Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial

Abstract

Objective: To evaluate microbiological effectiveness, that is, culture negativity of a non-blinded eradication protocol (Rx) compared with observation (Obs) in clinically stable cystic fibrosis participants with newly positive methicillin resistant Staphylococcusaureus (MRSA) cultures.

Design: This non-blinded trial randomised participants ages 4-45 years with first or early (≤2 positive cultures within 3 years) MRSA-positive culture without MRSA-active antibiotics within 4 weeks 1:1 to Rx or Obs. The Rx protocol was: oral trimethoprim-sulfamethoxazole or if sulfa-allergic, minocycline plus oral rifampin; chlorhexidine mouthwash for 2 weeks; nasal mupirocin and chlorhexidine body wipes for 5 days and environmental decontamination for 21 days. The primary end point was MRSA culture status at day 28.

Results: Between 1 April 2011 to September 2014, 45 participants (44% female, mean age 11.5 years) were randomised (24 Rx, 21 Obs). At day 28, 82% (n=18/22) of participants in the Rx arm compared with 26% (n=5/19) in the Obs arm were MRSA-negative. Adjusted for interim monitoring, this difference was 52% (95% CI 23% to 80%, p<0.001). Limiting analyses to participants who were MRSA-positive at the screening visit, 67% (8/12) in the Rx arm and 13% (2/15) in the Obs arm were MRSA-negative at day 28, adjusted difference: 49% (95% CI 22% to 71%, p<0.001). Fifty-four per cent in the Rx arm compared with 10% participants in the Obs arm remained MRSA-negative through day 84. Mild gastrointestinal side effects were higher in the Rx arm.

Conclusions: This MRSA eradication protocol for newly acquired MRSA demonstrated microbiological efficacy with a large treatment effect.

Trial registration number: NCT01349192.

Keywords: Bacterial Infection; Cystic Fibrosis; Infection Control.

Figure 1. CONSORT diagram of participant disposition

Flow diagram of participants through each stage of the randomized trial. Footnote: Nine participants did not meet the inclusion criteria of being clinically stable. One of these participants was subsequently re-screened but failed the inclusion criteria of MRSA positive culture at screening or within 6 months prior to screening. Eleven participants failed the inclusion criteria of MRSA positive culture at screening or within 6 months prior to screening. One participant did not meet the inclusion criteria by withdrawing their consent. One participant did not meet the inclusion criteria of having a documented CF diagnosis. Two participants met the exclusion criteria of receiving anti-MRSA antibiotics within 28 days prior to screening. One participant met the exclusion criteria of abnormal renal function at screening. One participant met the exclusion criteria that warranted a screen failure due to investigator's opinion. [2] Two participants randomized to the observational control arm withdrew with reason “Subject decision”. [3] The intent-to-treat (ITT) population is defined as participants who are randomized to a study arm and followed post randomization. The ITT population is used for all safety and secondary efficacy analyses. [4] One site, which enrolled a total of four participants (two in the treatment arm, two in the observational control arm), experienced numerous study conduct issues and protocol violations resulting in missing primary endpoint and other endpoint data. One of these four participants had withdrawn immediately following randomization to the observational control arm. The remaining three participants' data is summarized as available post-randomization. [5] The intent-to-treat efficacy (ITT-E) population consists of all the participants in the ITT population who were assessed for the primary microbiologic efficacy endpoint at baseline and Day 28. The ITT-E population is used for the primary efficacy analyses. [6] The per-protocol efficacy population (PPE) is comprised of all participants in the ITT-E population excluding the participants with major protocol violation or those non-compliant with oral antibiotic use during the first 28 days of the study. The PP population is used in sensitivity analyses of primary efficacy endpoint.

Figure 2. (A Rx and B Obs-arm) Participant-specific MRSA culture results through Day 168 by treatment arm

Individual participant MRSA culture status across time is shown. History of MRSA positive isolate is also shown. Participants with who are P. aeruginosa positive (Pa +) are indicated by □. Acute events treated with anti-MRSA active antibiotics are marked with an ‘X’. The locations of the ‘X’s indicate the timing of the antibiotic course in relationship to the study visits but do not represent an actual day as measured from screening. Participants enrolled prior to protocol amendment are marked with an asterisk (see Discussion).

Figure 2. (A Rx and B Obs-arm) Participant-specific MRSA culture results through Day 168 by treatment arm

Individual participant MRSA culture status across time is shown. History of MRSA positive isolate is also shown. Participants with who are P. aeruginosa positive (Pa +) are indicated by □. Acute events treated with anti-MRSA active antibiotics are marked with an ‘X’. The locations of the ‘X’s indicate the timing of the antibiotic course in relationship to the study visits but do not represent an actual day as measured from screening. Participants enrolled prior to protocol amendment are marked with an asterisk (see Discussion).

Figure 3. Relative change from screening in FEV₁ (Liters) over time by study arm (ITT Population)

Relative change in FEV₁ (Liters) from baseline to each post-baseline visit for both study arms in ITT population is shown. 95% confidence intervals (using t-distribution approximation) are included at each time point. The number of participants at each time point is included in a legend below the figure. Per protocol, participants younger than 6 years of age from both the treatment arm (n=3) and observational control arm (n=4) were not assessed for pulmonary function.