Dr Matthew Colidron @ MRF's Meningitis & Septicaemia in Children & Adults 2017+
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Single-dose oral ciprofloxacin prophylaxis as a meningococcal meningitis outbreak response: results of a cluster-randomized trial https://www.meningitis.org/mrf-conference-2017
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Dr Matthew Colidron @ MRF's Meningitis & Septicaemia in Children & Adults 2017+
- 1. Single-dose oral ciprofloxacin prophylaxis as a meningococcal meningitis outbreak response: results of a cluster-randomized trial d Madarounfa Health District, Niger Matthew Coldiron, Epicentre 15 November 2017
- 2. Study design and primary objective 3-arm cluster-randomized trial to assess the impact of prophylaxis with single-dose oral ciprofloxacin (to household contacts and to entire villages) on the overall meningitis attack rate during an epidemic. Ethics review: CCNE of Niger (003/2016/CCNE) and MSF-ERB (Ref: 1603) Funding: Médecins Sans Frontières Full methods: Coldiron et al. Trials 2017;18:294 Trial registry: clinicaltrials.gov NCT02724046
- 3. Interventions • Arm 1: standard care • Arm 2: ciprofloxacin to household contacts – Given by nurse at home <24h of case notification • Arm 3: ciprofloxacin to entire village – Village-wide distribution of ciprofloxacin <72h after declaration of first case from a village • Directly-observed, age-based dosing of ciprofloxacin, including children and pregnant women • Exhaustive censuses in each included village
- 4. Statistical analysis • Cluster-level t-test of log-transformed post-randomization attack rates – Inverse variance weights to account for heterogeniety among clusters • Poisson regression adjusting for (prespecified): – age structure of villages – time between randomization and start of epidemic – time between randomization and reactive vaccination – inclusion before/after rains • ICC calculated using ANOVA
- 5. Resistance sub-study methods • Sample size: 10 villages / 200 individuals in each arm (400 total) = 20 individuals randomly selected in each of 20 villages, individual written consent • Stool collection at days 0, 7 and 28 • Detection of the carriage of enterobacteriae resistant to cipro and/or cefotaxime by plating on selective media • Simplification of identification / confirmation methods after 5 villages showing very high prevalence of resistant bacteria • Quality control at IAME laboratory, Inserm, Paris, France
- 6. Timeline 20 April: Trial start criteria met in Madarounfa District, Niger 22 April: First villages included 10 May: First rains 12 May: First vaccination began 18 May: Last village included (50 villages total in 5 health areas) 23 May: Last case notified
- 7. Baseline characteristics of villages Standard care Household cipro Village-wide cipro Number of villages 18 17 15 Total population 26 162 23 621 22 177 Age of cases, mean±SD 18±13 17±15 18±17 Female population (%) 58 55 54 Proportion <30y (%) 78 77 76 Days between inclusion and reactive vaccination, mean±SD 11.1±7.8 10.8±9.5 12.2±8.8 Days between inclusion and first rains, mean±SD 7.2±7.1 6.4±8.1 7.1±6.5
- 8. Primary results * Adjusted for log(proportion of village <30y), days between inclusion and reactive vaccination, days from start of epidemic, and whether inclusion of village occurred after the first day of rainfall Standard care Household Cipro Village-wide cipro Post-randomization cases 113 91 43 Attack rate (95%CI), cases/100 000 people 432 (255-738) 386 (219-679) 194 (103-364) Crude attack rate ratio versus standard care (95%CI) Ref 0.89 (0.44-1.82) p=0.75 0.44 (0.18-1.12) p=0.08 Adjusted attack rate ratio versus standard care (95%CI)* Ref 0.88 (0.51-1.51) p=0.64 0.43 (0.22-0.86) p=0.02
- 9. Laboratory results • 52 samples sent from 247 post-randomization cases – 21 NmC, 31 negative • Standard care: 16 NmC from 28 tested • Household ppx: 5 NmC from 16 tested • Village-wide ppx: 0 NmC from 8 tested
- 11. Resistance sub-study - Results • Baseline carriage of resistant enterobacteriae was very high • Trend for increased prevalence of carriage of Cipro-R enterobacteriae after village-wide distribution – Non-significant difference in change between D7/D0 and D28/D0 between arms (p=0.12) No cipro Village-wide cipro Cipro-R (%) D0 95 95 D7 93 97 D28 95 99 ESBL (%) D0 91 94 D7 87 93 D28 93 93
- 12. Conclusion • Village-wide prophylaxis with single-dose oral ciprofloxacin <72h after meningitis case notification significantly reduced attack rates – Could be an attractive new strategy for epidemic response • Faster (can stockpile ciprofloxacin in-country) • Possibly cheaper (low cost of cipro, no cold chain or other materials) • 57% reduction in cases seems much larger than previous model-based estimates for reactive vaccination – Would have preferred more laboratory confirmations, but the confirmed cases follow the same trends • Need more information about potential impact of strategy on antibiotic resistance (both of meningococcus and gut flora)
Editor's Notes
- In the meningitis belt, outbreak response often includes reactive vaccination campaigns with polysaccharide vaccines, though we know that these often occur late. The situation is currently complicated by an insufficient quantity of vaccines, only 2.4 million doses of NmC-containing vaccine projected to be available for the 2018 season.
- We conducted a 3-arm cluster-randomized trial to evaluate the use of ciprofloxacin as an epidemic response strategy, and the primary outcome was overall meningitis attack rate during the epidemic.
- Villages were randomized after the first suspected case of meningitis was notified from the village. The first arm was our control arm. In the second arm, household members of suspected cases were offered single-dose oral ciprofloxacin within 24 hours of the case’s notification. In the third arm, we organized village-wide distributions of cipro within 72 hours of the case’s notification. All doses of ciprofloxacin were directly-observed, and offered to all persons in the village, including children and pregnant women.
- Again, our outcome of interest is overall attack rate, not individual-level efficacy. Attack rates were adjusted for timing of randomization during the epidemic, the rains, and also the time between randomization and the reactive vaccination campaign that was eventually organized.
- We also enrolled 200 participants from the control arm and 200 from the village-wide prophylaxis arm into a substudy to look at carriage of cipro-resistant faecal flora at baseline and then 7 and 28 days post-distributions. This sample size was based on an expected prevalence of carriage of 30% at baseline.
- The trial was quick, lasting only about a month, as the epidemic came late in the season. The vaccination campaign began after about 3 weeks of trial inclusions.
- We included 50 villages, with a total population of about 72 000 persons. As you can see from the table, randomization was successful.
- The attack rate in the control arm was 432 per 100 000, and in the household prophylaxis arm, it was 386. In the village-wide prophylaxis arm, it was 194. This difference was significant, and after adjustment, translates into approximately 57% reduction in attack rate. As an aside, in the household prophylaxis arm, we treated an average of 4% of the village. In the village-wide prophylaxis arm, the average coverage of the distributions was 76%, which we thought was excellent given the short timeframes, most were organized within 48 hours.
- About a quarter of suspected cases had samples sent, all that were positive were positive for NmC. No confirmed cases were seen in the village-wide prophylaxis arm, limiting our ability to calculate attack rate ratios for confirmed cases. But even though the denominators are relatively small, the overall trend in confirmed cases supports the primary results.
- These histograms show the timing of the cases in each arm, it seems like the bulk of the difference between the village-wide prophylaxis arm occurs here, during the first week after randomization, in line with what we know about the short, highly-localized nature of epidemics in a village.
- Carriage of cipro-resistant enterobacteriaceae was 95% at baseline in both arms, much higher than expected. These surprising results have been confirmed at a reference laboratory in Europe. No significant changes were seen over time, but we were underpowered to show any.
- To conclude, village-wide prophylaxis with single-dose oral ciprofloxacin reduced meningitis attack rates by 57% compared to control. To our knowledge, this is the first formal evaluation of antibiotic prophylaxis as an outbreak response in the meningitis belt since the 1950s, and shows highly promising results, particularly given the overall context of today. Further research is needed, particularly into the effects of the village-wide prophylaxis strategy on antimicrobial resistance (both of the meningococcus and also of intestinal flora), hopefully in areas with lower baseline resistance. We are preparing to carry out further studies in the 2018 season if appropriate epidemics present themselves.
- Thank you for your attention.