only agent studied that demonstrated a consistent stepwise increase in resistance from 1995 (0.7%) to 2001 (2.5%). In 2001, SXT resistance among E. coli isolates was >10% in all nine U.S. Bureau of the Census regions. At institutions testing >100 urinary isolates of E. coli (n 126) in 2001, ampicillin (range, 27.3 to 98.8%) and SXT (range, 7.5 to 47.1%) resistance rates varied widely while ciprofloxacin (range, 0 to 12.9%) and nitrofurantoin (range, 0 to 2.8%) resistance rates were more consistent. In 2001, the most frequent coresistant phenotypes were resistance to ampicillin and SXT (12.0% of all isolates; 82.3% of coresistant isolates) and resistance to ampicillin, ciprofloxacin, and SXT (1.4% of all isolates; 9.9% of coresistant isolates). Coresistance less frequently included resistance to nitrofurantoin (3.5% of coresistant isolates) than resistance to ciprofloxacin (15.8%), SXT (95.7%), and ampicillin (98.1%). In conclusion, among urinary isolates of E. coli from female outpatients in the United States, national resistance rates to SXT were relatively consistent (14.8 to 17.0%) from 1995 to 2001 but demonstrated considerable regional and institutional variation in 2001. Therapies other than SXT may need to be considered in some locations.
ABSTRACT Achromobacter spp. and Burkholderia cepacia complex (Bcc) are rare but diverse opportunistic pathogens associated with serious infections, which are often multidrug resistant. This study compared the in vitro antibacterial activity of the siderophore antibiotic cefiderocol against Achromobacter spp. and Bcc isolates with that of other approved antibacterial drugs, including ceftazidime-avibactam, ciprofloxacin, colistin, imipenem-relebactam, and meropenem-vaborbactam. Isolates were collected in the SIDERO multinational surveillance program. Among 334 Achromobacter spp. isolates [76.6% from respiratory tract infections (RTIs)], cefiderocol had minimum inhibitory concentration (MIC) 50/90 of 0.06/0.5 µg/mL overall and 0.5/4 µg/mL against 52 (15.6%) carbapenem-non-susceptible (Carb-NS) isolates. Eleven (3.3%) Achromobacter spp. isolates overall and 6 (11.5%) Carb-NS isolates were not susceptible to cefiderocol. Among 425 Bcc isolates (73.4% from RTIs), cefiderocol had MIC 50/90 of ≤0.03/0.5 µg/mL overall and ≤0.03/1 µg/mL against 184 (43.3%) Carb-NS isolates. Twenty-two (5.2%) Bcc isolates overall and 13 (7.1%) Carb-NS isolates were not susceptible to cefiderocol. Cumulative MIC distributions showed cefiderocol to be the most active of the agents tested in vitro against both Achromobacter spp. and Bcc. In a neutropenic murine lung infection model and a humanized pharmacokinetic immunocompetent rat lung infection model, cefiderocol showed significant bactericidal activity against two meropenem-resistant Achromobacter xylosoxidans strains compared with untreated controls ( P < 0.05) and vehicle-treated controls ( P < 0.05), respectively. Meropenem, piperacillin-tazobactam, ceftazidime, and ciprofloxacin comparators showed no significant activity in these models. The results suggest that cefiderocol could be a possible treatment option for RTIs caused by Achromobacter spp. and Bcc.
Abstract Objective: To identify independent risk factors for enteric carriage of vancomycin-resistant Enterococcus faecium (VREF) in hospitalized patients tested for Clostridium difficile toxin. Design: Retrospective case-cohort study. Setting: Tertiary-care teaching hospital. Patients: Convenience sample of 215 adult inpatients who had stool tested for C difficile between January 29 and February 25,1996. Results: 41 (19%) of 215 patients had enteric carriage of VREF. Five independent risk factors for enteric VREF were identified: history of prior C difficile (odds ratio [OR], 15.21; 95% confidence interval [CI 95 ], 3.30-70.10; P <.001), parenteral treatment with vancomycin for ≥5 days (OR, 4.06; CI 95 , 1.54-10.73; P =.005), treatment with antimicrobials effective against gram-negative organisms (OR, 3.44; CI 95 , 1.20-9.87; P =.021), admission from another institution (OR, 2.95; CI 95 , 1.21-7.18; P =.017), and age >60 years (OR 2.57; CI 95 , 1.13-5.82; P =.024). These risk factors for enteric VREF were independent of the patient's current C difficile status. Conclusions: Antimicrobial exposures are the most important modifiable independent risk factors for enteric carriage of VREF in hospitalized patients tested for C difficile .
The Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) study is the only ongoing nationwide antibiotic resistance surveillance program specific to ocular pathogens.To report resistance rates and trends among common ocular isolates collected during the first 5 years of the ARMOR study.This antibiotic resistance surveillance study was performed at an independent central laboratory. Clinical centers across the United States were invited to submit ocular isolates of Staphylococcus aureus, coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa. Isolates were collected from January 1, 2009, through December 31, 2013, and analyzed from January 16 to May 15, 2015.Minimum inhibitory concentrations for various antibiotic classes were determined by broth microdilution according to the guidelines of the Clinical and Laboratory Standards Institute. Minimum inhibitory concentrations were interpreted as susceptible, intermediate, or resistant based on established break points.A total of 3237 ocular isolates (1169 S aureus, 992 CoNS, 330 S pneumoniae, 357 H influenzae, and 389 P aeruginosa) were collected from 72 centers. Methicillin resistance was found among 493 S aureus isolates (42.2%; 95% CI, 39.3%-45.1%) and 493 CoNS isolates (49.7%; 95% CI, 46.5%-52.9%), and methicillin-resistant (MR) isolates had a high probability of concurrent resistance to fluoroquinolones, aminoglycosides, or macrolides (P < .001). Multidrug resistance to at least 3 additional antibiotic classes was found in 428 MR S aureus isolates (86.8%) and 381 MRCoNS isolates (77.3%). All staphylococcal isolates were susceptible to vancomycin. Resistance among S pneumoniae isolates was highest for azithromycin (113 isolates [34.2%]) whereas resistance among P aeruginosa and H influenzae was low against the antibiotics tested. Staphylococcal isolates from elderly patients were more likely to be MR, as were S aureus isolates obtained from the southern United States (P < .001). Methicillin resistance among staphylococci did not increase during the 5-year study period (P ≤ .22), and small decreases in resistance to ciprofloxacin among CoNS and MRCoNS and to tobramycin among CoNS (P ≤ .03) were found.Methicillin resistance was prevalent among staphylococcal isolates from ocular infections, with many strains demonstrating multidrug resistance. These findings are consistent with resistance trends reported for nonocular staphylococcal isolates. Overall ocular resistance did not increase during the 5-year study period. Continued surveillance of ocular isolates provides critical information to guide selection of topical antibacterials used for empirical management of ocular infections.
Abstract Background Multidrug-resistant (MDR) bacteria are frequently defined using the criteria established by Magiorakos et al [Clin Microbiol Infect 2012;18:268–81]. Difficult-to-treat resistance (DTR) [Kadri et al, Clin Infect Dis 2018;67:1803–14] is a novel approach to defining resistance in gram-negative bacilli focusing on treatment-limiting resistance to first-line agents (all β-lactams and fluoroquinolones). Methods Clinical and Laboratory Standards Institute–defined broth microdilution minimum inhibitory concentrations (MICs) were determined for imipenem/relebactam, ceftolozane/tazobactam, and comparators against respiratory, intraabdominal, and urinary isolates of Enterobacterales (n = 10 516) and Pseudomonas aeruginosa (n = 2732) collected in 26 US hospitals in 2015–2017. Results Among all Enterobacterales, 1.0% of isolates were DTR and 15.6% were MDR; 8.4% of P. aeruginosa isolates were DTR and 32.4% were MDR. MDR rates for Enterobacterales and DTR and MDR rates for P. aeruginosa were significantly higher (P < .05) in isolates collected in intensive care units (ICUs) than in non-ICUs and in respiratory tract isolates than in intraabdominal or urinary tract isolates. In addition, 82.4% of DTR and 92.1% of MDR Enterobacterales and 62.2% of DTR and 82.2% of MDR P. aeruginosa were imipenem/relebactam-susceptible, and 1.5% of DTR and 65.8% of MDR Enterobacterales and 67.5% of DTR and 84.0% of MDR P. aeruginosa were ceftolozane/tazobactam-susceptible. Conclusions MDR phenotypes defined using the Magiorakos criteria may overcall treatment-limiting resistance in gram-negative bacilli. In the US, DTR Enterobacterales were infrequent, while MDR Enterobacterales isolates and DTR and MDR P. aeruginosa were common. Imipenem/relebactam (Enterobacterales, P. aeruginosa) and ceftolozane/tazobactam (P. aeruginosa) retained in vitro activity against most DTR and MDR isolates.
The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. The production of β-lactamase is a key mechanism contributing to imipenem resistance in P. aeruginosa. Relebactam is a novel β-lactamase inhibitor, active against class A and C β-lactamases, that has been shown to restore imipenem susceptibility. In a series of studies, we assessed the interaction of relebactam with key mechanisms involved in carbapenem resistance in P. aeruginosa and to what extent relebactam might overcome imipenem non-susceptibility.