Practice Guidelines

CDC Releases Guidelines on Antimicrobial Agents for the Treatment and Postexposure Prophylaxis of Pertussis

Am Fam Physician. 2006 Jul 15;74(2):333-336.

The Centers for Disease Control and Prevention (CDC) has released guidelines on antimicrobial agents for the treatment and postexposure prophylaxis of pertussis. The full report was published in the December 9, 2005, issue of Morbidity and Mortality Weekly Report and is available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5414a1.htm.

Recommendations

The use of antibiotics and antimicrobial agents for postexposure prophylaxis eliminates Bordetella pertussis from the nasopharynx of infected persons. Early macrolide administration can reduce the duration and severity of symptoms and shorten the communicability period. Postexposure chemoprophylaxis can be given to asymptomatic contacts to prevent secondary cases, but symptomatic contacts should be treated as if they have pertussis.

TREATMENT

Erythromycin, clarithromycin (Biaxin), and azithromycin (Zithromax) are preferred for the treatment of pertussis in persons one month and older. In thoses younger than one month, the use of erythromycin and clarithromycin is not recommended, and azithromycin is preferred. For patients two months and older, an alternative agent, trimethoprim/sulfamethoxazole (TMP/SMX [Bactrim, Septra]), is available.

When choosing an antimicrobial for treatment or prophylaxis, the following factors should be taken into account: effectiveness, safety, tolerability, ease of adherence, and cost. Azithromycin and clarithromycin are as effective as erythromycin for treatment of pertussis in patients six months and older. They also are better tolerated and are associated with fewer and milder side effects than erythromycin. However, erythromycin is available in generic form and is less expensive.

POSTEXPOSURE PROPHYLAXIS

If there is no contraindication, a macrolide can be given as prophylaxis for persons who are in close contact with a patient who has pertussis. Before making a decision about postexposure chemoprophylaxis, the following factors should be evaluated: infectiousness, degree of exposure, potential consequences of severe pertussis in the contact, and possibilities for secondary exposure of persons at high risk (e.g., those younger than 12 months). Benefits should be weighed against the potential side effects of the drug.

Giving postexposure prophylaxis to asymptomatic household contacts within 21 days of the original patient’s cough onset can prevent symptomatic infection. Symptomatic household members should be treated as if they have pertussis. Postexposure prophylaxis should be administered in infants younger than 12 months or women in the third trimester of pregnancy, because they are at risk for severe and possibly deadly complications. The recommended antimicrobial agents and dosages for postexposure prophylaxis are the same as those for the treatment of pertussis (Table 1).

TABLE 1

Recommended Antimicrobial Treatment and Postexposure Prophylaxis for Pertussis, By Age Group

Age group Primary agents Alternate agent*
Azithromycin (Zithromax) Erythromycin Clarithromycin (Biaxin) TMP/SMX (Bactrim, Septra)

Infants younger than one month

Recommended agent. 10 mg per kg per day in a single dose for five days (only limited safety data available)

Not preferred (associated with infantile hypertrophic pyloric stenosis). Use if azithromycin is unavailable; 40 to 50 mg per kg per day in four divided doses for 14 days

Not recommended (safety data unavailable)

Contraindicated in infants younger than two months (risk for kernicterus)

Infants one to five months of age

10 mg per kg per day in a single dose for five days

40 to 50 mg per kg per day in four divided doses for 14 days

15 mg per kg per day in two divided doses for seven days

Contraindicated in infants younger than two months. For infants two months or older, TMP at a dosage of 8 mg per kg per day and SMX at a dosage of 40 mg per kg per day in two divided doses for 14 days

Infants (six months or older) and older children

10 mg per kg in a single dose on day 1, then 5 mg per kg per day (maximum: 500 mg) on days 2 through 5

40 to 50 mg per kg per day (maximum: 2 g per day) in four divided doses for 14 days

15 mg per kg per day (maximum: 1 g per day) in two divided doses for seven days

TMP at a dosage of 8 mg per kg per day, SMX at a dosage of 40 mg per kg per day in two divided doses for 14 days

Adults

500 mg in a single dose on day 1, then 250 mg per day on days 2 through 5

2 g per day in four divided doses for 14 days

1 g per day in two divided doses for seven days

TMP at a dosage of 320 mg per day, SMX at a dosage of 1,600 mg per day in two divided doses for 14 days


TMP/SMX = trimethoprim/sulfamethoxazole.

*—TMP/SMX can be used as an alternative agent to macrolides in patients two months and older who are allergic to macrolides, who cannot tolerate macrolides, or who are infected with a rare macrolide-resistant strain of Bordetella pertussis.

Reprinted from Centers for Disease Control and Prevention. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis. MMWR Recomm Rep 2005;54(RR–14):1–16.

TABLE 1   Recommended Antimicrobial Treatment and Postexposure Prophylaxis for Pertussis, By Age Group

View Table

TABLE 1

Recommended Antimicrobial Treatment and Postexposure Prophylaxis for Pertussis, By Age Group

Age group Primary agents Alternate agent*
Azithromycin (Zithromax) Erythromycin Clarithromycin (Biaxin) TMP/SMX (Bactrim, Septra)

Infants younger than one month

Recommended agent. 10 mg per kg per day in a single dose for five days (only limited safety data available)

Not preferred (associated with infantile hypertrophic pyloric stenosis). Use if azithromycin is unavailable; 40 to 50 mg per kg per day in four divided doses for 14 days

Not recommended (safety data unavailable)

Contraindicated in infants younger than two months (risk for kernicterus)

Infants one to five months of age

10 mg per kg per day in a single dose for five days

40 to 50 mg per kg per day in four divided doses for 14 days

15 mg per kg per day in two divided doses for seven days

Contraindicated in infants younger than two months. For infants two months or older, TMP at a dosage of 8 mg per kg per day and SMX at a dosage of 40 mg per kg per day in two divided doses for 14 days

Infants (six months or older) and older children

10 mg per kg in a single dose on day 1, then 5 mg per kg per day (maximum: 500 mg) on days 2 through 5

40 to 50 mg per kg per day (maximum: 2 g per day) in four divided doses for 14 days

15 mg per kg per day (maximum: 1 g per day) in two divided doses for seven days

TMP at a dosage of 8 mg per kg per day, SMX at a dosage of 40 mg per kg per day in two divided doses for 14 days

Adults

500 mg in a single dose on day 1, then 250 mg per day on days 2 through 5

2 g per day in four divided doses for 14 days

1 g per day in two divided doses for seven days

TMP at a dosage of 320 mg per day, SMX at a dosage of 1,600 mg per day in two divided doses for 14 days


TMP/SMX = trimethoprim/sulfamethoxazole.

*—TMP/SMX can be used as an alternative agent to macrolides in patients two months and older who are allergic to macrolides, who cannot tolerate macrolides, or who are infected with a rare macrolide-resistant strain of Bordetella pertussis.

Reprinted from Centers for Disease Control and Prevention. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis. MMWR Recomm Rep 2005;54(RR–14):1–16.

SPECIAL CONSIDERATIONS

The U.S. Food and Drug Administration has not approved any macrolide for use in infants younger than six months. Information regarding the safety and effectiveness of azithromycin and clarithromycin use in this age group is limited.

Small clinical studies propose that azithromycin and clarithromycin are similarly effective in patients one to five months of age and in older infants and children. These limited trials support the use of azithromycin and clarithromycin as first-line agents in infants one to five months of age. This is because of their in vitro effectiveness againstB. pertussis, their more convenient dosing, and their recognized safety and effectiveness in older children and adults. However, it should be noted that untreated infants with pertussis remain culture-positive for a longer duration than older children and adults.

SAFETY

A macrolide is contraindicated if there is a history of hypersensitivity. The common side effects of oral macrolides are gastrointestinal (e.g., nausea, vomiting, abdominal pain and cramps, diarrhea, anorexia) and rashes. Side effects are more common and severe with erythromycin therapy.

Specific Antimicrobial Agents

AZITHROMYCIN

Azithromycin is administered as a single daily dose, and it is classified as a Pregnancy Category B drug. Because they reduce absorption of azithromycin, antacids containing aluminum or magnesium should not be used by patients taking azithromycin. Physicians should be cautious about prescribing to patients with impaired hepatic function, and patients should be monitored if they also use agents that are metabolized by the cytochrome P450 enzyme system or other drugs for which pharmacokinetics change (e.g., digoxin, triazolam [Halcion], or ergot alkaloids). Possible side effects of azithromycin use include abdominal discomfort or pain, diarrhea, nausea, vomiting, headache, and dizziness.

ERYTHROMYCIN

A 14–day course of erythromycin is recommended because relapses have been reported after completion of a seven- to 10–day treatment regimen. Erythromycin is classified as a Pregnancy Category B drug. Although animal reproduction studies have not demonstrated a risk to the fetus, no sufficient or well-controlled trials in humans exist.

Erythromycin inhibits the cytochrome P450 enzyme system (CYP3A subclass). Using erythromycin in combination with a drug that is primarily metabolized by CYP3A can produce elevations in drug concentrations that could increase or prolong the therapeutic and adverse effects. There also have been reports of erythromycin interacting with drugs not thought to be metabolized by CYP3A (e.g., zidovudine [Retrovir], hexobarbital, phenytoin [Dilantin Infatabs], valproate [Depacon], theophylline, digoxin, and oral anticoagulants).

Possible side effects of erythromycin use include gastrointestinal irritation (e.g., epigastric distress, abdominal cramps, nausea, vomiting, and diarrhea), hypersensitivity reactions (e.g., skin rashes, drug fever, or eosinophilia), cholestatic hepatitis, and sensorineural hearing loss. Severe reactions such as anaphylaxis are uncommon.

CLARITHROMYCIN

Clarithromycin is a Pregnancy Category C drug. Although animal reproduction studies have demonstrated an adverse effect on the fetus, no well-controlled studies in humans exist.

Clarithromycin is an inhibitor of the cytochrome P450 enzyme system (CYP3A subclass), and using it in combination with a drug that is primarily metabolized by CYP3A can result in elevations in drug concentrations that could increase or prolong therapeutic and adverse effects. When the patient has impaired renal function, dosage and intervals between doses should be reevaluated.

Common side effects of clarithromycin use include epigastric distress, abdominal cramps, nausea, vomiting, and diarrhea. Hypersensitivity reactions, hepatotoxicity, and severe reactions such as anaphylaxis are uncommon. Because it is unknown if clarithromycin is associated with infantile hypertrophic pyloric stenosis, it should not be given to infants younger than one month. The drug is contraindicated if there is history of macrolide hypersensitivity.

ALTERNATE AGENT (TMP/SMX)

Clinical studies have shown that TMP/SMX effectively eliminates B. pertussis from the nasopharynx. Macrolide-resistant B. pertussis is uncommon, but TMP/SMX can be used as an alternative treatment in patients two months or older who have a contraindication to or cannot tolerate macrolide agents, or who are infected with a strain that is macrolide resistant. TMP/SMX should not be given to pregnant women or nursing mothers, or infants younger than two months because of the possible risk for kernicterus. TMP/SMX is a Pregnancy Category C drug. Although animal reproduction studies have shown an adverse effect on the fetus, no adequate or well-controlled studies in humans exist.

One possible side effect of TMP/SMX use is hypersensitivity skin reactions. Uncommon side effects include Stevens-Johnson syndrome, toxic epidermal necrolysis, blood dyscrasias, and hepatic necrosis. A higher incidence of severe side effects is associated with TMP/SMX being prescribed to older adults or to patients with impaired hepatic and renal functions, folate deficiency, or blood dyscrasias. If there is hypersensitivity to trimethoprim or sulfonamides, TMP/SMX is contraindicated.

Adequate fluid consumption is important in preventing crystalluria and renal stones. Drug interactions must be considered when TMP/SMX is used in combination with other drugs, including methotrexate, oral anticoagulants, antidiabetic agents, thiazide diuretics, anticonvulsants, and other antiretroviral drugs.

OTHER ANTIMICROBIAL AGENTS

No published information exists on the clinical effectiveness of other macrolides (e.g., roxithromycin, ketolides).

Other antimicrobials such as ampicillin, amoxicillin, tetracycline, fluoroquinolines, chloramphenicol (Chloromycetin), and cephalosporins have demonstrated varying degrees of in vitro inhibitory activity against B. pertussis; however, clinical effectiveness has not been confirmed. Tetracyclines, chloramphenicol, and fluoroquinolones may have harmful side effects when used in children. For these reasons, none of the above antimicrobial agents is recommended for treatment or postexposure prophylaxis of pertussis.


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