Strong Public Health Recommendations from Weak Evidence? Lessons Learned in Developing Guidance on the Public Health Management of Meningococcal Disease

Table 1

Summary of findings and recommendations for three research questions.

Assessment of evidence quality						Assessment for recommendations
Number of studies selected/number of studies reviewed	Design and quality	Inconsistency	Indirectness	Other modifying factors	Grade of evidence	Benefits	Harm	Costs and burdens	Values and preferences	Grade of recommendation
Research question: What is the effectiveness of chemoprophylaxis to a case of IMD before discharge from hospital in preventing further cases of IMD?
Population: cases of IMD and their household contacts
Intervention: administration of chemoprophylaxis (including therapeutic treatment if effective in carriage eradication) to case prior to discharge from hospital
Comparison: no chemoprophylaxis administered to case prior to discharge from hospital
Outcome: carriage in IMD cases; incidence of IMD in household contacts
4/349	All observational. No studies addressed the intervention	Different antibiotic regimens, times of swabbing, sampling, and study populations	Proxy outcome: prevalence of carriage following discharge from hospital	Small sample sizes. Study results are statistically homogenous	Very low	Potential reduction of the disease burden among close contacts of discharged cases	Low risk of treatment side effects	Very low cost and low burden for the patient (oral single dose)	Treatment widely accepted	Strong
Recommendation: chemoprophylaxis is recommended for patients with IMD on discharge from hospital unless an antibiotic regimen effective in eradicating carriage was used during hospital treatment
Implication for practice: easy to implement in hospital procedures; treatment is widely accepted
Research question: What is the effectiveness of chemoprophylaxis to contacts of a case of IMD who have shared the same transport vehicle as a case of IMD in preventing further cases among those contacts?
Population: contacts of diagnosed IMD cases sharing the same transport vehicle, for example, plane, boat, bus, and car
Intervention: administration of chemoprophylaxis to contacts sharing transport vehicle, following IMD diagnosis in a case
Comparison: no chemoprophylaxis administered to contacts sharing transport vehicle, following IMD diagnosis in a case
Outcome: incidence rate of IMD in contacts sharing a transport vehicle with IMD cases (up to 30 days)
7/103	Only reports on sporadic cases and 3 clusters linked to travel. No studies addressed the intervention	No consistency across case reports	Proxy outcome: risk of subsequent cases among fellow passengers whether prophylaxis was given or not	No studies clearly established evidence of transmission in transport vehicles	Very low	No evidence of reduction of subsequent cases among contacts sharing the same transport and taking prophylaxis	Low risk of treatment side effects but potential anxiety among those not receiving prophylaxis if targeted	Low cost of the intervention. However, contact tracing can lead to considerable cost and may not be feasible	Treatment likely to be accepted even if objective risk is low. Possible public pressure to give prophylaxis	Weak
Recommendation: sharing the same transport vehicle as a case of IMD is not, in itself, an indication for chemoprophylaxis
Implication for practice: a consistent European policy is highly desirable because high potential for confusion related to divergent cross-border policies. However, achieving consensus may not be easy
Research question: Which antibiotic regimes are most effective in eradicating carriage among adults?
Population: adult carriers of N. meningitidis
Intervention: administration of antibiotic (type, dose, duration, and route)
Comparison: no antibiotics, alternative type of antibiotic, alternative dose, alternative duration, or alternative route
Outcome: carriage of N. meningitidis at ≥7 days of follow-up. Occurrence of resistant strains of N. meningitidis after treatment
28	17 RCTs and 3 observational studies; no serious limitations	High consistency of results across studies	Proxy outcome: eradication of carriage. Only assessed in students/army for azithromycin and cefixime	High associations	High: rifampicin, ciprofloxacin, and ceftriaxone; Moderate: azithromycin and cefixime	The 5 antibiotics are highly effective (eradication in 79–100%)	Limited harm of antibiotics and mild side effects.; Emergence of resistance with rifampicin and interactions with other drugs	Low cost.; Lower burden for ciprofloxacin and azithromycin as single oral dose.; Ceftriaxone is intramuscular	High acceptability of intervention. A single oral dose is likely to be preferred	Strong for the 5 antibiotics.; Weak for “ciprofloxacin, azithromycin and ceftriaxone are preferred”
Recommendation: rifampicin, ciprofloxacin, ceftriaxone, azithromycin, and cefixime can be advised for chemoprophylaxis in adults. Ciprofloxacin, azithromycin, and ceftriaxone are preferred
Implication for practice: using ciprofloxacin, azithromycin, or ceftriaxone would require a change of practice in several countries but has a high feasibility at similar or lower cost. Surveillance of resistance is essential

Strength of association and imprecision [17].
Total reviewed not relevant because we identified a systematic review and selected 16 of the included studies as well as 9 studies through references of selected papers. Of the update search conducted in the period after the systematic review, 3/67 studies were included.
RCT: randomized clinical trial; IMD: invasive meningococcal disease.