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Three Part Question

In [a child diagnosed with whooping cough] are [Azithromycin or Clarithromycin compared with Erythromycin] as effective in [eradicating infection with fewer side effects]

Clinical Scenario

You are assessing a toddler who has presented with paroxysmal cough with a whoop and post tussive vomiting. A clinical diagnosis of 'whooping cough' is made and this is duly confirmed on pernasal swab cultures that reveal the growth of Bordetella pertussis (B. pertussis).
From history, you note that he is allergic to Penicillin and has been given Erythromycin for a previous episode of tonsillo– pharyngitis. His mother recalls that he suffered severe abdominal pain when taking it and did not complete the course. You wonder whether newer macrolides such as Azithromycin or Clarithromycin could be effective alternatives to Erythromycin for the treatment of Pertussis in this setting.

Search Strategy

Medline via Pubmed
Pertussis OR Whooping Cough and combining the search with Azithromycin, Clarithromycin separately. This was verified by an alternative search method using MeSH heading "Whooping Cough" and subheading "drug therapy" [MeSH]. Five relevant articles were found.
Secondary sources: Cochrane database and Best Bets. No further papers were identified.

Search Outcome

5 articles

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Langley et al 2004	477 children ( 6 mo – 16 Yr) with clinical symptoms of Pertussis were randomised to receive either Azithromycin (10 mg/Kg on day 1 followed by 5 mg/Kg once a day for 4 more days.) OR Erythromycin estolate (40 mg/Kg/day in 3 divided doses for 10 days).	Multicenter Randomised control trial. (1b)	Bacteriologic eradication: Negative cultures at the end of treatment.	Azithromycin group: 53 / 53 Vs Erythromycin group: 53 / 53. (Eradication 100 %.95 % C.I: 93.3 -100).	Group assignment not blinded after randomisation. Positive Nasopharyngeal (NP) cultures for Pertussis were found in 58/ 239 (Azithromycin group) and in 56/ 238 (Erythromycin group) Post treatment cultures not available on all subjects.
			Relapse: Positive cultures a week after end of treatment.	Azithromycin group : 0/51 (0 %;95 % C.I : 0- 7.0) Vs Erythromycin group: 0/ 53 (0 %; 95 % C.I: 0- 6.7)
			Adverse GI events:(parent completed diary)	Azithromycin Vs Erythromycin groups: Overall incidence of GI side effects were 18 .8 % Vs 41.2 %, NNT = 4.46. Nausea (2.9% Vs 8.4%; 95% CI: -8.9% to -2.0% ; NNT 18.1), vomiting (5.0% Vs 13.0%; 95% CI: -4.9% to -1.4% ; NNT= 12.5) Diarrhoea (7.1% Vs 11.8%; 95% CI: -9.0% to -0.3%; NNT = 21.2). No serious adverse events were recorded in either group.
			Compliance: (inspection of medication containers	90 % in the Azithromycin group Vs 55 % in the Erythromycin group.
Lebel et al 2001	153 children (< 16 yr ) with clinical symptoms of Pertussis received either Clarithromycin 7.5 mg/Kg /dose twice a day for 7 days (n=76) OR Erythromycin (13.3 mg/Kg/dose three times a day for 14 days (n =77).	Prospective randomised single blind trial. (1b)	Bacteriologic eradication: Negative post treatment cultures.	Negative post treatment cultures recorded in 31/ 31 on Clarithromycin (100 %; 95 % C.I: 88.8 -100).Vs 22/23 with Erythromycin (96%; 95 % C.I: 78.1 -99.9%).	35/ 76 in the Clarithromycin group and 27/ 77 in the Erythromycin group had positive cultures of B. Pertussis. 90% of subjects were appropriately immunised against pertussis. Post treatment cultures not available on all subjects.
			Adverse GI events	Seen in 45 % of those on Clarithromycin Vs 62 % of those on Erythromycin. (p = 0.035; NNT = 5.8)
			Compliance: (inspection of medication containers)	Mean percent of drug taken by the Clarithromycin group was 98.5% Vs 88.8 % by the Erythromycin group ( p <0.001
Pichichero et al 2003	34 subjects (29 culture positive and 5 PCR positive) were all given Azithromycin. (10 mg/Kg on day1 followed by 5 mg/Kg once a day for 4 more days.)	Prospective, open labelled, non comparative trial. (2b)	Bacteriologic eradication: Negative cultures / PCR at days 2-3 of treatment and days 14-21 post treatment.	1/ 34 (3 %) had positive cultures at 2-3 days on treatment.	Study group heterogeneous. No subset analysis available. 5 of the 34 subjects were adults. (Parents of children), 12 were between 10-20 yr of age and 17 were from the age of 6 mo to 10 yrs
			Adverse events	No serious adverse events recorded.
			Compliance	Reported 100 %.
Bace et al 1999	37 subjects with culture proven Pertussis. Mean age of patients 7.5 months (range 2- 18 months).60 % of them were not immunised against Pertussis. All received Azithromycin. Dose : 10 mg/Kg on day1 followed by 5 mg/Kg once a day for 4 more days (n=17) Vs 10 mg/Kg once daily for 3 days only (n=20)	Prospective, open labelled, non comparative trial. (2b)	Bacteriologic eradication: Negative cultures on day 7, 14 after commencement of treatment.	Positive cultures on day 7: 2/19 in the 3 day group (10.5%) Vs 0/16 in the 5 day group. 100 % bacterial eradication was seen on day 14 (0/16 Vs 0/16) in both groups.	Allocation criteria to either regime unclear. Relationship of transaminitis to dose used unclear.
			Relapse: Positive cultures on day 21 after start of treatment.	1/ 14 patients on the 3 day course (7.1 %). None on the 5 day course.
			Adverse events	Transient increase in liver enzyme ALT noted in up to 20.6 % of all subjects.
Aoyama et al 1996	17 patients (0- 13yrs) with culture proven Pertussis. 8/17 received Azithromycin (10 mg/Kg once a day for 5 days) while 9/17 received Clarithromycin (10 mg/Kg /day in two divided doses for 7 days). Each study subject was matched with two historical controls treated with Erythromycin (40-50 mg/Kg /day in three divided doses for 14 days). 58.8 % of subjects were not immunised against Pertussis.	Two separate open labelled trials using historical controls. (4)	Bacterial eradication: negative culture on 1 week after treatment	8 / 8 with Azithromycin (100%, 95% CI: 68.8-100%) Vs 13/16 (81 %, 95% CI: 54.4-96%) among controls given Erythromycin. 9 / 9 with Clarithromycin (100 %, 95% CI: 71.1-100%) Vs 16/ 18 (88.8%, 95% CI: 65.3-98.6%) among controls given Erythromycin.	Historical controls. Allocation criteria to medications unclear. Small study group.
			Relapse: positive culture at 2 weeks after treatment	None in either study or control groups.

Comment(s)

Antimicrobials are usually administered when Pertussis is suspected or confirmed .If the disease is already established (paroxysmal phase), antibiotics have little or no effect on the clinical course of the illness except to render the patient non infectious to others. This is important, so as to limit the spread of infection especially to the un immunised and young infants. A 2 week course of Erythromycin is the long established treatment for Whooping cough (American Academy of Pediatrics). It is known to reduce transmission and hasten clearance of B. Pertussis (Pichichero). However, gastrointestinal side effects seem quite limiting in a large proportion of patients treated with it (Halperin). This may have a bearing in ensuring compliance. Newer macrolides - Clarithromycin and Azithromycin are superior to Erythromycin in terms of absorption, acid stability and tissue penetration. They have longer half-life enabling less frequent dosing and shorter treatment courses (Aoyama). They are also known to have fewer side effects. From the available evidence it can be seen that the newer macrolides are at least as effective as Erythromycin to eradicate B. Pertussis infection. A significant reduction in adverse gastrointestinal side effects and a better compliance have been demonstrated. No serious side effects have been observed with these agents so far. Transient elevation in Alanine aminotransferase (ALT) has been demonstrated in Pichichero's study. Regarding prophylaxis, the current UK guideline is to administer a 7-day course of erythromycin, if a clinically suspected or confirmed case of pertussis is identified. The aim is to protect those at risk from pertussis – infants, especially neonates, all household contacts who are unimmunized and contacts who are 5 years or older if they did not receive a pre-school pertussis booster. There is no evidence of any benefit from chemoprophylaxis given more than 21 days from the date of onset of the primary case. Unimmunized or partially immunized cases and contacts should complete their course of vaccine (Dodhia). Clarithromycin and Azithromycin are potential, but not proven alternatives to Erythromycin for prophylaxis at present.

Clinical Bottom Line

A 5 day course of Azithromycin or a 7 day course of Clarithromycin is as effective as a 10- 14 day course of Erythromycin to eradicate Bordetella Pertussis infection. Azithromycin and Clarithromycin have fewer gastrointestinal side effects than Erythromycin. Patient compliance is better on the newer macrolides compared to Erythromycin.

References

1. Langley JM, Halperin SA, Boucher FD et al. Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics. 2004; 114(1): 96-101.
2. Lebel MH, Mehra S. Efficacy and safety of clarithromycin versus erythromycin for the treatment of pertussis: a prospective, randomized, single blind trial. Pediatr Infect Dis J. 2001; 20(12):1149-54.
3. Pichichero ME, Hoeger WJ, Casey JR. Azithromycin for the treatment of pertussis. Pediatr Infect Dis J. 2003; 22(9):847-9.
4. Bace A, Zrnic T, Begovac J et al. Short-term treatment of pertussis with azithromycin in infants and young children. Eur J Clin Microbiol Infect Dis. 1999;18(4):296-8.
5. Aoyama T, Sunakawa K, Iwata S et al. Efficacy of short-term treatment of pertussis with clarithromycin and azithromycin. J Pediatr. 1996; 129(5):761-4.
6. American Academy of Pediatrics. Pertussis. In: Pickering LK, ed. Red Book: 2003 Report of the Committee of Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2003:474.
7. Halperin SA, Bortolussi R, Langley JM, et al. Seven days of erythromycin estolate is as effective as fourteen days for the treatment of Bordetella pertussis infections. Pediatrics. 1997; 100:65 –71.
8. Dodhia, NS Crowcroft, J.C. Bramley and E. Miller. UK guidelines for use of erythromycin chemoprophylaxis in persons exposed to pertussis. Journal of Public Health Medicine 2002; 24:3:200-206.