Carbapenem combination therapy versus standard of care for persistent methicillin-susceptible Staphylococcus aureus bacteraemia.

BACKGROUND: Successful use of carbapenems in combination with cefazolin or oxacillin for treatment of MSSA bacteraemia has been described; however, comparative data to standard treatment approaches are lacking. METHODS: This was a multicentre, retrospective study of adult patients with MSSA bacteraemia for >48 h. Standard treatment was considered monotherapy with cefazolin, oxacillin or nafcillin. Combination therapy was defined as the addition of ertapenem or meropenem to standard treatment for at least 24 h. The primary outcome was duration of bacteraemia defined as time from administration of an antibiotic with in vitro activity to first negative blood culture. Time to blood culture sterilization was compared through risk-set matching with aid of a propensity score. RESULTS: Overall, 238 patients were included; 66% (157/238) received standard treatment and 34% (81/238) received combination therapy. The median (IQR) time to carbapenem initiation was 4.7 (3.63-6.5) days. Patients who received combination therapy were younger (P = 0.012), more likely to have endocarditis (P = 0.034) and had longer median duration of bacteraemia (P < 0.001). After applying risk-set matching, patients who received combination therapy experienced faster time to blood culture sterilization compared with control patients [HR = 1.618 (95% CI; 1.119-2.339) P = 0.011]. Using a paired hazard model, 90 day mortality rates were not statistically different among patients who received combination therapy versus matched controls [HR = 1.267 (95% CI; 0.610-2.678), P = 0.608]. DISCUSSION: Carbapenem combination therapy resulted in faster time to blood culture sterilization, but no differences in overall mortality rates. Randomized trials are critical to determine the utility of carbapenem combination therapy.

Rates of resistance to ceftazidime-avibactam and ceftolozane-tazobactam among patients treated for multidrug-resistant Pseudomonas aeruginosa bacteremia or pneumonia.

Among consecutive patients with multidrug-resistant Pseudomonas aeruginosa bacteremia or pneumonia we found those treated with ceftazidime-avibactam were more likely to develop resistance (defined as ≥4-fold increased MIC) than those treated with ceftolozane-tazobactam (40% vs. 10%; P=0.002). Ceftazidime-avibactam resistance was associated with new mutations in ampC and efflux regulatory pathways.

In-Class Cross-Reactivity among Hospitalized Patients with Hypersensitivity Reactions to Fluoroquinolones.

Results from this large, multicenter study suggest that patients with a confirmed ciprofloxacin, moxifloxacin, or levofloxacin hypersensitivity reaction are likely to tolerate other fluoroquinolones. Avoiding different fluoroquinolones in patients labeled with a ciprofloxacin, moxifloxacin, or levofloxacin allergy may not always be mandatory. This was a study of patients with a ciprofloxacin, moxifloxacin, or levofloxacin hypersensitivity reaction and a documented electronic medical record administration of a different fluoroquinolone. Numerically, the most common reaction risk occurred with a challenge to moxifloxacin (2/19; 9.5%), followed by ciprofloxacin (6/89; 6.3%), and levofloxacin (1/44; 2.2%).

Epidemiology and Clinical Outcomes of Non-HACEK Gram-Negative Infective Endocarditis.

Background: The objectives of this study were to describe the changing epidemiology of gram-negative infective endocarditis (GNIE) and to identify factors associated with treatment failure and death. Methods: Adult patients with GNIE were included if they met modified Duke criteria for definitive infective endocarditis (IE) between April 2010 and December 2021. Patients were identified using Boolean search terms. Clinical failure was a defined as a composite of all-cause 42-day mortality or microbiologic failure. All analyses were performed using Stata, version 15.1. Results: One-hundred twenty-three patients were included. The most common pathogens were Serratia spp. (43%), Pseudomonas aeruginosa (21%), and Klebsiella spp. (14%). Fifty-two percent of cases were among persons who injection drugs (PWID; n = 64), for whom Serratia spp. (70%) was the most common cause of GNIE. Overall, patients infected with P. aeruginosa had higher microbiologic failure rates than other patients (23% vs 6%; P = .004). Patients who received combination therapy (n = 53) had comparable median lengths of stay (23 vs 19.5 days; P = .412), microbiologic failure rates (11.3% vs 7.1%; P = .528), clinical failure rates (18.9% vs 22.9%; P = .592), and 90-day mortality rates (13.2% vs 25.7%; P = .088) as those treated with monotherapy. After applying stepwise logistic regression, male gender, Pitt Bacteremia Score, and not receiving surgical intervention despite a surgical indication were associated with clinical failure. Conclusions: This is the first study to identify Serratia spp. as the most common etiology of GNIE, which was particularly true among PWID. Microbiologic failures occurred most commonly among P. aeruginosa, and use of combination antimicrobial therapy did not improve clinical outcomes.

Effect of mild COVID-19 on health-related quality of life.

Background: Little is known about the effects of a mild SARS-CoV-2 infection on health-related quality of life. Methods: This prospective observational study of symptomatic adults (18-87 years) who sought outpatient care for an acute respiratory illness, was conducted from 3/30/2020 to 4/30/2021. Participants completed the Short Form Health Survey (SF-12) at enrollment and 6-8 weeks later, to report their physical and mental health function levels as measured by the physical health and mental health composite scores (PHC and MHC, respectively). PHC and MHC scores for COVID-19 cases and non-COVID cases were compared using t-tests. Multivariable regression modeling was used to determine predictors of physical and mental health function at follow-up. Results: Of 2301 enrollees, 426 COVID-19 cases and 547 non-COVID cases completed both surveys. PHC improved significantly from enrollment to follow-up for both COVID-19 cases (5.4 ± 0.41; P < 0.001) and non-COVID cases (3.3 ± 0.32; P < 0.001); whereas MHC improved significantly for COVID-19 cases (1.4 ± 0.51; P < 0.001) and decreased significantly for non-COVID cases (-0.8 ± 0.37; P < 0.05). Adjusting for enrollment PHC, the most important predictors of PHC at follow-up included male sex (ß = 1.17; SE = 0.5; P = 0.021), having COVID-19 (ß = 1.99; SE = 0.54; P < 0.001); and non-white race (ß = -2.01; SE = 0.70; P = 0.004). Adjusting for enrollment MHC, the most important predictors of MHC at follow-up included male sex (ß = 1.92; SE = 0.63; P = 0.002) and having COVID-19 (ß = 2.42; SE = 0.67; P < 0.001). Conclusion: Both COVID-19 cases and non-COVID cases reported improved physical health function at 6-8 weeks' convalescence; whereas mental health function improved among COVID-19 cases but declined among non-COVID cases. Both physical and mental health functioning were significantly better among males with COVID-19 than females.

Using capture-recapture methods to estimate influenza hospitalization incidence rates.

BACKGROUND: Accurate population estimates of disease incidence and burden are needed to set appropriate public health policy. The capture-recapture (C-R) method combines data from multiple sources to provide better estimates than is possible using single sources. METHODS: Data were derived from clinical virology test results and from an influenza vaccine effectiveness study from seasons 2016-2017 to 2018-2019. The Petersen C-R method was used to estimate the population size of influenza cases; these estimates were then used to calculate adult influenza hospitalization burden using a Centers for Disease Control and Prevention (CDC) multiplier method. RESULTS: Over all seasons, 343 influenza cases were reported in the clinical database, and 313 in the research database. Fifty-nine cases (17%) reported in the clinical database were not captured in the research database, and 29 (9%) cases in the research database were not captured in the clinical database. Influenza hospitalizations were higher among vaccinated (58%) than the unvaccinated (35%) in the current season and were similar among unvaccinated (51%) and vaccinated (49%) in the previous year. Completeness of the influenza hospitalization capture was estimated to be 76%. The incidence rates for influenza hospitalizations varied by age and season and averaged 307-309 cases/100,000 adult population annually. CONCLUSION: Using C-R methods with more than one database, along with a multiplier method with adjustments improves the population estimates of influenza disease burden compared with relying on a single-data source.

Proposed clinical indicators for efficient screening and testing for COVID-19 infection using Classification and Regression Trees (CART) analysis.

The introduction and rapid transmission of SARS-CoV-2 in the United States resulted in methods to assess, mitigate, and contain the resulting COVID-19 disease derived from limited knowledge. Screening for testing has been based on symptoms typically observed in inpatients, yet outpatient symptoms may differ. Classification and regression trees recursive partitioning created a decision tree classifying participants into laboratory-confirmed cases and non-cases. Demographic and symptom data from patients ages 18-87 years enrolled from March 29-June 8, 2020 were included. Presence or absence of SARS-CoV-2 was the target variable. Of 832 tested, 77 (9.3%) tested positive. Cases significantly more often reported diarrhea (12 percentage points (PP)), fever (15 PP), nausea/vomiting (9 PP), loss of taste/smell (52 PP), and contact with a COVID-19 case (54 PP), but less frequently reported sore throat (-27 PP). The 4-terminal node optimal tree had sensitivity of 69%, specificity of 78%, positive predictive value of 20%, negative predictive value of 97%, and AUC of 76%. Among those referred for testing, negative responses to two questions could classify about half (49%) of tested persons with low risk for SARS-CoV-2 and would save limited testing resources. Outpatient symptoms of COVID-19 appear to be broader than the inpatient syndrome.Initial supplies of anticipated COVID-19 vaccines may be limited and administration of first such available vaccines may need to be prioritized for essential workers, the most vulnerable, or those likely to have a robust response to vaccine. Another priority group could be those not previously infected. Those who screen out of testing may be less likely to have been infected by SARS-CoV-2 virus thus may be prioritized for vaccination when supplies are limited.

Changing Epidemiology and Decreased Mortality Associated With Carbapenem-resistant Gram-negative Bacteria, 2000-2017.

BACKGROUND: Carbapenem-resistant gram-negative bacteria (CRGNB) continue to present a global healthcare crisis. We aimed to identify emerging trends of CRGNB over nearly 2 decades and describe the impact of CRGNB on patient outcomes. METHODS: Patients from whom CRGNB were isolated between 2000 and 2017 were included in the study. Carbapenem resistance was defined by the most recent breakpoints and applied across the study period. Patient demographics, clinical characteristics, and outcomes were retrieved from the electronic health record. RESULTS: A total of 94 888 isolates from 64 422 patients were identified; 9882 (10%) isolates from 4038 patients were carbapenem-resistant. Pseudomonas aeruginosa was the most common CRGNB each year. The second most common CRGNB emerged in waves over time. Carbapenem daily defined doses increased in parallel with CRGNB rates (R2 = 0.8131). The overall 30-day mortality rate was 19%, which decreased from 24% in 2000 to 17% in 2017 (P = .003; R2 = .4330). Among patients with CRGNB bloodstream infections (n = 319), overall 30- and 90-day mortality rates were 27% and 38%, respectively. Charlson score (adjusted odds ratio [aOR], 1.11 per point), intensive care unit residence (aOR, 7.32), and severe liver disease (aOR, 4.8.4) were independent predictors of 30-day mortality, while receipt of transplantation was associated with lower rates of death (aOR, 0.39). Among patients admitted between 2011 and 2017 (n = 2230), 17% died during hospitalization, 32% were transferred to long-term care facilities, and 38% were discharged home. CONCLUSIONS: CRGNB emerged in waves over time, causing high rates of mortality. Despite increasing rates of CRGNB, overall patient outcomes have improved, suggesting that recognition and novel therapeutics have made a major impact.

Using Capture-Recapture Methods to Estimate Influenza Hospitalization Incidence Rates.

BACKGROUND: Accurate population estimates of disease incidence and burden are needed to set appropriate public health policy. The capture-recapture (C-R) method combines data from multiple sources to provide better estimates than is possible using single sources. METHODS: Data were derived from clinical virology test results and from an influenza vaccine effectiveness study from seasons 2016-2017 to 2018-2019. The Petersen C-R method was used to estimate the population size of influenza cases; these estimates were then used to calculate adult influenza hospitalization burden using a Centers for Disease Control and Prevention (CDC) multiplier method. RESULTS: Over all seasons, 343 influenza cases were reported in the clinical database and 313 in the research database. Fifty-nine cases (17%) reported in the clinical database were not captured in the research database, and 29 (9%) cases in the research database were not captured in the clinical database. Influenza hospitalizations were higher among vaccinated (58%) than the unvaccinated (35%) in the current season and were similar among unvaccinated (51%) and vaccinated (49%) in the previous year. Completeness of the influenza hospitalization capture was estimated to be 76%. The incidence rates for influenza hospitalizations varied by age and season and averaged 307-309 cases/100,000 adult population annually. CONCLUSION: Using Capture-Recapture methods with more than one database, along with a multiplier method with adjustments improves the population estimates of influenza disease burden compared with relying on a single data source.

Clinical and Genomic Epidemiology of Carbapenem-Nonsusceptible Citrobacter spp. at a Tertiary Health Care Center over 2 Decades.

Carbapenem-nonsusceptible Citrobacter spp. (CNSC) are increasingly recognized as health care-associated pathogens. Information regarding their clinical epidemiology, genetic diversity, and mechanisms of carbapenem resistance is lacking. We examined microbiology records of adult patients at the University of Pittsburgh Medical Center (UMPC) Presbyterian Hospital (PUH) from 2000 to 2018 for CNSC, as defined by ertapenem nonsusceptibility. Over this time frame, the proportion of CNSC increased from 4% to 10% (P = 0.03), as did daily defined carbapenem doses/1,000 patient days (6.52 to 34.5; R2 = 0.831; P < 0.001), which correlated with the observed increase in CNSC (lag = 0 years; R2 = 0.660). Twenty CNSC isolates from 19 patients at PUH and other UPMC hospitals were available for further analysis, including whole-genome short-read sequencing and additional antimicrobial susceptibility testing. Of the 19 patients, nearly all acquired CNSC in the health care setting and over half had polymicrobial cultures containing at least one other organism. Among the 20 CNSC isolates, Citrobacter freundii was the predominant species identified (60%). CNSC genomes were compared with genomes of carbapenem-susceptible Citrobacter spp. from UPMC and with other publicly available CNSC genomes. Isolates carrying genes encoding carbapenemases (blaKPC-2,blaKPC-3, and blaNDM-1) were also long-read sequenced, and their carbapenemase-encoding plasmid sequences were compared with one another and with publicly available sequences. Phylogenetic analysis of 102 UPMC Citrobacter genomes showed that CNSC from our setting did not cluster together. Similarly, a global phylogeny of 64 CNSC genomes showed a diverse population structure. Our findings suggest that both local and global CNSC populations are genetically diverse and that CNSC harbor carbapenemase-encoding plasmids found in other Enterobacterales.

Defining the incidence and risk factors of colistin-induced acute kidney injury by KDIGO criteria.

BACKGROUND: Acute kidney injury (AKI) remains a treatment-limiting toxicity of colistin. Recently developed clinical practice guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) group have harmonized definitions of AKI, but have not been widely applied to patients receiving colistin. METHODS: We retrospectively defined AKI by KDIGO definitions among adult patients receiving intravenous colistin for ≥ 3 days. Risk factors for AKI within 48 hours and 7 days of initiating colistin were determined by multivariable logistic regression. RESULTS: Among 249 patients treated with colistin, rates of AKI were 12% and 29% at 48 hours and 7 days, respectively. At 48 hours, patients in the intensive care unit were at increased risk for AKI. Within 7 days, colistin daily doses >5mg/kg, chronic liver disease, and concomitant vancomycin were independent predictors. Seven percent of patients required renal replacement therapy at a median of 5 days (range: 3-7) following colistin initiation. CONCLUSION: Safe use of colistin is promoted by early detection of AKI with KDIGO criteria, avoiding nephrotoxins, and limiting duration of therapy.

Carbapenem-Resistant Pseudomonas aeruginosa Bacteremia: Risk Factors for Mortality and Microbiologic Treatment Failure.

We reviewed 37 patients treated for bacteremia due to carbapenem-resistant (CR) Pseudomonas aeruginosa Although 65% of isolates were multiple-drug resistant, therapeutic options were available, as all were susceptible to ≥1 antibiotic. A total of 92% of patients received active antimicrobial therapy, but only 57% received early active therapy (within 48 h). Fourteen-day mortality was 19%. Microbiologic failure occurred in 29%. The Pitt bacteremia score (P = 0.046) and delayed active therapy (P = 0.027) were predictive of death and microbiologic failure, respectively.

Clinical Appraisal of Fosfomycin in the Era of Antimicrobial Resistance.

Fosfomycin is recommended as one of the first-line agents for treatment of urinary tract infections (UTIs) in the latest guidelines endorsed by the Infectious Diseases Society of America (IDSA) and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID). We evaluated the use of fosfomycin among inpatients at a tertiary care hospital between 2009 and 2013. UTI cases were defined using physician diagnosis and the National Healthcare Safety Network (NHSN) surveillance definitions. The number of patients treated with fosfomycin increased from none in 2009 to 391 in 2013. Among 537 patients who received fosfomycin for any indication during this period, UTI was the most common indication (74%), followed by asymptomatic bacteriuria (10%). All except 19 patients received a single dose of fosfomycin. Escherichia coli was the most common organism involved (52%). For 119 patients with UTIs, after exclusion of those with negative urine culture results, negative urinalysis results, receipt of additional agents, or indeterminate clinical outcomes, the clinical success rate at 48 h was 74.8%. Of 89 patients who met the criteria for NHSN-defined UTIs, 89.9% had successful outcomes. Recurrent infections occurred in 4.3% of cases, and mild adverse events were observed in 2.0%. All 100 randomly selected extended-spectrum ß-lactamase (ESBL)-producing E. coli clinical isolates from this period were susceptible to fosfomycin. In conclusion, the use of fosfomycin has increased substantially since implementation of the updated guidelines at this hospital. Fosfomycin was used mainly for the treatment of physician-diagnosed UTIs, and the clinical outcomes were generally favorable. Fosfomycin maintained activity against E. coli despite the increased use of the agent.

Doripenem MICs and ompK36 porin genotypes of sequence type 258, KPC-producing Klebsiella pneumoniae may predict responses to carbapenem-colistin combination therapy among patients with bacteremia.

Treatment failures of a carbapenem-colistin regimen among patients with bacteremia due to sequence type 258 (ST258), KPC-2-producing Klebsiella pneumoniae were significantly more likely if both agents were inactive in vitro, as defined by a colistin MIC of >2 µg/ml and the presence of either a major ompK36 porin mutation (guanine and alanine insertions at amino acids 134 and 135 [ins aa 134-135 GD], IS5 promoter insertion [P = 0.007]) or a doripenem MIC of >8 µg/ml (P = 0.01). Major ompK36 mutations among KPC-K. pneumoniae strains are important determinants of carbapenem-colistin responses in vitro and in vivo.

Epidemiology and clinical outcomes of patients with carbapenem-resistant Klebsiella pneumoniae bacteriuria.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) bacteriuria is a frequently encountered clinical condition, but its clinical impact is unknown. We conducted a retrospective cohort study to define the epidemiology and outcomes for patients with CRKP bacteriuria. Patients with positive urine cultures for CRKP were classified as having asymptomatic bacteriuria (ASB) or symptomatic urinary tract infection (UTI). Among 105 patients with CRKP bacteriuria, 80% (84/105 patients) and 20% (21/105 patients) had ASB and UTI, respectively. Older age (P = 0.002) and higher Charlson's comorbidity index scores (P = 0.001) were associated with ASB. The median duration of hospitalization prior to CRKP bacteriuria was significantly longer for patients with ASB versus UTI (8.5 versus 2 days; P = 0.05). In multivariate analysis, male sex (odds ratio [OR], 4.69 [95% confidence interval (CI), 1.44 to 15.26]; P = 0.01), solid-organ transplantation (OR, 4.50 [95% CI, 1.39 to 14.52]; P = 0.01), and neurogenic bladder (OR, 18.62 [95% CI, 1.75 to 197.52]; P = 0.01) were independently associated with UTI. Ten percent (8/84) of the patients with ASB received antimicrobial therapy. The treatment success rate for patients with UTIs was 90% (19/21 patients), including all patients who received doxycycline (n = 9). The overall 30-day mortality rate was 6% (6/105 patients); the deaths were unrelated to CRKP infections. Secondary CRKP infections, including UTIs, were notably absent among patients with ASB who were followed for 90 days. In conclusion, identification of CRKP in the urine was most commonly associated with ASB and did not lead to subsequent infections or death among asymptomatic patients. Factors associated with UTIs included male sex, solid-organ transplantation, and neurogenic bladder. Doxycycline may be an effective therapy for CRKP UTIs.

Real-world experience with echinocandin MICs against Candida species in a multicenter study of hospitals that routinely perform susceptibility testing of bloodstream isolates.

Reference broth microdilution methods of Candida echinocandin susceptibility testing are limited by interlaboratory variability in caspofungin MICs. Recently revised Clinical and Laboratory Standards Institute (CLSI) breakpoint MICs for echinocandin nonsusceptibility may not be valid for commercial tests employed in hospital laboratories. Indeed, there are limited echinocandin susceptibility testing data from hospital laboratories. We conducted a multicenter retrospective study of 9 U.S., Australian, and New Zealand hospitals that routinely tested Candida bloodstream isolates for echinocandin susceptibility from 2005 to 2013. Eight hospitals used Sensititre YeastOne assays. The Candida spp. were C. albicans (n=1,067), C. glabrata (n=911), C. parapsilosis (n=476), C. tropicalis (n=185), C. krusei (n=104), and others (n=154). Resistance and intermediate rates were ≤1.4% and ≤3%, respectively, for each echinocandin against C. albicans, C. parapsilosis, and C. tropicalis. Resistance rates among C. glabrata and C. krusei isolates were ≤7.5% and ≤5.6%, respectively. Caspofungin intermediate rates among C. glabrata and C. krusei isolates were 17.8% and 46.5%, respectively, compared to ≤4.3% and ≤4.4% for other echinocandins. Using CLSI breakpoints, 18% and 19% of C. glabrata isolates were anidulafungin susceptible/caspofungin nonsusceptible and micafungin susceptible/caspofungin nonsusceptible, respectively; similar discrepancies were observed for 38% and 39% of C. krusei isolates. If only YeastOne data were considered, interhospital modal MIC variability was low (within 2 doubling dilutions for each agent). In conclusion, YeastOne assays employed in hospitals may reduce the interlaboratory variability in caspofungin MICs against Candida species that are observed between reference laboratories using CLSI broth microdilution methods. The significance of classifying isolates as caspofungin intermediate and anidulafungin/micafungin susceptible will require clarification in future studies.

Risk factors for acquisition of multidrug-resistant Acinetobacter baumannii among cancer patients.

BACKGROUND: Data regarding multidrug-resistant (MDR) Acinetobacter baumannii infections among cancer patients are limited. METHODS: We conducted a case-control study to investigate the risk factors for acquisition of MDR A baumannii and the outcomes among cancer patients. Cases were inpatients with malignancy who had MDR A baumannii from any cultures between 2008 and 2011. Controls were inpatients with malignancy but no MDR A baumannii. RESULTS: A total of 31 case patients were matched with 62 control patients. Hematologic malignancy (P = .036), need for dialysis (P = .01), admission for other reasons except elective surgery (P = .03), transfer from other health care facilities (P = .02), prolonged intensive care unit stay (P = .004), mechanical ventilation (P < .001), pressor use (P = .001), tube feeding (P < .001), transfusion (P = .009), and prior antimicrobial use (P < .001) were identified as significant risk factors in univariate analysis. Need for dialysis (odds ratio [OR], 18.23; P = .04) and prolonged intensive care unit stay (OR, 19.28; P = .01) remained significant in multivariate analysis. Lengths of stay were 28 days for the case patients and 10 days for the control patients (P = .001). The 90-day mortality rates were 41.9% and 29.0%, respectively (P = .20). CONCLUSIONS: Acquisition of MDR A baumannii among cancer patients appears to be associated with general nosocomial infection risk factors rather than underlying malignancies.