2 regimens. C Anthony Hart1
1 Department of Medical Microbiology and Genitourinary Medicine, University of Liverpool Liverpool, England
Correspondence to: Dr Hart, CAHart@liverpool.ac.uk
This article comes from Clinical Evidence (2000;3:350-357), a new resource for clinicians produced jointly by the BMJ Publishing Group and the American College of Physicians—American Society of Internal Medicine. Clinical Evidence is an extensively peer-reviewed publication that summarizes the best available evidence on the effects of common clinical interventions gleaned from thorough searches and appraisal of the world literature. It became available in the United States late last year. Please see advertisement for more information or, alternatively, visit the web site at www.evidence.org.
QUESTIONS: What are the effects of prophylactic antibiotics on risk of disease in people exposed to someone with meningococcal disease? What are the effects of antibiotics in people with throat carriage of meningococcal disease?
INTERVENTIONS
In descending order of effectiveness
DEFINITION
Meningococcal disease is any clinical condition caused by Neisseria meningitidis (the meningococcus) groups A, B, C, or other serogroups. These conditions include purulent conjunctivitis, septic arthritis, meningitis, and septicemia with or without meningitis.
INCIDENCE/PREVALENCE
Meningococcal disease is sporadic in temperate countries and is most commonly caused by group B or C meningococci. The incidence in the United Kingdom varies from 2 to 8 cases per 100,000 people per year1 and in the United States from 0.6 to 1.5 per 100,000 population.2 Occasional outbreaks occur among close family contacts, secondary school pupils, and students living in student housing. Sub-Saharan Africa has regular epidemics caused by serogroup A, particularly in countries lying between Gambia in the west and Ethiopia in the east (the "meningitis belt"), where the incidence during epidemics reaches 500 per 100,000.3
ETIOLOGY/RISK FACTORS
Meningococcus infects healthy people and is transmitted by close contact, probably by exchange of upper respiratory tract secretions (table 1).4,5,6,7,8,9,10,11,12 Risk of transmission is greatest in the first week of contact.7 Risk factors include crowding and exposure to cigarette smoke.13 Children younger than 2 years have the highest incidence, with a second peak between ages 15 and 24 years. Currently an increased incidence of meningococcal disease is being seen among university students, especially among those in their first term and living in catered accommodations,14 although we found no accurate numeric estimate of risk from close contact in, for example, halls of residence. Close contacts of an index case have a much higher risk of infection than people in the general population.7,10,11 The risk of epidemic spread is higher with group A and C meningococci than with group B meningococci.4,6,8 What makes a meningococcus virulent is not known, but certain clones tend to predominate at different times and in different groups. Carriage of meningococcus in the throat has been reported in 10% to 15% of people; recent acquisition of a virulent meningococcus is more likely to be associated with invasive disease.
Table 1 Risk of infection among contacts
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* Compared with the risk in the general population.
PROGNOSIS
Mortality is highest in infants and adolescents and relates to disease presentation,15,16,17 Case-fatality rates in septicemia range from 19% to 25%; in meningitis plus septicemia, from 10% to 12%; and in meningitis alone, less than 1%.15,16,17
AIMS
To prevent disease in contacts.
OUTCOMES
Rates of infection, rates of eradication of throat carriage, and adverse effects of treatment.
METHODS
The author searched by MEDLINE and BIDS in December 1998 and drew from a collection of references from the pre-electronic data era. All studies were considered for inclusion. Clinical Evidence search and appraisal November 1999.
QUESTION: What are the effects of prophylactic antibiotics on the risk of disease in people exposed to someone with meningococcal disease?
We found no randomized evidence of the effects of antibiotics on the incidence of meningococcal disease among contacts. Observational data suggest that taking antibiotics reduces the risk of disease. We found no good evidence to address the question of which contacts should be treated.
Benefits
We found no systematic review and of randomized controlled trials (RCTs)
examining the effect of prophylactic antibiotic use in people who have been in
contact with someone with meningococcal disease. Rifampin [Rifampicin]:
We found only anecdotal data. Penicillin: We found 1 retrospective study
whose results cannot be generalized beyond the sample tested.18 Sulfadiazine: One observational cohort study
of soldiers in temporary troop camps in the 1940s compared the incidence of
meningococcal disease in camps where sulfadiazine was given to everyone after a
meningoccocal outbreak versus the incidence in camps where no prophylaxis was
given. The study reported a higher incidence of meningococcal disease in the
comparison camps (approximate figures, 2/7,000 vs 17/9,500 over 8 weeks).19
Harms
Rifampin: No excess adverse effects compared with placebo were found in
RCTs on throat carriage of meningococcal disease.20,21 However, rifampin is known to turn urine and contact
lenses orange and to induce hepatic microsomal enzymes, potentially rendering
oral contraception ineffective. Rifampin prophylaxis may be associated
with the emergence of resistant strains.22 Sulfadiazine:
One of 10 study participants experienced minor adverse events, including
headache, dizziness, tinnitus, and nausea.19
Comment
RCTs addressing this question are unlikely to be performed because the
intervention has few associated risks, and meningitis has high associated
risks. RCTs would also need to be large to find a difference in the incidence
of meningococcal disease. In the sulfadiazine cohort study, the 2 infected
people in the treatment group became infected only after leaving the camp.19
QUESTION: What are the effects of antibiotics in people with throat carriage of meningococcal disease?
RCTs have found that antibiotic therapy reduces throat carriage of meningococcus. We found no evidence that eradicating throat carriage reduces the risk of meningococcal disease.
Benefits
We found no systematic review. Incidence of disease: We found no RCTs or
observational studies examining whether eradicating throat carriage of
meningococcus reduces the risk of meningococcal disease. Throat carriage:
We found 5 placebo-controlled RCTs examining the effect of antibiotics on the
carriage of meningococcus in the throat (table 2).20,21, 23,24,25 All studies reported that antibiotics—rifampin,
minocycline hydrochloride, or ciprofloxacin hydrochloride—achieved high
rates of eradication (ranging from 90%-97%), except 1 trial of rifampin in
students with heavy growth on culture, where the rate of eradication was 73%.
Eradication rates with placebo ranged from 9% to 29%. We found 6 RCTs comparing
different antibiotic regimens (table 3). 26,27,28,29,30,31 Two RCTs found no significant difference between
rifampin and either minocycline, ciprofloxacin, or intramuscular ceftriaxone.27,30 In a third trial, households
were randomized to different treatments, and intramuscular ceftriaxone achieved
higher eradication rates than rifampin.29 Confidence in
this result, however, is reduced by its weaker, cluster randomization design.
In another trial, oral azithromycin proved as effective as rifampin in
eradicating meningococcal throat carriage.31
Table 2 Effect of antibiotics on throat carriage: results of placebo-controlled randomized controlled trials
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* Nine lost to follow-up.
† Twenty-three either did not have meningococci before therapy or did not provide a full set of cultures.
‡ Thirty-seven either did not have meningococci before therapy or did not provide a full set of cultures.
§ Seven were unavailable for follow-up.
|| One did not adhere to treatment.
Table 3 Effect of antibiotics on throat carriage: results of comparative randomized controlled trials
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* RR is calculated only for the 2 placebo-controlled trials. The
rest are comparative trials between 2 regimens.
† An analogue of sulfadiazone.
Harms
Minocycline: In 1 RCT, adverse effects (1 of nausea, anorexia, dizziness, and abdominal cramps)
were reported in 36% of participants.23 Rifampin:
See previous "Harms" section. Ciprofloxacin: In trials of
single-dose prophylactic regimens, no more adverse effects were reported than
occurred with comparison regimens or placebo.24,25,30 Ciprofloxacin is contraindicated in pregnancy and in
children because animal studies have indicated possible articular cartilage
damage in developing joints.32 Ceftriaxone: No
significant adverse effects were encountered in the 2 trials of ceftriaxone.29,30 In 1 trial, 12% of participants had
headache.28 Ceftriaxone is given as a single
intramuscular injection. Azithromycin: No serious or moderate adverse
effects were reported, but nausea, abdominal pain, and headache of short
duration were reported equally in the azithromycin- and rifampin-treated
groups.29
Comment
Eradication of meningococcal throat carriage is a well-accepted surrogate for
preventing meningococcal disease. It is unlikely that any RCT will be conducted
on the efficacy of prophylactic antibiotics in preventing secondary
community-acquired meningococcal disease in household contacts because the
number of participants required would be large.
Summary points
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References