Infectious Disease Update 02/25/19 Steven T. Park Division of Infectious Diseases Objectives

• Zosyn versus Meropenem for ESBL bacteremia • 7 versus 14 days for gram negative bacteremia • Oral versus IV for osteomyelitis “Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance” (MERINO trial)

Harris PNA et al. JAMA 2018. Sep 11; 320:984. Introduction

• Treatment of choice for ESBL organisms are thought to be carbapenems • Reports of failure of non-carbapenems in the past even when microbiologic data showed susceptibility • Most reported before CLSI lowered the breakpoints for Enterobacteriaceae • Recent reviews looking at retrospective data conclude that you can use non-carbapenems (Zosyn, Cefepime) for urine infections • However no randomized controlled trial testing this hypothesis • First randomized controlled trial testing whether Zosyn is equivalent to meropenem for ESBL bacteremia Design, Setting, Participants

• Non-inferiority, parallel group, randomized clinical trial • Hospitalized patients enrolled from 26 sites in 9 countries (mostly from Singapore, Australia, Italy, Saudi Arabia, and Turkey) from February 2014 to July 2017 • Patients over the age of 21 was eligible if he/she had at least 1 positive blood culture with E coli or Klebsiella spp that was non-susceptible to ceftriaxone but susceptible to pip-tazo and meropenem • Of 1646 patients screened, 391 were included in the study. • Meropenem 1g IV q8h (n = 191) or piperacillin/tazobactam 4.5g IV q6h (not extended infusion, n = 188) was given for a minimum of 4 days and up to 14 days. The duration of therapy was determined by the treating clinician.

Exclusion Criteria

• Patient not expected to survive more than 4 days • Patient allergic to a penicillin or a carbapenem • Patient with significant poly-microbial bacteremia (Gram positive skin contaminant in one set of blood cultures was not regarded as significant poly-microbial bacteremia) • Patients on palliative care • Pregnancy or breast-feeding • Use of concomitant antimicrobials in the first 4 days after enrollment with known activity against Gram-negative bacilli (except Bactrim may be continued as Pneumocystis prophylaxis) Objectives

Primary Outcome: 30-day mortality post bloodstream infection.

Secondary Outcomes: (1) Time to clinical and microbiologic resolution of infection – defined as number of days from randomization to resolution of fever (temperature > 38.0º C) PLUS sterilization of blood cultures. (2) Clinical and Microbiologic Success – defined as survival PLUS resolution of fever and leukocytosis PLUS sterilization of blood cultures. (Assessed on day 4, counted from the day of randomization--day 1--in order to determine a rapid response from the trial drug.) (3) Microbiologic resolution of infection – defined as sterility of blood cultures collected on or before day 4. (4) Microbiologic relapse – defined as growth of the same organism as in the original blood culture after the end of the period of study drug administration but before day 30. (5) Superinfection with a carbapenem or piperacillin-tazobactam resistant organism or Clostridium difficile - defined as growth of a meropenem or piperacillin-tazobactam resistant organism from any clinical specimen collected from day 4 of study drug administration to day 30 or a positive C. difficile stool test. This endpoint is important since one of the purposes of establishing an alternative to carbapenem therapy is to reduce infections with resistant organisms or C. difficile. Early termination of Trial

• Following the Data and Safety Monitoring Board (DSMB) review at 340 patients enrolled, a difference in the primary outcome was observed, at a significance level approximating the pre-specified stopping rule (P = .004) • DSMB recommended temporary suspension of the study on July 8, 2017, pending analysis once all 391 randomized patients had completed 30-day follow-up. • A decision to terminate the study on the grounds of harm and futility was made by the study management team, after discussion with site investigators, on August 10, 2017. This decision was made independently from the DSMB

Results

• Among 379 patients who were randomized appropriately and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome.

• A total of 23 of 187 patients (12.3%) randomized to piperacillin- tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1- sided 97.5%CI, −to 14.5%]; P = .90 for non-inferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin- tazobactam group and 3 of 191 (1.6%) in the meropenem group.

Major Limitations

• The inherent delays in the processing of blood cultures and susceptibility testing means that empirical therapy was not under control of the study team. Many patients (26.2%, 50/191) randomized to meropenem received a BLBLI empirically and, conversely, (13.8%, 26/188) of those randomized to piperacillin-tazobactam received a carbapenem.. (Although this would tend to bias toward non-inferiority.) • Step-down therapy (which was allowed on day 5 after randomization) with a carbapenem (eg, once-daily ertapenem) occurred in 20.1% (76/379) of all patients, even if randomized to piperacillin-tazobactam (Although this would trend to bias toward non-inferiority) • Unclear whether adequate source control was achieved in patients with a complex source of bloodstream infection • Although patients were recruited from diverse geographical and economic regions, only 2 patients were enrolled from North America (Canada). However, E coli strains causing BSI in this study are consistent with the STs and their associated ESBL genes previously described as prevalent in the United States Discussion

• The authors’ inability to demonstrate noninferiority of piperacillin-tazobactam to meropenem is especially interesting because several features of this trial design and patient population favored a non-inferiority effect. (In additional to empirical and step-down antibiotic therapy not being specified, with significant cross-over between antibiotic classes, the acuity of illness was lower than expected.)

• Only 3.9% of isolates were resistant to piperacillin-tazobactam. Mortality was unrelated to piperacillin- tazobactam resistance or to the MIC of piperacillin-tazobactam, although the number of isolates in each MIC category was small. This is notable, as some studies have suggested that poor response to piperacillin- tazobactam is seen primarily in ESBL-producing isolates with higher piperacillin-tazobactam MICs.(1)

• The authors (on their Twitter, @MerinoTrial) stated that they believe that inadequately treated bloodstream infection pushed people with significant comorbidities over the edge--that is, that death was hastened by suboptimal treatment of bloodstream infection.

• Most deaths were not due to infection and deaths were not in the early post-infection period. The authors postulate that the deleterious effects of sepsis may persist long after the infection “resolves,” for up to 2 years.

(1) Retamar P, López-Cerero L, Muniain MA, Pascual Á, Rodríguez-Baño J; ESBL-REIPI/GEIH Group. Impact of the MIC of piperacillin-tazobactam on the outcome of patients with bacteremia due to extended-spectrum-β-lactamase-producing Escherichia coli. Antimicrob Agents Chemother. 2013;57(7):3402- 3404. doi:10.1128/AAC.00135-13 7 vs 14 days of Antibiotic Therapy for uncomplicated gram-negative bacteremia: a non-inferiority randomized controlled trial Yahav et al. CID: 11 December 2018 BACKGROUND

• GNR bacteremia is an important clinical problem • Unclear how long this should be treated as few retrospective cohort studies have addressed this issue in recent years with conflicting results • This is the first randomized controlled trial assessing antibiotic duration in Gram-negative bacteremia. OBJECTIVES • To assess whether 7 days of appropriate antibiotic therapy is non- inferior to 14 days in patients with uncomplicated gram-negative bacteremia. • Primary outcome: a composite of the following (assessed from randomization to day 90): • All-cause mortality • Failure: including any of the following: • a. Relapse: a recurrent bacteremia due to the same microorganism occurring from day of randomization and until day 90 • b. Local suppurative complication that was not present at infection onset (e.g. renal abscess in pyelonephritis, empyema in pneumonia) • c. Distant complications of initial infection, defined by growth of the same bacteria as in the initial bacteremia • Hospital re-admissions or extended hospitalization; authors defined re-admission as a new hospitalization for any cause occurring after discharge from the index hospitalization. Extended hospitalization was defined as longer than 14 days starting from randomization date. OBJECTIVES

• Secondary outcomes (evaluated from day of randomization until day 30 unless stated otherwise) • Clostridium difficile associated diarrhea • Development of either clinically or microbiologically documented infection (other than the original Gram-negative bacteremia) within 90 days. • Number of hospital re-admissions until day 90 • Functional capacity at day 30 and time to return to baseline activity (in weeks, 0- immediate return to baseline activity, 12 – no return to baseline activity at end of follow up). • Development of resistance, defined as clinical isolates resistant to antibiotics previously used in the bacteremia episode. Surveillance sampling was not conducted. • Total in hospital days within 90 days • Total antibiotic days for 90 days • Adverse events: • Any diarrhea • Liver function test abnormalities, defined as elevated bilirubin x 1.5 of upper limit of normal or transaminases x 2.5 of upper limit of normal • Antibiotic rash • Acute kidney injury – defined according to RIFLE criteria as increased creatinine level x 1.5 from baseline or glomerular filtration rate (GFR) decrease >25% or urine output of <0.5 ml/kg/h for 6 hours METHODS

• Randomized, multicenter, open-label non-inferiority trial that included 604 patients between 1/2013 and 8/2017 in three academic centers (two in Israel and one in Italy.) • Inclusion criteria: • Hospitalized patients >18 years old • Gram-negative bacteremia in 1 or more blood cx, associated with e/o infection (hyper/hypothermia, a localized infection, sepsis or septic shock) • Receiving appropriate abx treatment for <=7 days, hemodynamically stable, afebrile for 48hrs • Source of bacteremia: primary/unknown source, urinary, abdominal, respiratory, CVC (w/ catheter removal before randomization), and skin/soft tissue • Either community or hospital-acquired bacteremia METHODS

• Exclusion criteria: • Source of bacteremia: endocarditis/endovascular infections, necrotizing fasciitis, osteomyelitis, abdominal abscesses (and other unresolved abdominal sources requiring surgical intervention), CNS infections, empyema, CVC-related (if catheter retained) • Polymicrobial growth in blood cx involving gram-positive organisms or anaerobes (growth of 2 or more different species of microorganisms in the same blood cx or growth of different species in 2 or more separate blood cx within 48hrs) • Salmonella, Brucella spp. • Specific immunosuppressive conditions: HIV, HSCT, neutropenia (on day of randomization or in 48hrs prior) • Clinical instability during 48hrs prior to randomization (MAP<60) despite fluid resuscitation and pressors • Repeated positive blood cx of the same organism separated by 24 hours regardless of abx treatment • Uncontrolled focus of infection (undrained abscess, etc.) • Fever >38C twice, or >38.5C once in the 48hrs prior to randomization METHODS

• Patients were assigned to short-course (7 days) or long-course (14 days) of antibiotic therapy, counting from 1st day of covering antibiotics, whether empirical or directed. • Type of empiric and directed antibiotics were chosen by the treating physicians, and decision of timing to oral antibiotic therapy was also left to the discretion of the treating physician. Blinding was not performed. • Outcome data following discharge was obtained through telephone interviews at days 30 and 90 after randomization, supplemented by access to national or regional healthcare databases. • A 10% non-inferiority margin was used. RESULTS

• Main source of bacteremia was urinary tract (411/604, 68%) and the main pathogens were Enterobacteriaceae (>60% E. coli, 543/604, 89.9%). • Type and route of administration (IV vs PO) of the antibiotics prescribed were also balanced between groups. • Primary composite outcome of mortality, clinical failure, readmissions or extended hospitalization at 90 days occurred in 140/306 (45.8%) patients in the short-arm and 144/298 (48.3%) in the long-arm. CI [-10.5% - 5.3%], establishing non-inferiority. • 36 (11.8%) deaths in the short duration group, 32 (10.7%) deaths in the long duration group. Discussion

• 7 days of antibiotic therapy was found to be non- inferior to 14 days of therapy in hospitalized patients with GN bacteremia (in terms of mortality, clinical failure, readmissions and prolonged hospitalization). • Functional decline is well described following sepsis, especially among the elderly, and a more rapid return to baseline (median of 2 vs 3 weeks) was found in patients in the short-duration arm, despite lack of superiority of other outcomes. • The authors noted that the dominance of Enterobacteriaceae (~90%) may limit the applicability of their results for GN non-fermenters such as Pseudomonas and Acinetobacter.

Introduction

• Osteomyelitis typically managed with combination surgery and 6 week course of IV antibiotics • Preference of IV antibiotics reflect broadly but unproven belief mentioned in influential article from 1970 (NEJM) • No randomized trial evaluating IV versus oral for osteomyelitis Methods • Multi-center, open label, parallel-group, randomized controlled non-inferiority study • Older than 18 years old • Native osteomyelitis extra-axial whether or not surgery required • Prosthetic joint and orthopedic fixation infections • Vertebral osteomyelitis • Treatment started as soon as possible after surgery (within 7 days) • Antibiotics chosen by infection experts • Oral rifampin allowed in IV group • In oral group, 5 days of IV allowed for unrelated intercurrent infections • Antibiotics before definitive treatment and after 42 days allowed by not governed by trial protocol Primary Outcome

Definitive treatment failure within 1 year after randomized defined as the presence of: 1. At least one clinical criterion (sinus tract or pus) 2. Microbiologic criterion of same bacteria isolated from 2 or more deep tissue samples or 1 culture from aspiration or biopsy or histologic criteria of inflammation

Treatment failure decided by group of experts who were blinded to treatment arm Secondary Outcomes

• Probably or possible treatment failure • Early discontinuation of the randomly assigned treatment strategy • IV complications • C. Dificile infection • Serious adverse effects • Health status • Adherence to treatment Results

• 1054 subjects underwent randomization • 1015 modified intent to treat protocol • 909 per protocol (needed to complete at least 4 weeks of assigned strategy) 466 oral 443 IV

Primary Outcome

Conclusions

• Oral therapy is noninferior to IV antibiotic therapy when used during the first 6 weeks for complex orthopedic infection as assessed by treatment failure at 1 year