Turkish Prospective Cohort Study on Carbapenem Resistant Klebsiella Pneumonia Bacteremia
Condition: Klebsiella Pneumonia; Bacteremia
MeSH terms: Pneumonia; Bacteremia; Klebsiella Infections
Study type: Observational

Summary: 
      Carbapenem-resistant Klebsiella pneumonia (CRKp) blood stream infections (BSI) cause
      substantial mortality among hospitalized patients. Treatment options for CRKp infections are
      limited and increasing resistance rates to few available drugs, i.e., colistin, is a big
      concern. This prospective multicenter observational study is designed to describe clinical
      characteristics and outcomes of patients with CRKp bacteremia in an oxacillinase-48 (OXA-48)
      endemic country to define predictors of mortality with a focus on the impact of mono versus
      combination therapies on mortality. The study will also investigate risk factors associated
      with colistin-resistant CRKp BSI.
    

Detailed description: 
      OBJECTIVES

      MAIN OBJECTIVE

        1. To compare the impact of combination therapy and monotherapy on mortality for patients
           with CRKp BSI

           SECONDARY OBJECTIVES

        2. To identify predictors of mortality for patients with CRKp BSI

        3. To compare the impact of appropriate and inappropriate empiric and targeted therapies on
           mortality for patients with CRKp BSI

        4. To identify the risk factors for colistin resistance among patients with ColR CRKp BSI.

      HYPOTHESES

      MAIN HYPOTHESIS

        1. Combination therapy is better than monotherapy to prevent 30-day mortality.

           i.Combination of one active drug with one inactive drug is not associated with lower
           probability of mortality as compared to monotherapy with one active drug if:

             -  the inactive drug is carbapenem with a minimum inhibitory concentration (MIC) of
                ≥16 mg/L or

             -  the inactive drug is any other antibiotic other than carbapenem or

             -  the patient is in low mortality score

           ii.Combination of two or more active drugs is associated with lower probability of
           mortality as compared to monotherapy with one active drug.

           iii.For colistin resistant CRKp, monotherapy with one active drug is associated with
           lower probability of mortality as compared to combination therapies including carbapenem
           with a MIC of ≥16 mg/L or colistin.

           SECONDARY HYPOTHESES

        2. Severe disease at BSI onset (admission to ICU, septic shock, INCREMENT-CPE
           (carbapenemase-producing Enterobacteriaceae) score 8-15, higher sequential organ failure
           assessment (SOFA) and Pitt bacteremia scores, Charlson Comorbidity Index ≥2, higher
           procalcitonin levels), carbapenemase type and carbapenem MIC of the isolate (CRKp
           isolates with a carbapenem MIC ≥16 mg/L, OXA-48 producing isolates), sequence type of
           the isolate (ST101 and ST258), colistin resistance delayed source control (>48 hours)
           and infection sources other than urinary tract are independent predictors of mortality.

        3. Appropriate empirical therapy, early targeted therapy, are independent predictors of
           survival. For colistin susceptible CRKp, empirical use of colistin within 24 hours of
           BSI onset is associated with lower probability of mortality.

        4. Previous colistin therapy, previous CRKp infection, previous intensive care unit (ICU)
           stay (last three months), length of hospital stay until index date is associated with
           colistin resistance. Mortality rates and length of hospital stay are higher among
           colistin resistant strains as compared to colistin susceptible strains.

        5. Effect of treatment type on mortality is modified by disease severity.

      STUDY DESIGN

      Prospective cohort study.

      Setting and study period

      Fourteen tertiary care hospitals from the four most populous cities in Turkey (Istanbul,
      Ankara, Izmir, Bursa) are included in the study. Study period is scheduled to be 25 June
      2018- 25 June 2019 or longer until pre-defined sample size is reached. Local investigators
      (infectious disease physicians and clinical microbiologists) will collect microbiological and
      clinical data. Site investigators will screen the microbiology laboratory logs daily to
      identify patients with CRKp bacteremia. All consecutive patients with CRKp bacteremia will be
      eligible to be evaluated for inclusion in the study. Patients who meet the inclusion criteria
      will be selected for the prospective cohort study and/or case-control study depending on
      colistin resistance pattern of the isolate. Site investigators will access patients' medical
      records and register relevant information using a web-based data entry system. Site
      investigators will also collect CRKp isolates and keep them in appropriate conditions until
      time of transfer for analysis. All CRKp isolates will be sent to the central microbiology
      laboratory for molecular analysis and colistin and ceftazidime-avibactam sensitivity testing.

      Sample size

      The expected mortality rate for CRKp BSI is approximately 40% based on previous studies (7,
      12) To detect a 17% decrease in mortality rate with combination therapy as compared to
      monotherapy, we calculated an overall sample size of 178 (α=0.05, power=0.8) (STATA 15.0,
      power analysis for the cox proportional hazards model) (7). Considering withdrawals and
      incomplete data, we aimed to recruit 200 patients.

      Given that we were able to recruit patients faster than expected within our study period (25
      June 2018- 25 June 2019), we decided to increase our power to 0.9.

      Follow up

      Patients will be evaluated for microbiologic eradication on day 3 by control blood cultures
      and primary source cultures. If CRKp is not eradicated on day 3, consecutive cultures will be
      taken on day 7 and 14, as required. Patients will also be evaluated for clinical response on
      day 7 and day 14 using 7th and 14th day SOFA scores, C-reactive protein, procalcitonin and
      leucocyte levels and clinical signs of infection. All patients will be followed for 30 days
      after index date. If the patient is discharged before completion of the 30 days, he/she will
      be contacted by phone on day 30 to assess the outcome.

      DEFINITIONS

      CRKp: K. pneumonia non-susceptible to at least one carbapenem according to EUCAST 2018
      breakpoints.

      Colistin-resistant (ColR) CRKp: CRKp resistant to colistin according to EUCAST breakpoints

      CRKp bacteremia: Presence of at least one set of blood culture positive for CRKp

      CRKp BSI: Presence of at least one set of blood culture positive for CRKp with evidence of
      systemic inflammatory response.

      Index date: The day of collection of the CRKp positive blood culture, infection onset, day 0.

      Active drug: Antibiotic with in vitro activity against the CRKp isolate (antibiotic which the
      isolate is susceptible or intermediate to)

      Inactive drug: Antibiotic without in vitro activity against the CRKp isolate (antibiotic
      which the isolate is resistant to)

      Empiric therapy: Treatment administered following blood culture collection and prior to
      antimicrobial susceptibility test results

      Targeted therapy: Treatment initiated or maintained after obtaining antimicrobial
      susceptibility test results

      Appropriate therapy: Treatment regimen that includes at least one active drug initiated
      within 5 days of the index date and administered for at least 48 hours (24 hours for the
      patients who died within 2 days of the index date)

      Early appropriate therapy: Treatment regimen that includes at least one active drug initiated
      within 2 days of the index date and administered for at least 48 hours (24 hours for the
      patients who died within 2 days of the index date)

      Inappropriate therapy: Treatment regimen that does not include any active drugs and/or
      treatment administered for less than 48 h and/or treatment initiated after 5 days of the
      index date.

      Monotherapy: Treatment with one active drug

      Combination therapy: Treatment with more than one active drug

      Primary bacteremia: Catheter-related bacteremia and bacteremia of unknown source

      Secondary bacteremia: Identical CRKp growth from a specific body site within BSI window
      period (3 days before and 3 days after positive blood culture)

      Polymicrobial bacteremia: Polymicrobial episodes (defined as ≥2 isolates of different
      microorganisms in samples taken ≤2 day apart from the same patient

      Suspected source: The source of bacteremia determined by the attending physician according to
      the clinical presentation of the patient, rather than by the culture growth.

      Source control: Central line removal, debridement, percutaneous or surgical drainage that are
      performed within 48 hours of BSI onset.

      VARIABLES

      Host variables: Age, sex, ward (ICU or non-ICU), hospital type and ward if transferred from
      another hospital, underlying diseases (Charlson Comorbidity Index), risk factors for
      acquisition of CRKp (previous infection: prior positive culture with CRKp, hospital stay for
      >48 hours in last three months, ICU stay for >48 hours in last three months, major surgery in
      previous month, antibiotic use in last three months: Carbapenem, colistin, other, invasive
      procedures performed within one week of BSI onset (insertion of central venous catheters,
      nasogastric tubes, foley catheters; endoscopy; endoscopic retrograde
      cholangiopancreatography; bronchoscopy; parenteral nutrition; mechanical ventilation),
      disease severity at index date: SOFA score, Pitt bacteremia score, INCREMENT-CPE score,
      presentation with septic shock, length of hospital stay until index date

      Infection variables: Infection acquisition (Community-acquired vs. hospital-acquired),
      primary or secondary bacteremia, source control, procalcitonin & C-reactive protein &
      leucocyte at day 0, 7 and 14, creatinine and glomerular filtration rate (GFR).

      Treatment variables: Antimicrobial therapy (duration, dosage (loading and maintenance),
      presence of prolonged infusion (only for carbapenems))

      Microbiological variables: Automated system used for isolate identification and antimicrobial
      susceptibility testing in the local laboratory, susceptibility profile of the CRKp isolates,
      MICs for carbapenem, colistin, tigecycline and ceftazidime-avibactam, carbapenemase type,
      sequence type

      MICROBIOLOGICAL STUDIES

      Identification and antimicrobial susceptibility testing of CRKp isolates will be performed at
      local laboratories. MICs will be interpreted according to EUCAST (European Committee on
      Antimicrobial Susceptibility Testing) criteria. Colistin susceptibility test results will be
      confirmed and ceftazidime-avibactam susceptibility results will be determined at reference
      laboratory by broth microdilution. Molecular studies to identify carbapenem resistance genes,
      colistin resistance mechanisms and CRKp sequence types will be performed at the reference
      laboratory. Genetic relatedness of the isolates will also be determined at reference
      laboratory.

      STATISTICAL ANALYSIS

      Survivor and non-survivor patients with CRKp bacteremia will be compared to identify
      predictors of mortality. Continuous variables will be compared using t-tests or Mann-Whitney
      U tests. Categorical variables will be evaluated with the χ2 or Fisher's exact test.
      Two-tailed tests will be used to determine statistical significance and a p value of < 0.05
      will be considered significant.

      Effect of treatment type (mono vs. combination therapies, appropriate vs. inappropriate and
      early vs. late start empiric and targeted therapies) on clinical or microbiological response
      at day 7 (and 14 if applicable) and on mortality at day 30 will be assessed by logistic
      regression and cox proportional hazards model, respectively. Independent variables that are
      either identified from univariate analysis as statistically significant or reported in the
      literature as being associated with the outcome will be used as covariates. Interaction
      between treatment type and disease severity/mortality scores will also be assessed and
      stratified analyses according to disease severity will be performed. Survival curves will be
      obtained by Kaplan-Meier method and compared using log-rank test.

      Propensity score for receiving combination therapy will be calculated using a logistic
      regression model. Age, sex, hospital, transfer from another hospital, history of
      hospitalization and antibiotic use, Charlson comorbidity index, ICU stay, SOFA score, Pitt
      bacteremia score, septic shock, procalcitonin level, infection acquisition type, source of
      infection will be included as independent variables in the model.

      ColR CRKp cases will be compared with colistin-sensitive (ColS) controls in a nested
      case-control analysis. Competing risks of death for ColR CRKp BSI will be assessed.

      Discriminating ability of the models will be assessed by estimating areas under the receiver
      operating characteristic (ROC) curves. Collinearity will be assessed by calculating variance
      inflation factors (VIFs) for each dependent variable in the analysis. Akaike information
      criteria (AIC) will be used for model selection.
    

Intervention name(s): Combination therapy
Intervention type(s): Drug
Intervention description(s): Patients who are given combination therapy will be allocated to this group.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        All adult hospitalized patients (≥18 years old) with clinically significant CRKp bacteremia
      
Keywords: Monotherapy; Combination therapy; Colistin-resistant; Klebsiella Pneumonia; Bacteremia; Blood stream infection