Update Update Treatment and Prophylaxis Treatment and Prophylaxis of Pertussis with Macrolide of Pertussis with Macrolide

AntibioticsAntibioticsTejpratap Tiwari, M. D.,

Bacterial Vaccine Preventable Diseases Branch Epidemiology and Surveillance Division

National Immunization ProgramCenters for Disease Control and Prevention

National Immunization ConferenceMarch 22, 2005

Background: ErythromycinBackground: Erythromycin

• Accepted antibiotic of choice for pertussis treatment, prophylaxis

• Usually recommended as 14-day course to prevent bacteriologic relapse

• Inexpensive

Erythromycin Erythromycin Compliance and SafetyCompliance 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

*Mahon et al. J Pediatr 2001;139:380 –4

Azithromycin and Clarithromycin Azithromycin and Clarithromycin vsvs Erythromycin 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)

Azithromycin (A) and Clarithromycin (C) Azithromycin (A) and Clarithromycin (C) Clinical StudiesClinical Studies

Author (Year) Study Design Control Group Study Arms

Aoyoma et al. 1996) Randomized Historical control group

A (8) , C( 9) vE(16, 18)

Bace et al. (1999) Non-comparative

Safety, two dose regime A (17) v A (20)

Bace et al. (2000)* Randomized Erythromycin A(9) v E(15)

Pichichero (2003) Non-comparative

Historical studies A (34)

Langely et al. (2004) Randomized Erythromycin group A( 58) v E (57)

Lebel et al. (2001) Randomized Erythromycin group C (31) vs E (23)

*Abstract

Treatment for Pertussis by Age-groupTreatment for Pertussis by Age-group

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 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 drugDose as above

SummarySummary

• 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

AcknowledgementsAcknowledgements

• CDC/NIP–Colleagues at Bacterial VPD Branch,

Epidemiology and Surveillance Division

• AAP/COID• AAFP• HICPAC

Thank YouThank You

RED BOOK 2003: RED BOOK 2003: Pertussis TreatmentPertussis 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.”

EXTRA SLIDESEXTRA SLIDES

HICPAC Guidelines, 2004HICPAC Guidelines, 2004Pertussis Treatment and ProphylaxisPertussis 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

Control of Communicable Diseases, 2004 Control of Communicable Diseases, 2004 Pertussis Treatment and ProphylaxisPertussis Treatment and Prophylaxis

• Treatment

–Minimum 7-day course of macrolide antibiotics

• Chemoprophylaxis (selective)

–A 7-day course of erythromycin, clarithromycin or azithromycin

Langley et al., 2004 *Langley et al., 2004 *Azithromycin Azithromycin vsvs Erythromycin 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

*Langley et al. Pediatrics 2004;114:96 –101

Langley et al., 2004* Langley et al., 2004* Safety Cohort (N=477) 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%

*Langley et al. Pediatrics 2004;114:96 –101

Efficacy Cohort*Efficacy Cohort*Culture-confirmed pertussis (N=114) 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)

*Langley et al. Pediatrics 2004;114:96 –101

Lebel et al., 2001*Lebel et al., 2001*Clarithromycin Clarithromycin vsvs Erythromycin 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)

*Lebel et al. PIDJ 2001;20:1149 –54.

Lebel et al., 2001*Lebel et al., 2001*Safety Cohort (N=153)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%

*Lebel et al. PIDJ 2001;20:1149 –54.

Efficacy Cohort Efficacy Cohort Culture-confirmed pertussis (N=62) 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

Lebel et al. PIDJ, 2001;20:1149 –54.

Azithromycin, Clarithromycin Azithromycin, Clarithromycin Safety in Infants Age <6 monthsSafety in Infants Age <6 months

• Not labeled for use in infants <6 months age*

–No published report IHPS or severe adverse events in neonates

*http://pdrel.thomsonhc.com/

Macrolides Macrolides Safety: FDA Pregnancy LabelSafety: 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

http://pdrel.thomsonhc.com/

HIPAC GuidelinesHIPAC GuidelinesHypersensitivity to MacrolidesHypersensitivity 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 Differences in Microbiologic Eradication Rates, 95% CIEradication 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)