Resistant Gram-negative Organisms Research Articles

Maternal Colonization Versus Nosocomial Transmission as the Source of Drug-Resistant Bloodstream Infection in an Indian Neonatal Intensive Care Unit: A Prospective Cohort Study.

Drug-resistant gram-negative (GN) pathogens are a common cause of neonatal sepsis in low- and middle-income countries. Identifying GN transmission patterns is vital to inform preventive efforts. We conducted a prospective cohort study, 12 October 2018 to 31 October 2019 to describe the association of maternal and environmental GN colonization with bloodstream infection (BSI) among neonates admitted to a neonatal intensive care unit (NICU) in Western India. We assessed rectal and vaginal colonization in pregnant women presenting for delivery and colonization in neonates and the environment using culture-based methods. We also collected data on BSI for all NICU patients, including neonates born to unenrolled mothers. Organism identification, antibiotic susceptibility testing, and next-generation sequencing (NGS) were performed to compare BSI and related colonization isolates. Among 952 enrolled women who delivered, 257 neonates required NICU admission, and 24 (9.3%) developed BSI. Among mothers of neonates with GN BSI (n = 21), 10 (47.7%) had rectal, 5 (23.8%) had vaginal, and 10 (47.7%) had no colonization with resistant GN organisms. No maternal isolates matched the species and resistance pattern of associated neonatal BSI isolates. Thirty GN BSI were observed among neonates born to unenrolled mothers. Among 37 of 51 BSI with available NGS data, 21 (57%) showed a single nucleotide polymorphism distance of ≤5 to another BSI isolate. Prospective assessment of maternal GN colonization did not demonstrate linkage to neonatal BSI. Organism-relatedness among neonates with BSI suggests nosocomial spread, highlighting the importance of NICU infection prevention and control practices to reduce GN BSI.

Fear of Missing Organisms (FOMO): the discordance among broad-spectrum empiric antibiotic therapy, microbiologic results, and definitive antibiotic therapy for diabetic foot infections and lower extremity osteomyelitis.

Empiric broad-spectrum antibiotic therapy is commonly prescribed for patients hospitalized with diabetic foot infections (DFI) and lower extremity osteomyelitis (OM). The primary objective was to evaluate the concordance between empiric antibiotic therapy, microbiologic results, and definitive antibiotic therapy with a focus on methicillin-resistant Staphylococcus aureus (MRSA) and resistant gram-negative organisms. The secondary objective was to evaluate the negative predictive values (NPV) of select risk factors for MRSA and resistant gram-negative organisms for microbiologic results with these organisms. Retrospective cohort study. Safety-net health system in Ohio. Adults hospitalized and receiving antibiotic therapy for DFI or lower extremity OM in 2021. For 259 unique patients, empiric therapies with activity against MRSA and resistant gram-negative organisms were administered to 224 (86.5%) and 217 (83.8%) patients, respectively. Definitive therapies with activity against MRSA and resistant gram-negative organisms were administered to 91 (35%) and 74 (28.6%) patients, respectively. Of 234 patients with microbiologic testing, 29 (12.4%) had positive cultures with MRSA and 41 (17.5%) with resistant gram-negative organisms. The NPVs of risk factors for MRSA and resistant gram-negative organisms for the absence of these organisms in culture were 91% and 85%, respectively. For patients hospitalized with DFI and lower extremity OM, our data suggest opportunities for substantial reductions in empiric therapies with activity against MRSA and resistant gram-negative organisms. The absence of risk factors for these organisms was reasonably good at predicting negative cultures with these organisms.

470: PREDICTION SCORING FOR PRIMARY RESISTANCE IN GRAM-NEGATIVE BACTEREMIA WITHIN A LARGE HEALTH SYSTEM

Introduction: Resistant Gram-negative organisms complicate successful treatment of infectious diseases in critically ill patients as common antibiotic agents are ineffective. Knowledge of risk factors associated with antimicrobial resistant Gram-negative infections is necessary to select appropriate antibiotic agents as culture results are not available immediately. The primary objective was to identify risk factors associated with primary resistance of selected Gram-negative bacteria isolated from blood and establish a scoring method to predict primary resistance. Methods: A total of 378 cases from 390 isolates were analyzed within the Banner health system. Fifty susceptible cases were identified for each of the following organisms: Pseudomonas aeruginosa (Ps), Escherichia coli (EC), Klebsiella pneumoniae (KP), and Enterobacter cloacae (Ent. c). The number of nonsusceptible cases were 50 for EC and KP, 27 for Ent. c and 50 for Ps. Results: The presence of chronic kidney disease (CKD), peripheral vascular disease (PVD), connective tissue disease (CTD), hemi/paraplegia, ventilator use, central vascular access, transfer from long term care facility, admission from outpatient parenteral antibiotic therapy, receiving chemotherapy, history of cerebral vascular accident, diabetes with complication and history of infection within the previous 6 months were strongly associated with resistance. A logistic regression model was developed for predicting primary resistance. An individual with no risk factors for primary resistance would have a predicted probability of resistance of 27%. Further analysis of these factors is required to remove any correlation bias and to develop a prediction scoring system to determine primary resistance. Conclusions: To conclude, this study was able to identify certain risk factors to be statistically significant (p< 0.05) to determine primary resistance which will help develop a prediction scoring system that will aid in appropriate antibiotic selection for the treatment of selected Gram-negative bacteremia infections.

In-vitro susceptibility testing methods for the combination of ceftazidime-avibactam with aztreonam in metallobeta-lactamase producing organisms: Role of combination drugs in antibiotic resistance era.

Resistance in Gram-negative organisms has become one of the leading threats in recent years. Of the different mechanisms described in the literature, resistance due to beta-lactamases genes have been overcomed by the use of a beta-lactamase inhibitor in combination with a beta-lactam antibiotic. When this combination is insufficient to counter metallo-beta-lactamases, a third antibiotic, has been added to restore susceptibility. One such recent combination is ceftazidime-avibactam with aztreonam. In this study, 60 isolates of multidrug-resistant organisms producing metallo-beta-lactamases were included to perform in-vitro antibiotic susceptibility testing against ceftazidime-avibactam and aztreonam alone and in combination using three different methods. Individual testing revealed 100% (60/60) resistance to both ceftazidime-avibactam and aztreonam in all the isolates. The disk diffusion method showed an inhibition zone size of 21 mm in all the isolates, with 16 isolates showing an increase in inhibition zone size of >16 mm. In the E-test fixed ratio method, MICs of ceftazidime-avibactam and aztreonam when used alone ranged from 8/4 µg l−1 to ≥256/4 µg l−1 and 16 µg l−1 to 256 µg l−1, respectively, but in combination, these MICs were reduced to 0.016/4 µg l−1 to 2/4 µg l−1 with FIC < 0.5 in all the isolates. Similar results were obtained with the E-test agar dilution method with more than a 16-fold reduction in MIC in all the isolates when avibactam concentration was fixed at 4 µg l−1. All three methods showed a 100% correlation with each other. The current study depicted the usefulness of combining ceftazidime-avibactam with aztreonam against organisms producing metallo-beta-lactamases and that disk diffusion methods can be used as a method for performing in-vitro antibiotic susceptibility testing of this combination.

Characterization of carbapenem-resistant gram-negative bacteria collected in the Sentinel Surveillance Program, 2018–2019

Background: Carbapenem resistance in gram-negative organisms is an important public health problem. The CDC conducted Sentinel surveillance in 2018–2019 to characterize these organisms from 9 facilities in 9 different states. Methods: Carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa (CRPA), and Acinetobacter spp (CRA) obtained from clinical samples of patients in acute-care or long-term care facilities were submitted to the CDC. Identification was confirmed using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF), and antimicrobial susceptibility testing (AST) was performed via broth microdilution for 27 antibiotics. All confirmed CRE and CRPA were tested for carbapenemase production (CP) using the modified carbapenem inactivation method (mCIM). The isolates that were mCIM-positive were assessed by real-time PCR for presence of blaKPC, blaNDM, blaVIM, and blaIMP. CP-CRE were also assessed for blaOXA-48-like. All confirmed CRA were tested for the same genes as CRPA and blaOXA-23–like, blaOXA-24/40-like, blaOXA-58–like, and blaOXA-235–like genes. Difficult-to-treat resistance (DTR) was defined as resistance to all β-lactams (excluding newer β-lactam combination agents) and quinolones tested. Results: The CDC confirmed 208 CRE, 161 CRPA, and 94 CRA. Table 1 summarizes AST results for a selection of drugs. We identified 112 (53.8%) mCIM-positive CRE and 6 (3.7%) mCIM-positive CRPA. The PCR results are summarized in Table 2. One mCIM-positive and PCR-negative isolate was positive in a metallo-β-lactamase screen. Conclusions: Resistance among CRE and CRPA to newer β-lactam combination agents was detected. Options for treating CRA are limited. Of 112 CP-CRE, 85.7% harbored blaKPC; CP-CRPA were rare (3.7%); and most CRA harbored blaOXA-23-like (55.3%) or blaOXA-24/40-like (30.9%). Whole-genome sequencing is planned to better understand gene variants, sequence types, and additional resistance markers present among the isolates.Funding: NoneDisclosures: None

Multicenter evaluation of contamination of the healthcare environment near patients with Candida auris skin colonization

Background:Candida auris is an emerging multidrug-resistant yeast that is transmitted in healthcare facilities and is associated with substantial morbidity and mortality. Environmental contamination is suspected to play an important role in transmission but additional information is needed to inform environmental cleaning recommendations to prevent spread. Methods: We conducted a multiregional (Chicago, IL; Irvine, CA) prospective study of environmental contamination associated with C. auris colonization of patients and residents of 4 long-term care facilities and 1 acute-care hospital. Participants were identified by screening or clinical cultures. Samples were collected from participants’ body sites (eg, nares, axillae, inguinal creases, palms and fingertips, and perianal skin) and their environment before room cleaning. Daily room cleaning and disinfection by facility environmental service workers was followed by targeted cleaning of high-touch surfaces by research staff using hydrogen peroxide wipes (see EPA-approved product for C. auris, List P). Samples were collected immediately after cleaning from high-touch surfaces and repeated at 4-hour intervals up to 12 hours. A pilot phase (n = 12 patients) was conducted to identify the value of testing specific high-touch surfaces to assess environmental contamination. High-yield surfaces were included in the full evaluation phase (n = 20 patients) (Fig. 1). Samples were submitted for semiquantitative culture of C. auris and other multidrug-resistant organisms (MDROs) including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended-spectrum β-lactamase–producing Enterobacterales (ESBLs), and carbapenem-resistant Enterobacterales (CRE). Times to room surface contamination with C. auris and other MDROs after effective cleaning were analyzed. Results:Candida auris colonization was most frequently detected in the nares (72%) and palms and fingertips (72%). Cocolonization of body sites with other MDROs was common (Fig. 2). Surfaces located close to the patient were commonly recontaminated with C. auris by 4 hours after cleaning, including the overbed table (24%), bed handrail (24%), and TV remote or call button (19%). Environmental cocontamination was more common with resistant gram-positive organisms (MRSA and, VRE) than resistant gram-negative organisms (Fig. 3). C. auris was rarely detected on surfaces located outside a patient’s room (1 of 120 swabs; &lt;1%). Conclusions: Environmental surfaces near C. auris–colonized patients were rapidly recontaminated after cleaning and disinfection. Cocolonization of skin and environment with other MDROs was common, with resistant gram-positive organisms predominating over gram-negative organisms on environmental surfaces. Limitations include lack of organism sequencing or typing to confirm environmental contamination was from the room resident. Rapid recontamination of environmental surfaces after manual cleaning and disinfection suggests that alternate mitigation strategies should be evaluated.Funding: NoneDisclosures: None

Evaluation of Ceftazidime Use in the Neonatal Intensive Care Unit and Association With Cephalosporin-Resistant Gram-Negative Bacteria.

Cefotaxime shortage in 2015 led to increased ceftazidime use in the neonatal intensive care unit (NICU). The purpose was to explore whether ceftazidime increases risk for development of resistant gram-negative organisms. Retrospective evaluation of NICU patients with cultures positive for Escherichia coli, Pseudomonas aeruginosa, Klebsiella species, or Stenotrophomonas maltophilia between January1, 2015 and August 31, 2020. Isolates were excluded if obtained from same patient and source within 90 days or if patient ≤7 days of life or admitted from a referring hospital. Data collection included demographics and clinical parameters, and culture/susceptibility data. The primary objective was comparison of pathogens and clinical parameters in those with and without third-generation cephalosporin resistance. The secondary objectives included a comparison between those with and without ceftazidime exposure and identification of factors associated with resistance. Comparisons were made using χ2, Fisher exact tests, or Wilcoxon tests. A logistic regression was used to identify risk factors for resistance. Overall, 349 isolates, representing 215 patients, were included. The most common source was endotracheal (n = 192, 55.0%) and pathogens were E coli (31.8%) and P aeruginosa (29.2%). Overall, 12.3% (n = 43) were resistant and these were obtained after longer parenteral nutrition (PN), central line access, and antibiotic days versus susceptible isolates. Higher resistance was noted after ceftazidime exposure versus no exposure, 19.1% versus 6.6%. Each day of ceftazidime was associated with 13% greater odds of P aeruginosa resistance (adjusted odds ratio: 1.13 [95% confidence interval: 1.03-1.23]). Ceftazidime duration was associated with increased risk for P aeruginosa resistance. Additional studies are needed to confirm these findings.

Outpatient antibiogram and predictors of ciprofloxacin and trimethoprim-sulfamethoxazole resistant urinary tract infections.

Context: Rising antibiotic resistance has transcended hospital boundaries and impacted individuals with community acquired urinary tract infections (UTI). Scant data on antibiotic resistance in outpatient settings exists and most studies in the United States (U.S.) have identified predictors of resistance in acute-care settings. Objective: Determine the antibiogram among Escherichia coli isolates and factors associated with ciprofloxacin and trimethoprim-sulfamethoxazole (TMP-SMX) resistant gram-negative urinary isolates. Study Design: Retrospective cohort study. Setting: Two primary care, safety-net clinics in Houston, TX between 11/2018 and 3/2020. Population studied: Patients aged 18 and older presenting with provider suspected uncomplicated or complicated UTI. Outcome measures: Resistance and predictors of resistance to UTI-relevant antibiotics. Results: Among 1265 cultures collected, 372 (28.4%) were positive. We detected E. coli (50.3%) and Group B Streptococcus (18.6%) most frequently. Our patient population consisted mostly of Hispanic (75.7%) females (92.5%) born outside the U.S. (67.3%) with a mean age of 47. Among patients with E. coli isolated (n=189), antibiotic resistance was highest to ampicillin (63%), TMP-SMX (44%), ciprofloxacin (31%), and cefazolin (30%); no or low resistance against amikacin (0%), fosfomycin (0%), and nitrofurantoin (2.7%) was detected. Approximately 12% of E. coli isolates were extended-spectrum beta-lactamase positive. Having a prior UTI caused by a TMP-SMX resistant gram-negative organism and being born outside the U.S increased the odds of TMP-SMX resistance by 3.71 (95% confidence interval: 1.6-9.2) and 3.08 (95% CI: 1.6-6.3), respectively. Having a complicated UTI (odds ratio (OR): 3.58; 95% CI: 1.1-12.1), prior fluoroquinolone use (OR: 6.81; 95% CI: 1.7-34.1) and a prior UTI with ciprofloxacin resistance (OR: 7.84; 95% CI: 3.2-20.7) increased the odds of having a ciprofloxacin resistance. Conclusion: The Infectious Disease Society of America cautions against prescribing an antibiotic if regional resistance exceeds 20%. We constructed an antibiogram and found resistance surpassed this threshold for TMP-SMX and ciprofloxacin and identified factors associated with resistance to these agents. Assessing these characteristics during clinical decision making may improve antibiotic-organism susceptibility concordance in primary care.

Evaluation of Individualized Cefepime Dosing Strategy Using Population Pharmacokinetics.

The use of population pharmacokinetics (PK) to optimize cefepime dosing could be an effective strategy, given the increasing prevalence of resistant gram-negative organisms. The objective of this study is to retrospectively compare dosing using a PK approach (intervention) vs traditional dosing (control) for cefepime in patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Adult hospitalized patients with HAP or VAP receiving cefepime for ≥72 hours were screened first from August 2018 to January 2019 to be included in the intervention group, then screened during the preintervention period from August 2017 to July 2018 for the control group. Clinical improvement on day 7 of cefepime therapy was achieved in 72% of the patients in the intervention group and 70% of the patients in the control group (P = .8110). However, the clinical cure rate in the intervention group was higher than that of the control group (50% vs 36.5%; P = .0034). Cefepime dosing using population PK appears to be a novel, effective, and safe dosing strategy for patients with HAP or VAP.

171. The Impact of COVID-19 on Healthcare-Associated Infections

BackgroundThe profound changes wrought by COVID-19 on routine hospital operations may have influenced performance on hospital measures, including healthcare-associated infections (HAIs). ObjectiveEvaluate the association between COVID-19 surges and HAI or cluster ratesMethods Design: Prospective cohort studySetting148 HCA Healthcare-affiliated hospitals, 3/1/2020-9/30/2020, and a subset of hospitals with microbiology and cluster data through 12/31/2020PatientsAll inpatientsMeasurementsWe evaluated the association between COVID-19 surges and HAIs, hospital-onset pathogens, and cluster rates using negative binomial mixed models. To account for local variation in COVID-19 pandemic surge timing, we included the number of discharges with a laboratory-confirmed COVID-19 diagnosis per staffed bed per month at each hospital.ResultsCentral line-associated blood stream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), and methicillin-resistant Staphylococcus aureus (MRSA) bacteremia increased as COVID-19 burden increased (P ≤ 0.001 for all), with 60% (95% CI, 23 to 108%) more CLABSI, 43% (95% CI, 8 to 90%) more CAUTI, and 44% (95% CI, 10 to 88%) more cases of MRSA bacteremia than expected over 7 months based on predicted HAIs had there not been COVID-19 cases. Clostridioides difficile infection (CDI) was not significantly associated with COVID-19 burden. Microbiology data from 81 of the hospitals corroborated the findings. Notably, rates of hospital-onset bloodstream infections and multidrug resistant organisms, including MRSA, vancomycin-resistant enterococcus and Gram-negative organisms were each significantly associated with COVID-19 surges (P < 0.05 for all). Finally, clusters of hospital-onset pathogens increased as the COVID-19 burden increased (P = 0.02).LimitationsVariations in surveillance and reporting may affect HAI data.Table 1. Effect of an increase in number of COVID-19 discharges on HAIs and hospital-onset pathogens Figure 1. Predicted mean HAI rates as COVID-19 discharges increase Predicted mean HAI rate by increasing monthly COVID-19 discharges. Panel a. CLABSI, Panel b, CAUTI Panel c. MRSA Bacteremia, Panel d. CDI. Data are stratified by small, medium and large hospitals.Figure 2. Monthly comparison of COVID discharges to clusters COVID-19 discharges and the number of clusters of hospital-onset pathogens are correlated throughout the pandemic.ConclusionCOVID-19 surges adversely impact HAI rates and clusters of infections within hospitals, emphasizing the need for balancing COVID-related demands with routine hospital infection prevention. Disclosures Kenneth Sands, MD, MPH, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Susan S. Huang, MD, MPH, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Stryker (Sage) (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Xttrium (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Ken Kleinman, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products) Edward Septimus, MD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products) Eunice J. Blanchard, MSN RN, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Russell Poland, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Micaela H. Coady, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Deborah S. Yokoe, MD, MPH, Nothing to disclose Julia Moody, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Richard Platt, MD, MSc, Medline (Research Grant or Support, Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Jonathan B. Perlin, MD, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)

1290. Ceftazidime-Avibactam Resistance Report in a Third Level Hospital in Mexico City

BackgroundThe surge of resistant Gram-negative organisms has been worrying infectious disease physicians and physicians in general because of the lack of a large number of antibiotics to which these organisms remain susceptible. Ceftazidime-Avibactam (CAZ-AVI) is a drug approved by the FDA to treat complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAIs) in combination with metronidazole, and recently for the treatment of nosocomial pneumonia. Worldwide resistance rates of Enterobacteriaceae to CAZ-AVI have been reported below 2.6%, and 4-8% for Pseudomonas aeruginosa. The FDA, CLSI, and EUCAST assigned the clinical breakpoints of susceptibility: MIC < /=8 mg/liter susceptible, and >/=8mg/liter, resistant. In Mexico, CAZ-AVI was approved in 2018, and its cost is very high compared to other antimicrobials, so its use is limited in very specific cases. The resistance rates to this antibiotic in the Mexican population remain largely unknown. MethodsWe tested 106 specimens for susceptibility to ceftazidime-avibactam using the disk Kirby-Bauer method. The inhibition zone diameter was determined in all cases and we considered the organism susceptible when the inhibition zone diameter was >=21 mm, and resistant with an inhibition zone diameter < = 20 mm. ResultsWe found 5 specimens (4.71%) resistant to ceftazidime-avibactam, corresponding to E. coli (3) and P. aeruginosa (2). Two of these were also resistant to colistin, and 4 to meropenem. All carbapenem-resistant isolates harbored Metallo-beta-lactamases genes, for E. coli was NDM gen, and for P. aeruginosa the VIM gene(GeneXpert® Cepheid). ConclusionThe ceftazidime-avibactam resistance among Gram-negative bacteria in our study is similar to the one reported in other international studies. We need more studies in our population to know the nationwide resistance to this antibiotic. Disclosures All Authors: No reported disclosures

Investigator-Driven Randomised Controlled Trial of Cefiderocol versus Standard Therapy for Healthcare-Associated and Hospital-Acquired Gram-negative Bloodstream Infection: Study protocol (the GAME CHANGER trial): study protocol for an open-label, randomised controlled trial

BackgroundIncreasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended-spectrum beta-lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital- and healthcare-associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii.Cefiderocol is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug-resistant (MDR) P. aeruginosa and A. baumannii. Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections and nosocomial pneumonia, but it has not yet been studied as treatment of bloodstream infection.MethodsThis study will use a multicentre, open-label non-inferiority trial design comparing cefiderocol and standard of care antibiotics. Eligible participants will be adult inpatients who are diagnosed with a bloodstream infection with a Gram-negative organism on the basis of a positive blood culture result where the acquisition meets the definition for healthcare-associated or hospital-acquired. It will compare cefiderocol with the current standard of care (SOC) antibiotic regimen according to the patient’s treating clinician. Eligible participants will be randomised 1:1 to cefiderocol or SOC and receive 5–14 days of antibiotic therapy. Trial recruitment will occur in at least 20 sites in ten countries (Australia, Malaysia, Singapore, Thailand, Turkey and Greece). The sample size has been derived from an estimated 14 day, all-cause mortality rate of 10% in the control group, and a non-inferiority margin of 10% difference in the two groups. A minimum of 284 patients are required in total to achieve 80% power with a two-sided alpha level of 0.05. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected.DiscussionWith increasing antimicrobial resistance, there is a need for the development of new antibiotics with broad activity against Gram-negative pathogens such as cefiderocol. By selecting a population at risk for multi-drug-resistant pathogens and commencing study treatment early in the clinical illness (within 48 h of index blood culture) the trial hopes to provide guidance to clinicians of the efficacy of this novel agent.Trial registrationThe GAME CHANGER trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number NCT03869437. Registered on March 11, 2019.

Healthcare microenvironments define multidrug-resistant organism persistence

Multidrug-resistant organisms (MDROs) colonizing the healthcare environment have been shown to contribute to risk for healthcare-associated infections (HAIs), with adverse effects on patient morbidity and mortality. We sought to determine how bacterial contamination and persistent MDRO colonization of the healthcare environment are related to the position of patients and wastewater sites. We performed a prospective cohort study, enrolling 51 hospital rooms at the time of admitting a patient with an eligible MDRO in the prior 30 days. We performed systematic sampling and MDRO culture of rooms, as well as 16S rRNA sequencing to define the environmental microbiome in a subset of samples. The probability of detecting resistant gram-negative organisms, including Enterobacterales, Acinetobacter spp, and Pseudomonas spp, increased with distance from the patient. In contrast, Clostridioides difficile and methicillin-resistant Staphylococcus aureus were more likely to be detected close to the patient. Resistant Pseudomonas spp and S. aureus were enriched in these hot spots despite broad deposition of 16S rRNA gene sequences assigned to the same genera, suggesting modifiable factors that permit the persistence of these MDROs. MDRO hot spots can be defined by distance from the patient and from wastewater reservoirs. Evaluating how MDROs are enriched relative to bacterial DNA deposition helps to identify healthcare micro-environments and suggests how targeted environmental cleaning or design approaches could prevent MDRO persistence and reduce infection risk.

The Impact of Coronavirus Disease 2019 (COVID-19) on Healthcare-Associated Infections.

BackgroundThe profound changes wrought by COVID-19 on routine hospital operations may have influenced performance on hospital measures, including healthcare-associated infections (HAIs). We aimed to evaluate the association between COVID-19 surges and HAI and cluster rates.MethodsIn 148 HCA Healthcare-affiliated hospitals, 3/1/2020-9/30/2020, and a subset of hospitals with microbiology and cluster data through 12/31/2020, we evaluated the association between COVID-19 surges and HAIs, hospital-onset pathogens, and cluster rates using negative binomial mixed models. To account for local variation in COVID-19 pandemic surge timing, we included the number of discharges with a laboratory-confirmed COVID-19 diagnosis per staffed bed per month.ResultsCentral line-associated blood stream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), and methicillin-resistant Staphylococcus aureus (MRSA) bacteremia increased as COVID-19 burden increased. There were 60% (95% CI, 23-108%) more CLABSI, 43% (95% CI, 8-90%) more CAUTI, and 44% (95% CI, 10-88%) more cases of MRSA bacteremia than expected over 7 months based on predicted HAIs had there not been COVID-19 cases. Clostridioides difficile infection was not significantly associated with COVID-19 burden. Microbiology data from 81 of the hospitals corroborated the findings. Notably, rates of hospital-onset bloodstream infections and multidrug resistant organisms, including MRSA, vancomycin-resistant enterococcus and Gram-negative organisms were each significantly associated with COVID-19 surges. Finally, clusters of hospital-onset pathogens increased as the COVID-19 burden increased.ConclusionCOVID-19 surges adversely impact HAI rates and clusters of infections within hospitals, emphasizing the need for balancing COVID-related demands with routine hospital infection prevention.

Antibiotic Approvals in the Last Decade: Are We Keeping Up With Resistance?

To review the spectrum of activity, efficacy, safety, and role in therapy of all antibiotics and related biologics approved by the Food and Drug Administration (FDA) in the last decade. A literature search was performed using PubMed and Google Scholar (2010 to end May 2021) with the search terms' name of the antibiotic or the biologic. Data were also obtained from the prescribing information, FDA, and ClinicalTrials.gov websites. All relevant English-language, late phase clinical trials assessing the safety and efficacy of the identified drugs were included. Review articles and references of retrieved articles were evaluated for relevant data. Antibiotic resistance is a public health crisis, and antibiotic development is imperative to outpace the ability of bacteria to develop resistance. Only 17 new systemic antibiotics and 1 related biologic have been approved by the FDA since 2010. Among these drugs, 14 were approved for common bacterial infections, 1 was approved for Clostridioides difficile infection (CDI), 1 was licensed to prevent CDI recurrence, and 2 were approved for drug-resistant tuberculosis. Very few antibiotics are in clinical development. The arrival of these new antibiotics was welcomed with great enthusiasm, particularly when they met previously unmet medical needs. Unfortunately, the majority of them represent modifications to existing chemical structures rather than new drug classes. Despite the availability of these antibiotics, managing patients with deep-seated infections and those with extensively resistant gram-negative organisms remains challenging. The number of new antibiotics and their indications are not keeping up with resistance and the needs of the patients.

Prophylactic application of antibiotics selects extended‐spectrum β‐lactamase and carbapenemases producing Gram‐negative bacteria in the oral cavity

Prophylactic administration of broad-spectrum antibiotics in surgery can change the oral microbiome and induce colonization of oral cavity with Gram-negative bacteria including multidrug (MDR) or extensively drug resistant (XDR) organisms which can lead to lower respiratory tract infections. The aim of the study was to analyse the Gram-negative isolates obtained from oral cavity of the mechanically ventilated patients in ICUs, after prophylactic application of antibiotics and their resistance mechanisms and to compare them with the isolates obtained from tracheal aspirates from the same patients. The antibiotic susceptibility was determined by broth dilution method. PCR was applied to detect genes encoding β-lactamases. Marked diversity of Gram-negative bacteria and resistance mechanisms was found. High resistance rates and high rate of blaCTX-M and carbapenemase encoding genes (blaVIM-1 , blaOXA-48 ) were found among Klebsiella pneumoniae. Pseudomonas aeruginosa was found to harbour blaVIM and in one strain blaPER-1 gene, whereas Acinetobacter baumannii produced OXA-23-like and OXA-24/40-like oxacillinases and was XDR in all except one case. All XDR isolates belong to international clonal lineage II (IC II). The main finding of the study is that the prophlylactic application of antibiotics in surgery intensive care units (ICUs) is associated with the colonization of oral cavity and lower respiratory tract with Gram-negative bacteria. The identity of Gram-negative bacteria in oral cavity reflected those found in endotracheal aspirates leading to conclusion that oral swab as non-invasive specimen can predict the colonization of lower respiratory tract with resistant Gram-negative organisms and the risk for development of ventilator-associated pneumonia.

Usefulness of BioFire FilmArray BCID2 for Blood Culture Processing in Clinical Practice.

ABSTRACTRapid pathogen characterization from positive blood cultures (BC) can improve management of patients with bloodstream infections (BSI). The FilmArray blood culture identification (BCID) assay is a molecular test approved for direct identification of BSI causing pathogens from positive BC. A recently updated version of the panel (BCID2) comprises improved species identification characteristics and allows for the detection of one expanded-spectrum β-lactamase (ESBL)- and several carbapenemase-encoding genes. Here, the clinical performance of the BCID2 assay for species identification in 180 positive BCs was evaluated. BCID2 results were concordant with the standard of care (SOC) in 159/180 (88.3%) BCs; 68/74 (91.9%) and 71/74 (96.0%) of all samples growing monobacterial, Gram-positive or Gram-negative pathogens, respectively, were identified, in agreement with SOC results. Nonconcordance was related to the detection of additional pathogens by the BCID2 assay (n = 4), discrepant species identification (n = 4), or failure of BCID2 to detect on-panel pathogens (n = 1). A number (12/31; 38.7%) of discordant results became evident in polymicrobial BC specimens. BCID2 identified the presence of blaCTX-M-carrying species in 12 BC specimens but failed to predict third-generation cephalosporin resistance in four isolates exhibiting independent cephalosporin resistance mechanisms. Carbapenem resistance related to the presence of blaVIM-2 or blaOxa-48-like was correctly predicted in two isolates. In conclusion, the BCID2 assay is a reliable tool for rapid BC processing and species identification. Despite inclusion of common ESBL- or carbapenemase-encoding markers, the multifactorial nature of β-lactam resistance in Gram-negative organisms warrants combination of BCID2 with (rapid) phenotypic susceptibility assays.

Advances in novel antibiotics to treat multidrug-resistant gram-negative bacterial infections.

Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately.

Rapid prototyping vaccine approach in mice against multi-drug resistant Gram-negative organisms from clinical isolates based on outer membrane vesicles.

Hospital-acquired infections due to multi-drug resistant Gram-negative organisms (MDRGNO) pose a major threat to global health. A vaccine preventing colonization and consecutive infection with MDRGNO could be particularly valuable, as therapeutic options become increasingly limited. Outer membrane vesicles (OMV) of Escherichia coli strain CFT073 as well as three MDRGNO strains that had caused severe infections in humans were administered intranasally to mice, with and without cholera toxin as an adjuvant. The humoral immune responses were comparatively matched with the sera of patients, who had suffered an infection caused by the respective bacterium. Additionally, systemic and local toxicity was evaluated. Intranasal vaccination with OMV could elicit solid humoral immune responses (total IgM and IgG), specific for the respective MDRGNO in mice; decoration of vital bacterial membranes with antibodies was comparable to patients who had survived systemic infection with the respective bacterial isolate. After intranasal vaccination of mice with OMV no signs of local or systemic toxicity were observed. Intranasal vaccination with OMV may open up a rapid vaccine approach to prevent colonization and/or infection with pathogenic MDRGNOs, especially in an outbreak setting within a hospital. It may also be an option for patients who have to undergo elective interventions in centers with a high risk of infection for certain common MDRGNO. Future studies need to include challenge experiments as well as phase I trials in humans.

Changing Resistance Pattern among Gram-Negative Bacilli from Cancer Patients with Respiratory Infections at a Cancer Center

Cancer patients due to their immune-compromised nature are more prone to infections among which respiratory tract infections (RTIs) are frequently reported to account for 3 to 5% of deaths. In recent years, antibiotic resistance among respiratory pathogens is increasing emergently. The present study was conducted retrospectively at the microbiology division of a tertiary care hospital over 4 years (Jan 2016 – Dec 2019) aimed to find out the bacterial etiology of RTIs in cancer patients. Patients of all age groups, suspected of RTI recorded in microbiology registers were included in the study. During the study period, out of 2918 specimens (Jan 2016- Dec 2019) received in the microbiology lab, 2,065 (70%) specimens showed meaningful growth, whereas 269 (9%) specimens showed contaminated growth, 584 (20%) specimens showed no growth. From the 2,065 specimens, 1420 bacterial isolates were recovered. Out of the total 1420 isolates identified, 912 (64%) were gram-negative bacilli (GNB) and 508 (35.7%) were gram-positive organisms. About 19.6 % of patients were in the age group of fewer than 20 years, 54.4% in 21–60 years and 26% were of more than 60 years of age. The male-to-female ratio was 60.1:39.9. Trends of antimicrobial resistance among the leading pathogens causing RTI were studied in two phases, i.e., from 2016–2017 (phase I) and 2018–2019 (phase II). Phase I and II showed an increasing trend in resistance to cephalosporins and a declining trend in resistance to aminoglycosides (resistance to gentamicin was relatively high when compared with amikacin). In Phase I (2016 and 2017) resistance to Beta Lactams ranged from 66 to 97% and it is relatively high in phase II (2018 and 2019). But in contrast to other gram-negative isolates, Acinetobacter spp were more resistant to most groups of antibiotics during both Phases I (85–97%) and II (95–97%). Multidrug resistance (resistance to three or more than three drugs) was observed in most of the total isolates during the study period. The increasing trend of resistance in gram-negative organisms is alarming. Judicious use of older and newer antimicrobial agents is essential to prevent the emergence of multidrug-resistant bacteria. The development of newer therapeutic alternatives to address the problem of MDR GNBs is needed.