S170
Chemoprophylaxis for Bacterial Infections: Principles of and Application to Meningococcal Infections Benjamin Schwartz
From the Division of Infectious Diseases, Department of Pediatrics, Emory University, Atlanta, Georgia
Prophylaxis with antibiotics for the prevention of disease among persons exposed to patients with certain bacterial infections may provide the opportunity to avoid potential morbidity and mortality and the associated economic and social costs of illness. Prophylaxis with antibiotics is both feasible and desirable when the disease in question is severe, when specific risk groups can be defined, and when a safe, effective, and affordable prophylactic agent is available. If all three criteria are not met, institution of prophylaxis would likely be unnecessary, misdirected, or ineffective. The question of safety is paramount in the choice of a prophylactic antibiotic agent, since many more individuals will receive prophylaxis than would develop disease in the absence of intervention. Any adverse effects that might occur among those receiving prophylaxis must therefore be carefully weighed against the risk and severity of the disease. Efficacy is important since an ineffective prophylactic agent not only provides a false sense of security to the person who receives it but also results in continued carriage of a virulent organism, which may then be spread to others. Efficacy depends on the activity of the antimicrobial agent against the particular organism at the site of the infection and the patient's compliance with the prophylactic regimen. Carriage of many bacterial species occurs in the pharyngeal mucosa, so that the penetration of an antibiotic into the saliva in addition to antibiotic activity against the organism are important considerations. Since patients who receive prophylaxis are not ill, com-
Please address requests for reprints to Dr. Benjamin Schwartz, Division of Infectious Diseases, EmoryUniversity, 69 ButlerStreetSE, Atlanta, Georgia 30303. Reviews of Infec:tious Diseases 1991;13(Suppl2):Sl70-3 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1301-0037$02 .00
pliance may be decreased when several doses of antibiotic are required or when adverse effects occur, so that the most effective regimen will be the simplest and safest. A final consideration is cost. The question of the cost effectiveness of providing antibiotics to many individuals as opposed to the incurrence of the direct and indirect costs associated with the development of the disease must be considered. The adverse effectsof prophylaxis and their associated costs must be included in this calculation. Where resources are limited, other strategies to prevent or restrict the spread of disease, such as immunoprophylaxis with vaccination, must be weighed against the benefits of chemoprophylaxis. Prophylaxis with antibiotics is currently recommended for contacts of persons with invasive disease caused by Neisseria meningitidis and Haemophilus influenzae. Infection with either of these organisms may have severe consequences, groups at risk for infection among patient contacts have been defined, and effectivetherapy to eradicate pharyngeal carriage of these organisms exists. Since the group at risk for infection with H. injluenzae is limited to young children, prophylaxis is recommended for personnel of day care centers or for household members when an unvaccinated child ~4 years of age is in the household. In contrast, infections with N. meningitidis occur in all age groups, and broader prophylactic measures are recommended. The remainder of this paper will focus on prophylaxis for infections with N. meningitidis and summarize the results of a study that compared prophylactic agents by application of the principles of effective prophylaxis previously described.
Epidemiologic Background Over 5,000 cases of invasive meningococcal disease occur in the United States each year. In 1985, the Advisory Com-
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on July 2, 2015
Chemoprophylaxis with antibiotics is both feasibleand desirable for prevention of a potentially serious disease when specificgroups at risk can be defined and when a safe, effective, and affordable prophylactic agent is available. Although the AdvisoryCommittee on Immunization Practicesrecommendsrifampinfor prophylaxisof meningococcal disease,there are failuresoftreatment and adverse reactions associated with the administration of this drug, and it cannot be used during pregnancy. In 1987, during an outbreak of group A meningococcal disease in Saudi Arabia, the efficacyof a single intramuscular dose of ceftriaxone was compared with the standard regimen of rifampin for eradication of pharyngeal carriage of Neisseria meningitidis among persons at risk. roUow-up cultures indicated successful eradication for 97% ofthose who receivedceftriaxone and 75% of those who received rifampin. Thus, although ceftriaxone exceeds rifampin in fulfilling the criteria for an effective prophylactic agent, recommendations regarding its use still must be made with caution because of limited clinical experience.
RID 1991;13 (Suppl 2)
Prophylaxis for Meningococcal Infections
in one study, incidental eradication of N. meningitidis from 29 pharyngeal carriers was noted [10].
Patients and Methods The setting of the investigation was an outbreak of group A meningococcal disease that occurred following the Haj (the annual pilgrimage to the holy places of Islam in Saudi Arabia) [11]. Each year approximately one million pilgrims from countries throughout the world travel to Saudi Arabia for the haj, arriving up to 1 month before and leaving up to 2 months after the 5-day period of the haj. With the additional influx of Saudi Arabian pilgrims, the population in and around Mecca during the haj increases from 700,000 to almost 3 million persons. In 1987, meningococcal meningitis occurred among pilgrims who arrived early in Mecca; this situation initiated an outbreak of disease that spread among hajis and then among unvaccinated residents of Saudi Arabia. To limit secondary spread of disease, prophylactic rifampin was provided to family members and other close contacts of patients. Provision of prophylaxis, however, was not easy in this setting. The diversity of languages and mobility of the pilgrims made compliance uncertain. Among the resident population, similar problems as well as the lack of a convenient formulation for children and difficulty in dispensing doses to large families with many children contributed to the difficulties of providing prophylaxis. The comparative efficacy of prophylaxis with rifampin or ceftriaxone for pharyngeal carriage of N. meningitidis was investigated among residents of Jedda, a city of 1.5 million people 72 km from Mecca. All persons with suspected meningococcal disease in Jedda were cared for at a single infectious disease hospital. Cases of meningococcal disease were defined on the basis of CSF or blood cultures that were positive for N. meningitidisor on the basis of a comparable clinical syndrome (purulent CSF in association with high protein and low glucose levels). Household contacts of patients were included in the study if they had not received prior chemoprophylaxis. In addition, 125 laborers who were living in a small 16-room compound with a patient with meningitis were included. Case households were randomized to receive rifampin or ceftriaxone, family members were interviewed to determine risk factors for disease or carriage, and oropharyngeal swab specimens were obtained for culture. Antibiotic prophylaxis was then administered. The rifampin regimen was 600 mg for adults and 10 mg/kg for children, twice a day for 2 days. The first dose was taken in the presence of the study team. Ceftriaxone was given in a single im dose of 250 mg for adults and 125 mg for children under 15 years of age. The ceftriaxone was diluted in 1% lidocaine to decrease the pain of injection, and all recipients were observed for 30 minutes following injection for possible reactions (none occurred). For each case household, a random neighborhood control
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on July 2, 2015
mittee on Immunization Practices recommended prophylactic treatment of persons who had contact with patients with meningococcal disease in specific high-risk settings, including within households, day care centers, and closed populations such as the military. Unless the causal organism is known to be sensitive to sulfadiazine, the drug of choice is rifampin (oral administration of a 600-mg dose twice a day for 2 days is recommended) [1]. This recommendation is based on results of studies that show a secondary attack rate among household contacts of patients with meningococcal disease of ""700/100,000 and among day care contacts of such patients of ""400/100,000 [2]. A study by Munford et al. of an outbreak of group C meningococcal disease in Brazil showed a secondary attack rate of 1.6% among household contacts [3]. Most secondary cases occur within the first week following exposure, but risk of infection continues to be increased for 1-2 months. In a study of secondary meningococcal infections in Belgium, when coprimary cases were eliminated, about half of the secondary cases occurred within the first week following exposure, 20 % occurred in the second week, and the remaining 30 % occurred thereafter [3]. These data emphasize the importance of providing prophylaxis early as well as the value ofproviding prophylaxis up to several weeks following exposure. Although the Advisory Committee on Immunization Practices recommends rifampin as the agent of choice for prophylaxis of meningococcal disease, there are several disadvantages attendant with its use: it fails to eradicate meningococci in 20 % of patients who carry these organisms in the pharynx [4], and meningococcal disease has been documented to occur following prophylaxis [5]. Adverse effects, including headache, dizziness, and gastrointestinal symptoms, occur in one-quarter of patients who receive prophylaxis with rifampin [6]; the drug is teratogenic in animals and is not recommended for use during pregnancy. Availabilityof a suspension formulated for children is limited, and because of potential toxicity, dosing for children must adhere to a milligram per kilogram basis. The four-dose regimen and the frequency of adverse effects may discourage compliance. In addition, several studies havedocumented the emergence of resistant strains of meningococci following prophylactic treatment with this drug [7, 8]. In 1987 an outbreak of group A meningococcal meningitis occurred in Saudi Arabia that provided an opportunity to evaluate the efficacy of rifampin as compared with ceftriaxone, a third-generation cephalosporin, for prophylaxis of meningococcal disease. The choice of ceftriaxone as a potential chemoprophylactic agent was based on the drug's low MIC for N. meningitidis, on the fact thata high level of concentration in saliva can be achieved that exceeds the MIC for >24 hours following a single im dose [9], and on the fact that a low incidence of adverse reactions is associated with its use. A single im dose of ceftriaxone has been shown to be effective for the eradication of pharyngeal Neisseriagonorrheae;
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Schwartz
Sl72
Table 1. Participants in a study of antimicrobial prophylaxis for pharyngeal carriage of N. meningitidis, Jedda, 1987. Study group Case contacts Treated with ceftriaxone Treated with rifampin Controls
No. in group
No. (%) of carriers
347 179 168 124
116 (33) 75 (42) 41 (24) 16 (13)
Table 2. Efficacy of prophylaxis during an outbreak of group A meningococcal disease, Jedda, 1987. No. of patients cured/total no. of patients (%) Treatment Ceftriaxone Rifampin No antibiotics
1w
2w
66/68 (97) 27/36 (75)*
62/64 (97) 22/27 (81)t 5/12 (42)
2/10 (20)
NOTE. This table was reprinted with permission from Lancet [II]. * After I week, P = .001 when treatment with ceftriaxone was compared with treatment with rifampin. t After 2 weeks, P = .02 when treatment with ceftriaxone was compared with treatment with rifampin.
received either prophylactic agent. The most commonly reported adverse effectamong recipients of ceftriaxone was headache, which was mentioned by 12 % of recipients. However, because of differences in language and culture, the accuracy of reports of minor adverse effectsis doubtful. Antibiotic sensitivity testing was done on a sample of 17 isolates of N. meningitidis. For all isolates, the MIC of ceftriaxone was
Chemoprophylaxis for Bacterial Infections: Principles of and Application to Meningococcal Infections Benjamin Schwartz
From the Division of Infectious Diseases, Department of Pediatrics, Emory University, Atlanta, Georgia
Prophylaxis with antibiotics for the prevention of disease among persons exposed to patients with certain bacterial infections may provide the opportunity to avoid potential morbidity and mortality and the associated economic and social costs of illness. Prophylaxis with antibiotics is both feasible and desirable when the disease in question is severe, when specific risk groups can be defined, and when a safe, effective, and affordable prophylactic agent is available. If all three criteria are not met, institution of prophylaxis would likely be unnecessary, misdirected, or ineffective. The question of safety is paramount in the choice of a prophylactic antibiotic agent, since many more individuals will receive prophylaxis than would develop disease in the absence of intervention. Any adverse effects that might occur among those receiving prophylaxis must therefore be carefully weighed against the risk and severity of the disease. Efficacy is important since an ineffective prophylactic agent not only provides a false sense of security to the person who receives it but also results in continued carriage of a virulent organism, which may then be spread to others. Efficacy depends on the activity of the antimicrobial agent against the particular organism at the site of the infection and the patient's compliance with the prophylactic regimen. Carriage of many bacterial species occurs in the pharyngeal mucosa, so that the penetration of an antibiotic into the saliva in addition to antibiotic activity against the organism are important considerations. Since patients who receive prophylaxis are not ill, com-
Please address requests for reprints to Dr. Benjamin Schwartz, Division of Infectious Diseases, EmoryUniversity, 69 ButlerStreetSE, Atlanta, Georgia 30303. Reviews of Infec:tious Diseases 1991;13(Suppl2):Sl70-3 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1301-0037$02 .00
pliance may be decreased when several doses of antibiotic are required or when adverse effects occur, so that the most effective regimen will be the simplest and safest. A final consideration is cost. The question of the cost effectiveness of providing antibiotics to many individuals as opposed to the incurrence of the direct and indirect costs associated with the development of the disease must be considered. The adverse effectsof prophylaxis and their associated costs must be included in this calculation. Where resources are limited, other strategies to prevent or restrict the spread of disease, such as immunoprophylaxis with vaccination, must be weighed against the benefits of chemoprophylaxis. Prophylaxis with antibiotics is currently recommended for contacts of persons with invasive disease caused by Neisseria meningitidis and Haemophilus influenzae. Infection with either of these organisms may have severe consequences, groups at risk for infection among patient contacts have been defined, and effectivetherapy to eradicate pharyngeal carriage of these organisms exists. Since the group at risk for infection with H. injluenzae is limited to young children, prophylaxis is recommended for personnel of day care centers or for household members when an unvaccinated child ~4 years of age is in the household. In contrast, infections with N. meningitidis occur in all age groups, and broader prophylactic measures are recommended. The remainder of this paper will focus on prophylaxis for infections with N. meningitidis and summarize the results of a study that compared prophylactic agents by application of the principles of effective prophylaxis previously described.
Epidemiologic Background Over 5,000 cases of invasive meningococcal disease occur in the United States each year. In 1985, the Advisory Com-
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on July 2, 2015
Chemoprophylaxis with antibiotics is both feasibleand desirable for prevention of a potentially serious disease when specificgroups at risk can be defined and when a safe, effective, and affordable prophylactic agent is available. Although the AdvisoryCommittee on Immunization Practicesrecommendsrifampinfor prophylaxisof meningococcal disease,there are failuresoftreatment and adverse reactions associated with the administration of this drug, and it cannot be used during pregnancy. In 1987, during an outbreak of group A meningococcal disease in Saudi Arabia, the efficacyof a single intramuscular dose of ceftriaxone was compared with the standard regimen of rifampin for eradication of pharyngeal carriage of Neisseria meningitidis among persons at risk. roUow-up cultures indicated successful eradication for 97% ofthose who receivedceftriaxone and 75% of those who received rifampin. Thus, although ceftriaxone exceeds rifampin in fulfilling the criteria for an effective prophylactic agent, recommendations regarding its use still must be made with caution because of limited clinical experience.
RID 1991;13 (Suppl 2)
Prophylaxis for Meningococcal Infections
in one study, incidental eradication of N. meningitidis from 29 pharyngeal carriers was noted [10].
Patients and Methods The setting of the investigation was an outbreak of group A meningococcal disease that occurred following the Haj (the annual pilgrimage to the holy places of Islam in Saudi Arabia) [11]. Each year approximately one million pilgrims from countries throughout the world travel to Saudi Arabia for the haj, arriving up to 1 month before and leaving up to 2 months after the 5-day period of the haj. With the additional influx of Saudi Arabian pilgrims, the population in and around Mecca during the haj increases from 700,000 to almost 3 million persons. In 1987, meningococcal meningitis occurred among pilgrims who arrived early in Mecca; this situation initiated an outbreak of disease that spread among hajis and then among unvaccinated residents of Saudi Arabia. To limit secondary spread of disease, prophylactic rifampin was provided to family members and other close contacts of patients. Provision of prophylaxis, however, was not easy in this setting. The diversity of languages and mobility of the pilgrims made compliance uncertain. Among the resident population, similar problems as well as the lack of a convenient formulation for children and difficulty in dispensing doses to large families with many children contributed to the difficulties of providing prophylaxis. The comparative efficacy of prophylaxis with rifampin or ceftriaxone for pharyngeal carriage of N. meningitidis was investigated among residents of Jedda, a city of 1.5 million people 72 km from Mecca. All persons with suspected meningococcal disease in Jedda were cared for at a single infectious disease hospital. Cases of meningococcal disease were defined on the basis of CSF or blood cultures that were positive for N. meningitidisor on the basis of a comparable clinical syndrome (purulent CSF in association with high protein and low glucose levels). Household contacts of patients were included in the study if they had not received prior chemoprophylaxis. In addition, 125 laborers who were living in a small 16-room compound with a patient with meningitis were included. Case households were randomized to receive rifampin or ceftriaxone, family members were interviewed to determine risk factors for disease or carriage, and oropharyngeal swab specimens were obtained for culture. Antibiotic prophylaxis was then administered. The rifampin regimen was 600 mg for adults and 10 mg/kg for children, twice a day for 2 days. The first dose was taken in the presence of the study team. Ceftriaxone was given in a single im dose of 250 mg for adults and 125 mg for children under 15 years of age. The ceftriaxone was diluted in 1% lidocaine to decrease the pain of injection, and all recipients were observed for 30 minutes following injection for possible reactions (none occurred). For each case household, a random neighborhood control
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on July 2, 2015
mittee on Immunization Practices recommended prophylactic treatment of persons who had contact with patients with meningococcal disease in specific high-risk settings, including within households, day care centers, and closed populations such as the military. Unless the causal organism is known to be sensitive to sulfadiazine, the drug of choice is rifampin (oral administration of a 600-mg dose twice a day for 2 days is recommended) [1]. This recommendation is based on results of studies that show a secondary attack rate among household contacts of patients with meningococcal disease of ""700/100,000 and among day care contacts of such patients of ""400/100,000 [2]. A study by Munford et al. of an outbreak of group C meningococcal disease in Brazil showed a secondary attack rate of 1.6% among household contacts [3]. Most secondary cases occur within the first week following exposure, but risk of infection continues to be increased for 1-2 months. In a study of secondary meningococcal infections in Belgium, when coprimary cases were eliminated, about half of the secondary cases occurred within the first week following exposure, 20 % occurred in the second week, and the remaining 30 % occurred thereafter [3]. These data emphasize the importance of providing prophylaxis early as well as the value ofproviding prophylaxis up to several weeks following exposure. Although the Advisory Committee on Immunization Practices recommends rifampin as the agent of choice for prophylaxis of meningococcal disease, there are several disadvantages attendant with its use: it fails to eradicate meningococci in 20 % of patients who carry these organisms in the pharynx [4], and meningococcal disease has been documented to occur following prophylaxis [5]. Adverse effects, including headache, dizziness, and gastrointestinal symptoms, occur in one-quarter of patients who receive prophylaxis with rifampin [6]; the drug is teratogenic in animals and is not recommended for use during pregnancy. Availabilityof a suspension formulated for children is limited, and because of potential toxicity, dosing for children must adhere to a milligram per kilogram basis. The four-dose regimen and the frequency of adverse effects may discourage compliance. In addition, several studies havedocumented the emergence of resistant strains of meningococci following prophylactic treatment with this drug [7, 8]. In 1987 an outbreak of group A meningococcal meningitis occurred in Saudi Arabia that provided an opportunity to evaluate the efficacy of rifampin as compared with ceftriaxone, a third-generation cephalosporin, for prophylaxis of meningococcal disease. The choice of ceftriaxone as a potential chemoprophylactic agent was based on the drug's low MIC for N. meningitidis, on the fact thata high level of concentration in saliva can be achieved that exceeds the MIC for >24 hours following a single im dose [9], and on the fact that a low incidence of adverse reactions is associated with its use. A single im dose of ceftriaxone has been shown to be effective for the eradication of pharyngeal Neisseriagonorrheae;
S171
Schwartz
Sl72
Table 1. Participants in a study of antimicrobial prophylaxis for pharyngeal carriage of N. meningitidis, Jedda, 1987. Study group Case contacts Treated with ceftriaxone Treated with rifampin Controls
No. in group
No. (%) of carriers
347 179 168 124
116 (33) 75 (42) 41 (24) 16 (13)
Table 2. Efficacy of prophylaxis during an outbreak of group A meningococcal disease, Jedda, 1987. No. of patients cured/total no. of patients (%) Treatment Ceftriaxone Rifampin No antibiotics
1w
2w
66/68 (97) 27/36 (75)*
62/64 (97) 22/27 (81)t 5/12 (42)
2/10 (20)
NOTE. This table was reprinted with permission from Lancet [II]. * After I week, P = .001 when treatment with ceftriaxone was compared with treatment with rifampin. t After 2 weeks, P = .02 when treatment with ceftriaxone was compared with treatment with rifampin.
received either prophylactic agent. The most commonly reported adverse effectamong recipients of ceftriaxone was headache, which was mentioned by 12 % of recipients. However, because of differences in language and culture, the accuracy of reports of minor adverse effectsis doubtful. Antibiotic sensitivity testing was done on a sample of 17 isolates of N. meningitidis. For all isolates, the MIC of ceftriaxone was
