The causative agents of pertussis disease, Bordetella pertussis and Bordetella parapertussis, are susceptible to a range of antibiotics in vitro, including penicillins, macrolides, ketolides, quinolones, tetracyclines, chloramphenicol and trimethoprim-sulfamethoxazole. B. pertussis shows in vitro resistance to most oral cephalosporins.1 However, in contrast to other bacterial diseases, the exact relationships between the pharmacokinetics and pharmacodynamics of these antibiotics in vivo and the in vitro susceptibility of the organism are unknown. Also in contrast to other bacterial diseases, the effect of the antibiotics on the symptoms of pertussis is not well-documented.
ANTIBIOTIC SUSCEPTIBILITY TESTING OF B. PERTUSSIS
Because of the complex and technically demanding nature of the procedures, antibiotic susceptibility testing of clinical isolates of B. pertussis is rarely done in practice. The culture of B. pertussis can be done only on special media, such as Bordet-Gengou medium or charcoal-horse blood agar. Furthermore, in contrast to other bacteria, methods for antibiotic sensitivity testing of the organism are not standardized. If testing is performed, methods include macro- and microbroth dilution, agar dilution methods, breakpoint methods and the E-test.2 Conventional disk diffusion methods are not feasible, because their results are not reproducible.3
Another reason for not performing routine antimicrobial testing is that no data support an increasing antimicrobial resistance. Since 1994, very few cases of erythromycin-resistant isolates have been published, and there are no data to suggest that the resistance is spreading.4–6 The mechanism for erythromycin resistance has been identified as a mutation of the erythromycin-binding site in the bacterial 23S ribosomal RNA gene.7 With this evidence, a recent review article concluded that routine antibiotic susceptibility testing of B. pertussis isolates is not necessary.1 However, monitoring of the antimicrobial susceptibility of the organism should be continued on selected isolates as part of an overall surveillance system.
ANTIBIOTIC TREATMENT OF PERTUSSIS
Erythromycin is regarded to be the treatment of choice for the management of B. pertussis infection.1,8 It is given mostly as erythromycin estolate, because of its higher levels of active antibiotic in respiratory tract secretions. However, erythromycin ethylsuccinate has also been effective and can be used in countries where erythromycin estolate is not licensed.9
To eradicate detectable bacteria from the upper respiratory tract, a 14-day course of erythromycin is often recommended,1 based on the observation that very few patients harbored detectable B. pertussis in their airways after 7–10 days of treatment. The 2003 Red Book 10 recommends 15–20 mg/kg/d divided into 4 doses, with a maximum of 2 g/d. However, a recent study has shown a similar efficacy of a 7-day treatment regimen with erythromycin estolate 40 mg/kg/d, compared with a standard 14-day course.11 When begun after pertussis symptoms became evident, both regimens resulted in negative cultures after 5–7 days and prevented a relapse in coughing frequency. Erythromycin treatment in infants younger than 2 weeks of age has been associated with pyloric stenosis.10,12–14
Azithromycin is effective against B. pertussis in vitro, and studies have shown that 3- to 5-day courses are as effective as a 14-day course of erythromycin for eradication of detectable B. pertussis in infants and young children.15–17 The Red Book recommends that azithromycin should be taken at a dosage of 10–12 mg/kg/d, once daily for 5 days.10 Persistence of positive culture after treatment with azithromycin has been reported, but the reason for the failure was unclear.8
Clarithromycin has been shown to possess in vitro activity similar to that of erythromycin, and a 7-day course was as effective in eradicating detectable B. pertussis as the standard 14-day course of erythromycin.15,18 In addition, the compliance was significantly higher in the clarithromycin-treated patients because of a reduced incidence of adverse events. The Red Book recommends a dosage of 15–20 mg/kg/d, divided in 2 doses, with a maximum of 1 g/d given for 7 days.10
Because of its mode of action comparable with that of erythromycin and its similarity in pharmacokinetics, roxithromycin can also be used, for empiric reasons, in treating B. pertussis infection.15
Consequently newer macrolides such as azithromycin or clarithromycin may replace erythromycin as the standard for treatment of B. pertussis infection because they achieve higher concentrations in respiratory secretions. These macrolides also have fewer gastrointestinal side effects, which are frequent with erythromycin and limit its compliance.1 Some concern has been raised about whether correct biometric methods to compare the equivalence with erythromycin therapy have always been used in published studies.19
Trimethoprim-sulfamethoxazole may also be an acceptable alternative to macrolide treatment of B. pertussis infection in adolescents and adults. However, clinical data with this treatment are rare. The same is true for the fluoroquinolones (ciprofloxacin and moxifloxacin), which have good in vitro activity against B. pertussis and may have potential use for the treatment of B. pertussis infection in adults. As yet, however, no supporting clinical data are available.1
The use of quinolones in children is controversial, because of potential adverse events20; in many countries, the quinolones are not licensed for use in children.
Most studies on the antibiotic therapy for B. pertussis infection agree that macrolides (and probably other antibiotics) reduce the bacterial load in the upper airways, leading to negative culture in most cases after 5–7 days, and that the therapy will thus reduce the infectiousness of the patient.
EFFECT OF ANTIBIOTIC THERAPY ON DISEASE DURATION AND SYMPTOMS
Very few studies have used clinical endpoints to determine the efficacy of antibiotic therapy for B. pertussis infection. Erythromycin, when given early (during the catarrhal phase) in the course of the disease, has been shown to reduce the severity and the duration of disease.21 Controversial results have been reported about its efficiency when treatment was started during the paroxysmal phase. One German study reported a decrease of coughing intensity,9 whereas other studies found no effect.1,8,22 Although expert opinion on this point is somewhat divided because of the lack of clinical data, the Red Book summarizes that “antimicrobial agents given during the catarrhal phase may ameliorate the disease. After paroxysms are established … antimicrobial agents usually have no discernible effect on the course of the illness.”10
PROPHYLAXIS/PREVENTION OF PERTUSSIS
Active immunization against pertussis with whole cell and/or acellular pertussis vaccines is the mainstay for prevention of disease and should always remain the “first-line” approach.23
Outbreak Prophylaxis in Children.
Close contact with a case of pertussis represents a serious risk for acquiring the infection in unvaccinated individuals; thus, in Canada, azithromycin, clarithromycin or erythromycin prophylaxis is recommended for close household contacts of patients with pertussis, with some clinical data supporting its use.24 The U.K. guidelines restrict the use of erythromycin prophylaxis only for the protection of those with greatest risk from pertussis, that is, young infants.25 One study suggests that when the index case has had paroxysmal cough for >11–12 days, erythromycin prophylaxis is not effective in preventing spread of disease in households, and it may have no effect in preventing clinical pertussis.26 As a consequence, the U.K. guidelines point out that there is no benefit from erythromycin chemoprophylaxis given >21 days from the date of onset of the primary case.
Outbreak Prophylaxis in Adults.
The optimum dosage and duration of erythromycin prophylaxis in adults are unknown; thus the 14-day, 3 times daily or 4 times daily treatment regimens with up to 2 g/d are recommended, although its (predominantly gastrointestinal) side effects significantly limit patient compliance.1,27 As an alternative, azithromycin was used in a study of a hospital-wide outbreak of a pertussis-like illness; and after 4 weeks, the outbreak rapidly resolved.27 Approximately 82% of patients who received azithromycin prophylaxis were fully compliant for all days of therapy. An evidence-based review of literature on the use of erythromycin in preventing secondary transmission of pertussis to close contacts of primary cases found that apart from prophylaxis in newborns,28 erythromycin had little effect in preventing secondary transmission.29 The authors concluded that in countries where effective pertussis vaccines are in use, erythromycin prophylaxis should be confined to close contacts of cases, particularly unimmunized or partially immunized infants, who would be most susceptible to the complications of pertussis, or adults who come in close contact with those vulnerable children.29
Pertussis is still a major, global, public health threat that primarily needs to be tackled with national immunization programs. However, antibiotics have a role in the prevention and management of pertussis disease.
Although erythromycin is regarded as the standard therapy for pertussis, clarithromycin and azithromycin appear to be equally effective and less reactogenic. The treatment reduces the infectivity and ameliorates symptoms when given early in the course of the disease. For outbreak prophylaxis, erythromycin has been shown to be efficacious, but azithromycin, clarithromycin and other macrolides are superior in terms of their higher levels in respiratory secretions and reduced gastrointestinal toxicity and, therefore, should be preferred treatments over erythromycin.
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