1. Update Treatment and Prophylaxis of Pertussis with Macrolide Antibiotics
Tejpratap Tiwari, M. D.,
Bacterial Vaccine Preventable Diseases Branch
Epidemiology and Surveillance Division
National Immunization Program
Centers for Disease Control and Prevention
National Immunization Conference
March 22, 2005
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2. Background: Erythromycin
Accepted antibiotic of choice for pertussis treatment, prophylaxis
Usually recommended as 14-day course to prevent bacteriologic relapse
Inexpensive
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3. Erythromycin Compliance and Safety
Compliance: ~20% patients discontinue
Gastrointestinal side effects (~30%)
Demanding regimen (3- 4 daily doses, 14 days)
Safety
Increased risk infantile hypertrophic pyloric stenosis (IHPS), infants <2 weeks old*
Drug-interactions, cytochrome P450
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*Mahon et al. J Pediatr 2001;139:380 –4

4. Azithromycin and Clarithromycin vs Erythromycin
Good in vitro activity against Bordetella pertussis
More resistant to acid pH, better absorbed
Greater tissue concentrations, longer plasma half-life
Fewer (1 or 2) daily doses, shorter course (5 days or 7 days)
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5. Azithromycin (A) and Clarithromycin (C) Clinical Studies
Author (Year)
Study Design
Control Group
Study Arms
Aoyoma et al. 1996)
Randomized
Historical control group
A (8) , C( 9) v
E(16, 18)
Bace et al. (1999)
Non-comparative
Safety, two dose regime
A (17) v A (20)
Bace et al. (2000)*
Erythromycin
A(9) v E(15)
Pichichero (2003)
Historical studies
A (34)
Langely et al. (2004)
Erythromycin group
A( 58) v E (57)
Lebel et al. (2001)
C (31) vs E (23)
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*Abstract

6. Treatment for Pertussis by Age-group
Erythromycin
Clarithromycin
Azithromycin
>6 mth
40-50 mg/kg/d in 4 divided doses (max 2 gm/d) X 14 d
15 mg/kg/day in 2 divided doses (max 500 mg/dose) X 7 d
10 mg/kg/day (max 500 mg) single dose on day 1 then 5 mg/kg/day (max 250mg) on day 2 –5
1-5 mth
As above
10 mg/kg/day, single daily dose X 5 d
<1 mth
Use as alternate drug in doses above (Risk of IHPS)
(Safety data unavailable)
Preferred drug
Dose as above
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7. Summary Macrolides, preferred antimicrobial agents
Erythromycin, clarithromycin, or azithromycin are appropriate first-line agents for persons age >1 month
Azithromycin, preferred choice for infants <1 month of age
Use TMX-SMZ as alternate agent
Consider safety, evaluate concurrent medications for potential interactions, adherence to the prescribed regimen, and cost
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8. Acknowledgements CDC/NIP
Colleagues at Bacterial VPD Branch, Epidemiology and Surveillance Division
AAP/COID
AAFP
HICPAC

9. Thank You

10. RED BOOK 2003: Pertussis Treatment
“The drug of choice is erythromycin estolate (40 –50 mg per day, orally in 4 divided doses; maximum 2 g/day. The recommended duration of therapy to prevent relapse is 14 days.
Studies have documented that the newer macrolides, azithromycin dihydrate (10–12 mg kg per day, orally, in 1 dose for 5 days; maximum 600 mg day) or clarithromycin (15–20 mg/kg per day, orally, in 2 divided doses; maximum 1 g/day for 7 days), may be as effective as erythromycin and have fewer adverse effects and better compliance.”
In the US, health-care providers and state health departments frequently consult with AAP/COID’s RED BOOK for guidance on treatment and drug dosing for pertussis.
The current COID/AAP report (RED BOOK 2003) states that
“The drug of choice is erythromycin estolate (40 –50 mg per day, orally in 4 divided doses; maximum 2 g/day. The recommended duration of therapy to prevent relapse is 14 days.
Studies have documented that the newer macrolides, azithromycin dihydrate (10 –12 mg kg per day, orally, in 1 dose for 5 days; maximum 600 mg day) or clarithromycin (15 –20 mg/kg per day, orally, in 2 divided doses; maximum 1 g/day for 7 days), may be as effective as erythromycin and have fewer adverse effects and better compliance is appropriate.”
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11. EXTRA SLIDES

12. HICPAC Guidelines, 2004 Pertussis Treatment and Prophylaxis
Adults
Erythromycin estolate, 500 mg, 4 times/day
Erythromycin delayed-release tablet, 333 mg, 3 times daily,
Children age >2 weeks,
Erythromycin 40–50 mg/kg day for 14 days
Infants aged <2 weeks, or adults intolerant to EE
Azithromycin 10–12 mg/kg/day x 5–7 days
Azithromycin 10mg/kg on Day 1 then 5 mg/kg/day x 4 days (single dose)
Clarithromycin for 10–14 days 15–20 mg/kg/day in two divided doses
New HICPAC’s “Guidelines for Preventing Health-Care Associated Pneumonia, 2003” was published earlier this year. Note the recommendation of a tid dosing schedule using delayed-release erythromycin preparations for pertussis in adults and
the recommendation for azithromycin as the preferred first line agent in infants <2 weeks of age.
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13. Minimum 7-day course of macrolide antibiotics
Control of Communicable Diseases, 2004 Pertussis Treatment and Prophylaxis
Treatment
Minimum 7-day course of macrolide antibiotics
Chemoprophylaxis (selective)
A 7-day course of erythromycin, clarithromycin or azithromycin
And even more recently, the 2004 edition of the Control of Communicable Diseases in Man (from APHA) has recommended:
Minimum 7-day course of macrolide antibiotics for treatment, and for chemoprophylaxis (for selective contacts).
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14. Langley et al., 2004 * Azithromycin vs Erythromycin
Multi-center, randomized, equivalence trial
Suspect pertussis cases (n=477), aged 6 months –16 years
Azithromycin (n=238)
10 mg/kg single dose day 1; then
5mg/kg/day single daily dose days 2–5
Erythromycin estolate (n=239)
40 mg/kg/day, 3 doses/day x 10 days
Of the two other studies, Langley and co-workers in Canada
recently published results from a multi-center, open, randomized, equivalence clinical trial, that compared azithromycin and erythromycin estolate treatments for pertussis
477 suspected cases of pertussis, with age ranging from 6 months to 16 years, were enrolled and randomized to receive either
Azithromycin 10 mg/kg single dose on day 1 then 5 mg/kg/day as a single daily dose on day 2–5 (n=238) OR
Erythromycin estolate 40 mg/kg/day in 3 divided doses x 10 days (n=239)
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*Langley et al. Pediatrics 2004;114:96 –101

15. Langley et al., 2004* Safety Cohort (N=477)
Rate of gastrointestinal adverse events
Azithromycin group (n=238): 18%
Erythromycin group (n=239): 40%
Compliance with 100% doses
Azithromycin, 90%
Erythromycin, 55%
All 477 enrolled participants who received more than 1 dose of either agent were evaluated for adverse events.
Gastro intestinal side effects were significantly different in the two study groups. In the azithromycin group, 18% of persons reported GI adverse events as compared to 40% in the erythromycin group.
Children who were randomized to the Azithromycin group were more likely to comply with antimicrobial therapy.
90% in the azithromycin group took 100% of doses as compared to 55% in the erythromycin group.
Did anyone discontinue treatment???
*Langley et al. Pediatrics 2004;114:96 –101
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16. Efficacy Cohort* Culture-confirmed pertussis (N=114)
Bacterial eradication at end of treatment
Azithromycin (days 5 –7)
(n=53), 100% (95% CI:93–100)
Erythromycin (days 10 –12)
(n=53), 100% (95% CI: 93 –100)
Recurrence, 1 week post-treatment
Azithromycin (n=51), 0% (95% CI: 0–7)
Erythromycin (n=53), 0% (95% CI: 0–6.7)
All culture-confirmed pertussis cases at enrollment were included in an analysis of treatment efficacy per protocol using bacterial eradication rates at the end of treatment, and relapse rate 1 week after completion of treatment as end points.
Post-treatment bacterial eradication rates were 100% in both groups (for all cases with available cultures) [Azithromycin group (n=53/53), erythromycin group (n=53/53)].
The difference in failure rates between the two groups was 0% (95% CI 0,6; 7)
No recurrence was observed 1 week post-treatment (in patients who were culture negative at the end of treatment) in either group for cases with available culture.
Azithromycin (n=51), erythromycin (n=53).
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*Langley et al. Pediatrics 2004;114:96 –101

17. Lebel et al., 2001* Clarithromycin vs Erythromycin
Randomized, prospective, single-blind
Compared safety, efficacy
Suspect pertussis (n=153)
Ages 1 month –16 years
Erythromycin estolate, 40 mg/kg/day (max 1 gm daily), 3 doses/day X 14 days (n=77)
Clarithromycin, 15 mg/kg/day (max 1 gm daily), 2 doses/day X 7 days (n=76)
[In the 6th study, another Canadian study], Lebel et al. 2001, reported on a prospective, single blind (investigator), randomized study, that compared the safety and efficacy of clarithromycin, and erythromycin treatments for pertussis.
133 clinical pertussis cases with ages ranging from 1 month and 16 years, assigned to a course of either
Erythromycin estolate 40 mg/ kg/day (maximum 1 gm daily) administered in 3 divided daily doses for 14 consecutive days (N=77) OR
Clarithromycin 15 mg/kg/day in 2 divided doses for seven days (N=76).
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*Lebel et al. PIDJ 2001;20:1149 –54.

18. Lebel et al., 2001* Safety Cohort (N=153)
Rates of gastrointestinal adverse events
Clarithromycin (n=76): 32%
Erythromycin (n=77): 44%
Compliance (mean % of drug taken)
Clarithromycin, 98.5%
Erythromycin, 88.6%
All 153 enrolled participants were included in an analysis of adverse events.
The occurrence of gastrointestinal adverse events was lower in the clarithromycin group (32%) as compared to the group that received erythromycin (44%).
Compliance was significantly better in the clarithromycin group (mean, 98.5%) as compared to the erythromycin group (mean 88.6%).
Four patients discontinued treatment (EE-3 (Rash, V & Diarr, V & R & Abd pain); CLAR -1 (vomiting)
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*Lebel et al. PIDJ 2001;20:1149 –54.

19. Efficacy Cohort Culture-confirmed pertussis (N=62)
Post-treatment bacterial eradication similar
Clarithromycin (days 8–10 ), (31/31)
Erythromycin (days 15–18), (22/23)
Study limitation
Sample size insufficient to demonstrate equivalence
Cases with a positive culture at the time of of enrolment were included in the analysis for efficacy of treatments. (ITT; C27, E35) ;
The end point was -ive NP cultures for B. pertussis on completion of Rx and at 1 month for cases with +ive post-treatment cultures.
Post treatment bacterial eradication was similar for both groups
A study limitation was though there was no difference in microbiologic eradication rates between the Rx groups, the enrolled sample size was insufficient to demonstrate equivalence of Rx.
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Lebel et al. PIDJ, 2001;20:1149 –54.

20. Azithromycin, Clarithromycin Safety in Infants Age <6 months
Not labeled for use in infants <6 months age*
No published report IHPS or severe adverse events in neonates
Neither azithromycin nor clarithromycin is labeled for use in infants <6 months of age.
There are no published reports on the use of azithromycin or clarithromycin in infants <6 months or of case reports of IHPS in infants following azithromycin use.
Limited data are available for azithromycin use in neonates. In a report pending publication, IHPS was not observed among a small sample of neonates (58) who received azithromycin for prophylaxis against pertussis. In the Lebel study, serious adverse events were not observed in the subset of 19 children ages <6 months (C=19, E=18) *
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21. Macrolides Safety: FDA Pregnancy Label
Erythromycin, azithromycin (Category B)
Animal studies, no adverse effect on fetus
No clinical trials in pregnant women
Clarithromycin (Category C)
Animal studies, adverse effects on fetus
No clinical trials in pregnancy
Both Erythromycin and azithromycin are labeled a Category B Drug for pregnancy by the FDA.: meaning that while there is no evidence of impaired fertility or harm to the fetus due to erythromycin or azithromycin in animal studies, there are, however, no well-controlled studies in pregnant women to demonstrate safety.
 Clarithromycin is labeled a Category C Drug for pregnancy by the FDA.: There is evidence of harm to the fetus due to clarithromycin in animal studies (cleft lip, cardiovascular anomalies) . There are however, no adequate and well-controlled studies in pregnant women. .
However, animal reproduction studies are not always predictive of human response. One prospective study* that enrolled 157 women exposed to clarithromycin in early pregnancy reported no significant elevation of rates of major or minor malformations.
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22. HIPAC Guidelines Hypersensitivity to Macrolides
Adults:
Trimethoprim (TMP) –sulfamethoxazole (SXT) 1 double-strength tablet, twice daily X 14 days
Children:
8 mg/kg/day TMP, 40 mg/kg/day SXT, divided doses
Exception:
Pregnant woman at term
Nursing mother
Infant aged <2 months)

23. Differences in Microbiologic Eradication Rates, 95% CI
Author (Year)
Microbiologic Eradication Rate (%)
Comparison Groups
Difference between rates (95% CI)
Aoyama (1996)
A – 100 (8/8)
C – 100 (9/9)
E – 89 (16/18)
A (8) v E (16)
C (9) v E (18)
11 (-24 –34)
11 (-23 –34)
Bace (2000)
A – 100 (9/9)
E – 100 (15/15)
A(9) v E (15)
0 (-33 –21)
Lebel (2001)
C – 100 (31/31)
E – 96 (22/23)
C (31) v E (23)
4 (-7 –22)
Halperin (2004)
A – 100 (53/53
E – 100 (53/53)
A v E
0 (-7 –7)
(Although with limited sample size) All these studies, show an overall trend of effectiveness similar to that of erythromycin
In addition, the newer macrolide groups experienced fewer adverse events as compared to erythromycin.
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