P&T News: February 1998
Teri L. Vrchoticky, Pharm.D. and Jane C. Chandramouli,
Pharm.D.
Peer Review Status: Internally Peer Reviewed Loreen
Herwaldt, M.D. and Douglas H. Jones, M.D.
More recently, Iowa, and in particular Johnson County, has experienced a resurgence of pertussis cases (Figure 2). In 1997, 74 cases were reported from throughout Johnson County school districts and work places.
Edwards and Karzon3 recently hypothesized reasons for persistence of pertussis in the U.S.:
The purpose of this article is to review the epidemiology and pathophysiology of pertussis and to discuss current methods and treatment recommendations.
Epidemiology
Prior to vaccine availability, the estimated incidence of
pertussis was 100 cases per 100,000 population.3 From 1922 to 1948,
pertussis ranked as the leading cause of death from communicable
disease among children in the U.S. less than 14 years old.1 After the
vaccine was introduced, cases dropped to 0.5 to 1.5 cases per
100,000. Although pertussis can occur in persons of any age, infants
less than six months of age and children less than 5 years old are
most frequently infected, typically 35% and 60% of reported cases,
respectively.6 Figure 3 shows the age distribution for reported cases
of B. pertussis infection for 1996. Complications from
pertussis also occur most frequently in children during their first
year of life. Data from the Centers for Disease Control and
Prevention indicate that in 1992 to 1993 infants less than one year
of age made up 42% of all reported pertussis cases and 87% of
deaths.' The most frequently reported complications of pertussis
include: pneumonia, seizures, encephalopathy, hospitalization, and
death. Surveillance data from 1980 to 1989 in the U.S. indicate that
pneumonia, seizures, and encephalopathy occurred in 21.7%, 3.0%, and
0.9%, respectively, of infants with pertussis.6
Adults and adolescents who have been immunized against B. pertussis may become infected because immunity, whether conferred by infection or vaccination, is not life long.7,8 Additionally, adolescents and adults with pertussis are often misdiagnosed because they present with milder disease and non-specific symptoms. However, older persons with underlying disease such as asthma or cystic fibrosis can become very ill.
Pathogenesis
Pertussis, a gram-negative bacillus, is found only in the human
species and is most commonly transmitted via aerosol droplets.3,7
Transmission also can occur through indirect contact with a recently
contaminated inanimate object.'' Following exposure to B. pertussis,
the incubation period ranges from 7 to 21 days. The organism produces
several virulence factors that are responsible for the pathogenesis
and clinical features of the disease.
Pertussis is primarily a toxin-mediated disease. After inhalation, the organism attaches to ciliated cells of the respiratory tract via adhesive factors [e.g., filamentous hemagglutinin (FHA), pertactin (PER), fimbriae (FIM), and pertussis toxin (PT)]. The organism then multiplies and migrates down the respiratory tract and releases toxins [e.g., tracheal cytotoxin (TCT) and adenylate cyclase (AC)] which cause local damage including loss of ciliated cells.1,3 This damage results in improper functioning and inflammation of the respiratory epithelial cells.1,7 Pertussis antigens appear to allow the organism to evade host defenses, in that lymphocytosis is promoted but chemotaxis is impaired.
Clinical Manifestations
The clinical course of pertussis can be separated into three stages:
catarrhal, paroxysmal, and convalescent.7 S The first stage, the
catarrhal stage, is characterized by an insidious onset of mild upper
respiratory symptoms, rhinorrhea, malaise, low-grade fever, and a
non-specific dry cough. Patients are most contagious during the
catarrhal stage which typically lasts 1 to 2 weeks. The paroxysmal
stage is marked by worsening of the cough which evolves into
paroxysms, or short expiratory bursts, followed by an inspiratory
gasp which can result in the classic whoop. Infants, older children
and adults may have the cough with no whoop. The paroxysms are
typically worse at night and patients can experience several attacks
per day.8 The attacks may be severe enough to cause cyanosis and
often end with an episode of vomiting. During the paroxysmal stage
which usually lasts from 1 to 6 weeks, communicability of the disease
decreases rapidly.5 The final, convalescent stage begins with a
gradual decrease in the number and severity of paroxysms. 1,7,8
Although the cough generally disappears in 2 to 3 weeks, cough and
paroxysms often reoccur when triggered by subsequent respiratory
infections.
Treatment and Prophylaxis
Independent of disease stage, antibiotic treatment of pertussis
limits the spread of the disease by eradicating the bacteria from the
nasopharynx.6 It should be noted that secondary attack rates
among susceptible household contacts exceed 80%. Administration of
antibiotics during the catarrhal stage shortens the duration and
decreases symptom severity of the disease. However, once the
paroxysmal stage has begun, antimicrobials have little effect on the
clinical course of the disease.9
Erythromycin is currently the drug that is recommended for treatment and prevention of B. pertussis in adults and children.6,7,9-11 Erythromycin shows high in vitro activity against several pertussis species and readily distributes into the lung tissue. To date, only one isolate of erythromycin-resistant B. pertussis has been identified.12 Erythromycin, 40 to 50 mg/kg/day (maximum 2 grams/day), should be given in two to four divided doses for 14 days. Although earlier trials reported bacterial relapse with less than two weeks of drug therapy, a recent report by Halperin et al suggests that seven days of erythromycin therapy may be equally efficacious.13
Many persons do not tolerate erythromycin. Fortunately, recent clinical studies have reported successful eradication of B. pertussis with other antibiotics. Azithromycin (10 mg/kg/day) for 5 days, clarithromycin (10 mg/kg/day) for 7 days and cotrimoxazole (8 mg/kg/day) for 14 days have demonstrated eradication rates equal to or greater than erythromycin.14,15
Aoyama et al randomized 17 pediatric patients to receive either azithromycin (10 mg/kg/day) for five days or clarithromycin (10 mg/kg/day) for 7 days.14 Each patient was matched with historical controls who had received erythromycin (40 to 50 mg/kg/day) for 14 days. All groups had culture-proven B. pertussis. Eradication rates at one week were 100% (9/9) in the clarithromycin group versus 89% (16/18) in the erythromycin group and 100% (8/8) in the azithromycin group versus 81% (13/16) in the historical erythromycin group. Eradication was 100% at two weeks after treatment. Additionally, the MICs for all three antibiotics were the same (<0.003 to 0.05) for 60 stains of B. pertussis isolated. Hoppe et al conducted a randomized trial to compare the efficacy of erythromycin ethylsuccinate (50 to 80 mg/kg/day) to co-trimoxazole (6 to 10 mg/kg/day trimethoprim) for the treatment of pertussis in 55 pediatric patients with positive nasopharyngeal swab (NPS) cultures.15 Treatment was considered successful following 14 days of antibiotic therapy if NPS cultures were negative. All 28 patients treated with erythromycin were culture negative at two weeks as were all but one of the 27 patients treated with co-trimoxazole. Adverse effects were small in either group. The authors concluded that co- trimoxazole is an effective alternative for the treatment of B. pertussis.
Although clinical studies testing the efficacy of fluoroquinolones have not been conducted in humans, two different in vitro studies by Hoppe el al have shown susceptibility of B. pertussis to levofloxacin and ciprofloxacin. 16 17
Because of the limited number of published trials evaluating the efficacy of other macrolides and their associated high cost, erythromycin should be utilized as first-line therapy for the treatment or prophylaxis of pertussis infection. The exception to this rule would be if the patient has a history of or develops severe gastrointestinal intolerance while taking erythromycin.
Drug Average Daily Dosage
|
Table 1. Dosages and Costs of Antibiotic Therapy for the Treatment and Prophylaxis of Pertussis | |
|
Drug |
Average Daily Dosage |
|
Erythromycin6,7 |
Pediatric: 40 to 50 mg/kg/day in 4 divided doses x 14
days* |
|
Co-trimoxazole6,15 |
Pediatric: 8 mg/kg/day** in two divided doses x14
days |
|
Clarithromycin14 |
Pediatric: 10 mg/kg/day in two divided doses x 7 days |
|
Azithromycin14 |
Pediatric: 10 mg/kg/day once daily x 5 days |
|
* Pediatric prices are based on doses for a 30 kg child.
| |
Antibiotic therapy is recommended for all household contacts or other close contacts, such as those in child care, irrespective of age and vaccination status. Prompt treatment of household contacts limits secondary transmission.
The Centers for Disease Control and Prevention recommendations for health-care workers exposed to or infected with pertussis include: 18
Prevention
Prevention of B. pertussis through vaccination remains the
most effective way to control the spread of the disease. In the U.S.,
the highest recorded annual incidence of pertussis occurred in 1934
when greater than 260,000 cases were reported. The incidence of
reported pertussis disease declined substantially as use of
whole-cell DTP vaccines became widespread. By 1970, the reported
incidence had declined by over 99%." Approximately 70% of U.S.
children complete the five-dose vaccination series for B.
pertussis which possesses a reported efficacy of 70 to 90%.18,19
Contrary to public belief, protection from the vaccine is not
life-long. The vaccine is only 52% efficacious five years after
immunization and has virtually no efficacy 12 years past
immunization.6,7,8
The whole-cell vaccine contains inactivated B. pertussis cells, several antigens (e.g., proteins, lipopolysaccharide, peptidoglycan, lipids, etc.), and endotoxin. The vaccine is available in combination with diphtheria and tetanus toxoids. Whole-cell vaccines have been associated with many adverse reactions; these reactions are thought to occur secondarily to endotoxin in the vaccine. Local reactions (e.g., pain, swelling, erythema at injection site) and mild systemic reactions (e.g., fever, drowsiness, irritability, and poor appetite) occur most commonly. More severe reactions such as persistent crying,seizures, and hypotonic hyporesponsiveness are rare. Acute encephalopathy, the most severe reaction, is extremely rare (O to 10.5 cases per I million doses) and scientific evidence has not established a causative relationship between this reaction and vaccine administration.19
Concerns about the safety of the whole-cell vaccine prompted the development of more purified pertussis vaccines that are associated with a lower frequency of adverse events and are effective in preventing pertussis disease.19
Acellular pertussis vaccines contain purified, inactivated pertussis cell components and, unlike the whole-cell vaccine, contain little or no endotoxin.19 The acellular vaccines are available in combination with diphtheria and tetanus toxoids as DTaP for use in children. Clinical trials have shown various acellular vaccines to possess similar efficacy (59 to 89%) and lower rates of adverse reactions than the whole-cell vaccines (Figure 4).
Three acellular vaccines are currently licensed in the United States: Tripedia[R], ACEL-IMUNE[R], and Infanrix[R]. Although originally licensed in 1991 for only the fourth and fifth doses of the DPT vaccine schedule for children 15 months to 7 years, DTaP vaccines are now recommended for all five doses. Table 2 shows the currently recommended dosing schedule.
|
Table 2. Routine Diphtheria, Tetanus, and Pertussis Vaccination Schedule for Children Age less than 7 Years in the United States, 1997(19) | |||
|
Dose |
Age |
Customary age/interval |
Product(1,2,3) |
|
Primary 1 |
2 months |
Age 6 weeks or older |
DTaP |
|
Primary 2 |
4 months |
4-8 weeks after first dose* |
DTaP |
|
Primary 3 |
6 months |
4-8 weeks after second dose* |
DTaP |
|
First Booster |
15-18 months** |
6-12 months after third dose* |
DTaP(4) |
|
Second Booster |
Age 4-6 years, before entering kindergarten or elementary school (not necessary if fourth dose [first booster] is administered after fourth birthday) |
|
DTaP |
1. Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP); diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP) is an acceptable alternative to DTaP for all of the five doses.
2. Use diphtheria and tetanus toxoids, adsorbed (DT) if
encephalopathy has occurred after administration of a previous dose
of pertussis-containing vaccine.
If the child is age 2 I year at the time the first dose of DT is
administered, a third dose administered 6-12 months after the second
dose completes primary vaccination with DT.
3. Whenever possible, the same DTaP product should be used for all doses. If the same product is not available, Tripedia, ACEL-IMUNE, and Infanrix can be used interchangeably.
*Prolonging the interval does not require restarting the series.
**If the interval between the third and fourth doses is 2 6 months and the child is not likely to return for a visit at the recommended age, the fourth dose of either DTaP or DTP may be administered as early as age 12 months.
4. Tri HIBit can be administered as the fourth dose following a primary series with either DTaP or whole-cell DTP and a primary series with any Haemophilus influenzae type conjugate vaccine.
Special Considerations for Vaccination6
1) Pertussis vaccination is not recommended at this time for persons
aged > 7 years old. Vaccination of adults with the
whole-cell vaccine resulted in unacceptably high reaction rates.20
Additionally, the current DTaP vaccines contain more diphtheria
toxoid than is recommended for persons > 7 years of age.
Acellular vaccine has been administered to adults without significant
adverse events. However, recommendations regarding routine
vaccination of adults will require additional research.21,22
2) Infants and young children who have a personal or family history of seizures are at greater risk for seizures after administration of whole-cell pertussis vaccine. DTaP is the vaccine of choice for these children. Acetaminophen or ibuprofen should be administered to these children at the time of DTaP vaccination and every four hours for 24 hours thereafter to reduce the possibility of post-vaccination fever.
3) Children who have had well-documented pertussis disease should be given DT vaccine for the remaining doses of the vaccination series to ensure they are protected against diphtheria and tetanus. Some experts recommend including the pertussis component for subsequent vaccinations of infants because they may have a suboptimal immune response following B. pertussis infection.
Conclusions
Pertussis infection remains a major cause of morbidity and
mortality throughout the world. Despite a longstanding vaccination
program, the number of reported pertussis cases has increased over
the last two decades. Resurgence of the disease is thought to be
secondary to an increasing population of susceptible adults and to
decreased vaccination rates among children because of adverse events
associated with the whole-cell vaccine. The goal of acellular vaccine
development was to increase primary vaccination among young children
and provide a vaccine suitable for adolescents and adults. Clinical
trials evaluating the efficacy of acellular pertussis vaccines in
adults are currently under way in the U.S.8 Current priorities
include educating parents about the acellular vaccine and
investigating the use of acellular vaccines to boost immunity in
adults and older children. In addition, health care workers must
promptly diagnose, isolate, and treat patients who are infected with
B. pertussis or who are exposed to a person with whooping
cough to prevent the spread of this organism.
References