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 Note: place CDC logo on all slides except #1 – Title slide

Background: Erythromycin Accepted antibiotic of choice for pertussis treatment, prophylaxis Usually recommended as 14-day course to prevent bacteriologic relapse Inexpensive Note: place CDC logo on all slides except #1 – Title slide

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 Note: place CDC logo on all slides except #1 – Title slide *Mahon et al. J Pediatr 2001;139:380 –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) Note: place CDC logo on all slides except #1 – Title slide

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) Note: place CDC logo on all slides except #1 – Title slide *Abstract

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 Note: place CDC logo on all slides except #1 – Title slide

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 Note: place CDC logo on all slides except #1 – Title slide

Acknowledgements CDC/NIP Colleagues at Bacterial VPD Branch, Epidemiology and Surveillance Division AAP/COID AAFP HICPAC

Thank You

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.” Note: place CDC logo on all slides except #1 – Title slide

EXTRA SLIDES

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. Note: place CDC logo on all slides except #1 – Title slide

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). Note: place CDC logo on all slides except #1 – Title slide

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) Note: place CDC logo on all slides except #1 – Title slide *Langley et al. Pediatrics 2004;114:96 –101

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 Note: place CDC logo on all slides except #1 – Title slide

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). Note: place CDC logo on all slides except #1 – Title slide *Langley et al. Pediatrics 2004;114:96 –101

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). Note: place CDC logo on all slides except #1 – Title slide *Lebel et al. PIDJ 2001;20:1149 –54.

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) Note: place CDC logo on all slides except #1 – Title slide *Lebel et al. PIDJ 2001;20:1149 –54.

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. Note: place CDC logo on all slides except #1 – Title slide Lebel et al. PIDJ, 2001;20:1149 –54.

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) *http://pdrel.thomsonhc.com/ Note: place CDC logo on all slides except #1 – Title slide

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. Note: place CDC logo on all slides except #1 – Title slide http://pdrel.thomsonhc.com/

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, 2 divided doses Exception: Pregnant woman at term Nursing mother Infant aged <2 months)

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. Note: place CDC logo on all slides except #1 – Title slide