The Prevention and Treatment of Whooping Cough

Release Date: March 1, 2011

Expiration Date: March 31, 2013

FACULTY:

Lela S. Fung, PharmD, BCPS
Clinical Pharmacy Specialist, Neonatology/Pediatrics
Via Christi Hospitals Wichita
Wichita, Kansas
Adjunct Clinical Assistant Professor
University of Kansas School of Pharmacy
Department of Pharmacy Practice
Lawrence, Kansas
Adjunct Clinical Assistant Professor
University of Missouri–Kansas City School of Pharmacy
Division of Pharmacy Practice and Administration
Kansas City, Missouri

FACULTY DISCLOSURE STATEMENTS:

Dr. Fung has no actual or potential conflicts of interest in relation to this activity. This activity contains discussion of medication use for indications not approved by the FDA.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-11-006-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To provide participants with an up-to-date review of Bordetella pertussis infection, treatment options, and prevention strategies.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Discuss the epidemiology of Bordetella pertussis infection in the United States.
  2. Review treatment options for active B pertussis infections.
  3. Discuss recommended preventive measures, including vaccines and postexposure prophylaxis.

Pertussis, also known as whooping cough, is a contagious acute respiratory tract infection that continues to affect patients of all ages despite widespread vaccination. It is caused by Bordetella pertussis, a gram-negative aerobic coccobacillus that is transferred from host to host through droplets produced by coughing, sneezing, or talking.1 Pertussis infection poses a high risk for infants, leading to hospitalization, pneumonia, dehydration, weight loss, and even death. Although pertussis is commonly perceived as a childhood illness, substantial increases in adolescent and adult cases have been reported, confirming the necessity for health care providers (HCPs) to obtain adequate knowledge of the infection.

Epidemiology

Annually, 30 million to 50 million cases of pertussis are reported worldwide, with 300,000 associated deaths.2 In the United States in 2009, about 17,000 cases were reported to the CDC.2 Adolescents and adults accounted for approximately 40% of all reported pertussis cases in 2009, but infants less than 6 months old were the most susceptible to severe complications and death, with a 60% increase from 2008 to 2009.2 More than half of all infants less than 1 year old require hospitalization for pertussis.2

Annually, approximately 200,000 cases of pertussis were reported in the U.S. prior to the introduction of the combination diphtheria-tetanus-pertussis vaccine in the 1940s.3 Use of this vaccine reduced the incidence dramatically; however, the last two decades have been plagued with a resurgence of pertussis and notable increases in infection in adolescents and adults.1,3,4 The increased incidence rates may be attributed to enhanced surveillance as a result of improved awareness among HCPs, improved diagnostic techniques; and diminishing immunity.5

Both vaccine-induced immunity and infection-acquired immunity have been associated with a diminution in protection. The protection has been shown to wane after 7 to 20 years for naturally acquired pertussis and after 4 to 12 years for vaccination.5 The whole-cell formulation—the first available pertussis vaccine—was replaced by the acellular formulation in 1997. The two formulations do not appear to have substantially different durations of immunity: Antibody levels are nearly undetectable 2 years postimmunization with either vaccine, but immunity remains.6 Booster vaccinations are recommended for patients aged 11 to 12 years; adults aged 19 to 64 years who never had a pertussis vaccination should receive one instead of the usual tetanus booster.4,7 Further research on rates of waning immunity would aid in the development of recommendations for optimal age for and frequency of booster vaccination.

Clinical Presentation

Following an incubation period of 5 to 21 days, symptoms of pertussis manifest in three stages: catarrhal, paroxysmal, and convalescent.1 Nonspecific symptoms with insidious onset that resemble a viral upper respiratory tract infection—e.g., rhinorrhea, lacrimation, malaise, cough, low-grade fever, nonproductive cough, and conjunctival inflammation—are characteristic of the catarrhal stage, which may last 1 to 2 weeks.3,4,8 Patients with pertussis are most contagious during the catarrhal and early paroxysmal stages.4

Gradually, the cough becomes more severe and frequent, marking the beginning of the paroxysmal stage, which can last 2 to 8 weeks. The characteristic severe coughing spells present as multiple forceful coughs during a single exhalation followed by an inspiratory whoop, posttussive cyanosis, and posttussive emesis. These episodes occur throughout the day, but may be more severe at night. Oral intake of food can trigger coughing spells, so weight loss due to poor nutritional intake and frequent vomiting may occur. Leukocytosis and lymphocytosis are common.

The paroxysms gradually improve, and the patient transitions to the convalescent stage. In this stage, white blood cell counts normalize and the cough becomes milder and less frequent. However, recurrent cough can occur with physical exertion or the onset of viral respiratory infection. The convalescent stage may last for 1 to 2 weeks, and the total duration of illness can be 6 to 12 weeks.3,4,8

Some symptoms and the timing of the symptoms are unique to pertussis; however, the disease may manifest atypically in certain populations. Coughing spells in young infants can lead to apnea, but these patients may not exhibit the inspiratory whoop.3 Partially immunized children may experience milder disease. The catarrhal stage may be shorter than expected or completely absent; the typical whoop and leukocytosis may not occur, and the paroxysmal cough may not last as long (≥3 weeks less).3

Immunized individuals, especially adolescents and adults, may have a milder clinical course that can be confused with other infections or with asthma.8 The most common symptom of pertussis in older patients is persistent cough lasting more than 1 month, but posttussive emesis and the inspiratory whoop generally do not occur. Adults and older patients also may experience diaphoresis, facial flushing, syncope, sleep disturbances, and myalgias.3

Diagnosis

Patients of all ages should be tested for pertussis, and treatment should be considered for those presenting with a cough of more than 2 weeks’ duration who develop a paroxysmal feature, whooping, or posttussive emesis. Pertussis should also be on the differential diagnosis list for infants with severe cough, apnea, or bradycardia of any duration.3 Pertussis may be easily misdiagnosed because of concurrent infections and alterations in clinical presentation based on vaccination status. Proper diagnosis of pertussis in a timely manner is important for reducing its severity and preventing it from spreading.

There are several methods for diagnosing pertussis. Isolation of B pertussis in a culture of a nasopharyngeal aspirate or swab is considered the gold standard.1,8 B pertussis is difficult to grow in culture, and it can take 7 to 12 days to confirm growth.4 Culturing is recommended during the first 3 weeks of illness because the yield is highest during the catarrhal phase.8 However, this method is less sensitive in patients who have received antimicrobial therapy, and it is a poor confirmatory test when used alone late in the clinical course.4,8 The CDC recommends combining culturing with polymerase chain reaction (PCR) assay to confirm a pertussis diagnosis within 4 weeks of symptom onset or for a cough lasting 3 weeks.4

Using PCR assay to detect B pertussis is 94% sensitive compared with 15% sensitivity for culture.4 PCR assay can confirm a pertussis diagnosis within 1 or 2 days and is not affected by antimicrobial therapy.4 PCR tests can yield false-positives, however, so the CDC recommends using them in combination with culturing.4

Direct fluorescent antibody (DFA) testing has been used for pertussis diagnosis for about 40 years.4 The test is inexpensive, provides rapid results, and can still determine a positive result in the presence of antibiotic therapy.4 However, cross-reactivity with normal nasopharyngeal flora results in false-positives, and the CDC no longer recommends the use of DFA tests for diagnostic purposes.3,4

Serology is most often used in epidemiologic studies, but it can be helpful for diagnosing pertussis late in the disease course of adolescents and adults when culture and PCR tests are negative.4,5 Enzyme-linked immunosorbent assay (ELISA) uses B pertussis proteins as antigens to promote increases in serum levels of immunoglobulin (Ig) A or IgG. Two serum samples are collected 2 to 4 weeks apart, ideally between the catarrhal and convalescent stages. Diagnosis is confirmed if titers increase more than twofold from the first to the second sample. Antibody responses may be altered in vaccinated patients or those who are reinfected with pertussis. In reinfected patients, a rapid increase in antibody titers may occur before the acute serum sample is obtained. The early peak in antibody titers can hamper the detection of a significant titer increase between the acute and convalescent stage samples, thereby impeding serologic diagnosis.3,5 Another limitation of serologic testing is its use in young infants, since patients younger than 3 months may not develop measurable antibody responses.5 Since the procurement of acute phase serum samples is difficult, single-serum-sample ELISA may be a useful diagnostic tool for adolescents and adults.3,5

The CDC classifies pertussis cases as clinical, confirmed, or probable.4 Clinical cases are defined as an acute cough for 14 days in an outbreak setting or in addition to one of the following: paroxysmal cough, posttussive emesis, inspiratory whooping, or no other apparent cause. Confirmed cases either consist of an acute cough illness of any duration plus a positive B pertussis culture or meet criteria for a clinical definition, but also include positive PCR assay or epidemiologic link to a confirmed case. Probable cases meet criteria for a clinical definition, plus all of the following: negative PCR assay, negative B pertussis culture, and no epidemiologic link to a confirmed case. The CDC recommends treatment for patients with clinical or probable pertussis regardless of laboratory test results.4

Treatment

Within 3 to 4 weeks of symptom onset, 80% to 90% of patients will spontaneously clear B pertussis from the nasopharynx.3 When pertussis is recognized early and antimicrobial therapy is initiated during the catarrhal stage, the disease may be ameliorated. However, antibiotics usually have no discernible effect on the course of illness if paroxysms are established.9 To limit the spread of the infection, especially to infants, antibiotics are recommended even in cases when the clinical course most likely will be unaffected.5

Macrolides are the antibiotics of choice for the treatment of pertussis. There are very few published reports of resistance to macrolides, and no data to suggest spreading resistance; therefore, susceptibility testing generally is not performed.9 Erythromycin, azithromycin, and clarithromycin are considered first-line agents by the American Academy of Pediatrics.10 Recommended dosing and treatment duration appear in TABLE 1.3,10

tbl1

Erythromycin may be used to treat pertussis in infants older than 1 month, children, and adults. Gastrointestinal (GI) irritation, the most common adverse effect (AE), can lead to gastric distress, abdominal cramps, nausea, vomiting, and diarrhea. AEs are dose-related and may be minimized by having the patient take enteric-coated tablets or ester derivatives with food. An increased risk of infantile hypertrophic pyloric stenosis (IHPS)— hypertrophy of the pylorus that results in gastric outlet obstruction—has been reported in neonates (age <1 month) during erythromycin administration. Therefore, azithromycin is preferred in neonates even though it is not FDA-approved for use in this population.11

Azithromycin is often preferred over other macrolides because of its once-daily dosing. AEs include abdominal discomfort or pain, diarrhea, nausea, vomiting, headache, and dizziness. The incidence of AEs has been observed to be lower than for erythromycin, leading to increased compliance. In a study of 477 pediatric patients, approximately 19% of those treated with azithromycin experienced GI AEs versus 41% of erythromycin-treated patients, and 90% of azithromycin patients were 100% compliant versus 55% of erythromycin patients.12 Patients should be cautioned that concomitant use of aluminum- or magnesium-containing antacids may reduce the rate of azithromycin absorption. Cases of IHPS have been reported with azithromycin use, but azithromycin remains the drug of choice for neonates. All infants receiving macrolide treatment must be monitored for IHPS during the treatment course and for 1 month after completion.10

Clarithromycin is chemically and metabolically similar to erythromycin; likewise, it is not recommended for infants younger than 1 month because of the potential risk of IHPS. The most common AEs of clarithromycin are similar to those of other macrolides: epigastric distress, abdominal cramps, nausea, vomiting, and diarrhea. Potential drug interactions are similar to those for erythromycin, since clarithromycin also inhibits CYP3A4. Clarithromycin does not require dose adjustment in hepatic impairment, but in renal dysfunction the dose should be decreased and given less frequently.11

Trimethoprim/sulfamethoxazole (TMP-SMZ) is used in patients older than 2 months in whom macrolide agents are contraindicated or not tolerated.11 Macrolide-resistant B pertussis is rare, but TMP-SMZ may be used in resistant cases. AEs associated with TMP-SMZ include hypersensitivity skin reactions and GI distress. A higher incidence of AEs may be seen in older adults or in patients with hepatic or renal dysfunction, folate deficiency, or blood dyscrasias. Patients should be advised to maintain sufficient fluid intake to prevent crystalluria and nephrolithiasis.11

Other antimicrobial agents have in vitro activity against B pertussis, but clinical effectiveness has not been demonstrated.11 Amoxicillin and ampicillin demonstrated ineffective clearing of B pertussis from the nasopharynx, possibly secondary to poor penetration into respiratory secretions. Although cephalosporins have varying degrees of in vitro activity against B pertussis, the minimum inhibitory concentration is extremely high and renders cephalosporins clinically useless in pertussis. Tetracyclines, chloramphenicol, and fluoroquinolones also have demonstrated in vitro activity, but the risk of harmful AEs outweighs the potential benefits against pertussis.11 Owing to the lack of clinical efficacy data, the abovementioned agents cannot currently be recommended for the treatment or prophylaxis of pertussis.

With the exception of antibiotics, no pharmacologic agents have been shown to interfere with disease progression. Studies examining the efficacy of antihistamines, corticosteroids, beta-adrenergic agonists, and immunoglobulins for symptom relief are few. The only trial that evaluated antihistamines did not find a significant difference in paroxysmal cough between patients receiving diphenhydramine 5 mg/kg/day divided into 3 doses versus patients taking placebo.13

The most recent study of immunoglobulins assessed the rate of improvement as measured by the number of paroxysmal coughing episodes (≥8 coughs within 10 seconds) in infants hospitalized for pertussis.14 Subjects were randomized to receive a single IV infusion of pertussis immunoglobulin or placebo. The immunoglobulin was well tolerated, but no significant difference between the treatment and placebo groups was observed in the rate of improvement or the number of coughing episodes per hour. The study was prematurely terminated secondary to expiration of the product and the unavailability of additional product. This phase III study did not produce results that would promote the development of another immunoglobulin product.14

Corticosteroids and beta-adrenergic agonists have been studied for the symptomatic treatment of pertussis. In a study assessing the effect of dexamethasone on hospital length of stay, a dose of 0.3 mg/kg/day for 4 days was given to infants younger than 6 months with clinically diagnosed pertussis. There was no significant difference in duration of hospital stay between infants who received dexamethasone or placebo. Two studies evaluating the use of oral albuterol did not find differences in paroxysmal cough per 24 hours. A thorough literature search failed to identify additional studies examining the use of OTC cough and cold agents, steroids, beta-adrenergic receptor agonists, leukotriene receptor antagonists, or anticholinergics in patients diagnosed with pertussis. Currently, evidence is insufficient to support the use of any agents for symptom management in pertussis patients.13

Prevention

In the U.S., pertussis vaccines have been routinely recommended for infants and children for decades. Whole-cell vaccines, first introduced in the 1940s, demonstrated efficacy rates ranging from 36% to 90%.15 Differences in content of the major protective antigens against pertussis were noted in the various marketed vaccines.15 The use of whole-cell vaccines did not control the circulation of all pertussis isolates, and the isolates that remained in circulation were just as virulent as those in the prevaccine era.16

Instead of using heat-killed bacteria, acellular pertussis vaccines consist of purified, detoxified toxins and adhesions. Bacterial virulence became the major target of the vaccine, as opposed to the broad immune response against hundreds of bacterial proteins seen in the wholecell vaccine approach.16

Acellular vaccines were introduced in the 1990s because of the heterogeneity of whole-cell vaccines and concerns regarding the high incidence of AEs.3,15 The current vaccine for children is a combination of diphtheria, tetanus, and acellular pertussis (DTaP). The recommended vaccination schedule in the U.S. for infants and children is a five-dose series: at ages 2, 4, and 6 months, with boosters at 15 to 18 months and 4 to 6 years. The most common AEs are fever and injection-site erythema or swelling.1

There are booster vaccines specifically formulated for adolescents and adults. TABLE 2 lists the vaccines available in the U.S.17 These vaccines include tetanus, diphtheria, and acellular pertussis (Tdap), but contain reduced quantities of diphtheria and pertussis compared with the DTaP formulations.1 The Advisory Committee on Immunization Practices (ACIP) recommends that children aged 7 to 10 years who have not completed the entire series receive a single dose of Tdap.18 The ACIP also recommends the use of Tdap instead of the tetanus-diphtheria toxoid (Td) vaccine in patients aged 11 to 12 years.3 Adolescents aged 11 to 19 years should receive a single booster dose of Tdap instead of Td if they have sufficiently completed the recommended childhood Td or DTaP series and have not yet received a Td booster. For adolescents who have already received Td, a single dose of Tdap should be administered at least 5 years later to protect against pertussis.

tbl2

Adults who have not received a Td booster in more than 10 years should receive the Tdap booster instead of Td. Also, adults with anticipated close contact with an infant should be vaccinated with Tdap 1 month prior to contact. To reduce the risk of local and systemic reactions, boosters should be spaced at least 5 years apart. However, the ACIP states that Tdap may be given as early as 2 years after receipt of the last Td vaccine in high-risk situations.3

The ACIP recommends that pregnant patients who did not get a Td booster should receive one during pregnancy.19 HCPs may choose to administer a Tdap booster to pregnant patients instead of Td. The ACIP recommends vaccinating in the second or third trimester to minimize AEs. Evidence regarding the safety and efficacy of the Tdap vaccine during pregnancy is lacking, and risks must be explained to the patient. Transplacental antibodies may provide protection for the fetus, but theoretically can interfere with the infant’s immune response. Postpartum vaccination with Tdap prior to discharge from the hospital or birthing center—instead of Td during pregnancy—is an option if adequate protection against tetanus and diphtheria is expected throughout the pregnancy.19

Hundreds of errors have been reported with the Tdap and DTaP vaccines because of their similar names and abbreviations.20 Fortunately, there is guidance on how to rectify mistakes. The capital letters in “DTaP” indicate larger quantities of the diphtheria and pertussis components, which are used solely in infants and children.20 If a child mistakenly receives a Tdap vaccine for one of the first three vaccines in the series, the correct product should be administered as soon as possible. If the error occurs with the fourth or fifth dose, DTaP administration is not necessary. If an adolescent or adult inadvertently receives DTaP instead of Tdap, the DTaP counts as the booster and no revaccination is necessary.10

In addition to vaccines, postexposure prophylaxis is another method for preventing the infection from spreading. The transmission rate from an infected individual to a close contact (someone who had face-to-face exposure within 3 feet of a symptomatic patient) may be as high as 80% to 100%.1 A close contact also is someone who has had direct contact with respiratory, oral, or nasal secretions from a symptomatic patient or who has been in a confined space in close proximity to a symptomatic patient for more than an hour. Prophylaxis can be administered to close contacts and to those at high risk for severe or complicated pertussis. Administration of appropriate antibiotics to an asymptomatic close contact within 21 days of cough onset in the infected patient may prevent symptomatic infection. Postexposure prophylaxis should be administered to all infants and to pregnant patients in the third trimester, since severe infections occur most commonly in young infants. The antimicrobial agents used for prophylaxis are the same ones used for treatment.12

In the health care setting, certain precautions should be taken to prevent pertussis transmission to HCPs and other patients. Droplets produced by infected individuals can travel up to 3 feet and be deposited on mucosal surfaces of susceptible hosts.1 Patients with suspected or confirmed pertussis should be placed in a private room or at least 3 feet away from another patient. If the room has curtains, these should be drawn to create further separation. HCPs should wear a surgical mask when contact within 3 feet of the potentially infected patient is anticipated. Droplet precautions should remain in place until the patient has received 5 days of effective antimicrobial therapy.1

Future Initiatives

The primary goal concerning pertussis is to reduce the incidence in young infants, since pertussis in this population is the most severe, leads to hospitalization, and may be fatal. In addition to conferring immunity to the young infant, another important area to address is possible transmission to the infant from family members or HCPs. Given that vaccine-mediated immunity wanes after several years, particular emphasis should be placed on booster vaccinations and appropriate postexposure prophylaxis in communities.

Established in 2001, the Global Pertussis Initiative (GPI) is a scientific forum of experts from 17 countries whose purpose is to evaluate the status of pertussis and develop immunization strategies to improve disease control.21 Currently, vaccination schedules vary in different countries. The GPI has discussed universal adolescent and adult immunization and selective immunization of new mothers, close contacts to newborns, HCPs, and child care providers. Clinical trials of maternal vaccination could determine the degree of protection for the fetus and the risks of the infant not responding to regularly scheduled active immunizations. Vaccination immediately after birth also is being considered. Although the neonate’s immune system is not fully developed and may not adequately develop antibodies after a vaccine, neonatal immunization is a promising area of research.5,15 Additionally, efforts to improve current vaccines or develop new vaccines to induce longer immunity are currently underway.5

Conclusion

Pertussis continues to be poorly controlled despite national immunization programs. Current vaccination schedules do not provide lifelong immunity, and reported cases of pertussis continue to increase, especially in adolescents and adults. Improvements in vaccines, vaccine schedules, awareness about pertussis, and other preventive measures are vital for overcoming waning immunity and potential transmission of disease to high-risk groups. Eradication of pertussis—the ultimate goal—will be achieved only through further research and HCP advocacy.

REFERENCES

  1. Sandora TJ, Gidengil CA, Lee GM. Pertussis vaccination for health care workers. Clin Microbiol Rev. 2008;21:426-434.
  2. Pertussis (whooping cough) surveillance & reporting. www.cdc.gov/pertussis/ surv-reporting.html. Accessed November 30, 2010.
  3. Raguckas SE, VandenBussche HL, Jacobs C, Klepser ME. Pertussis resurgence: diagnosis, treatment, prevention, and beyond. Pharmacotherapy. 2007;27:41-52.
  4. Gregory DS. Pertussis: a disease affecting all ages. Am Fam Physician. 2006;74:420-426.
  5. Bamberger ES, Srugo I. What is new in pertussis? Eur J Pediatr. 2008;167:133139.
  6. Wendelboe AM, Van Rie A, Salmaso S, Englund JA. Duration of immunity against pertussis after natural infection or vaccination. Pediatr Infect Dis J. 2005;24:S58-S61.
  7. Edwards K, Freeman DM. Adolescent and adult pertussis: disease burden and prevention. Curr Opin Pediatr. 2006;18:77-80.
  8. Singh M, Lingappan K. Whooping cough: the current scene. Chest. 2006;130:1547-1553.
  9. Wirsing von König CH. Use of antibiotics in the prevention and treatment of pertussis. Pediatr Infect Dis J. 2005;24:S66-S68.
  10. Pertussis (whooping cough). In: Pickering LK, Baker CJ, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:509-519.
  11. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC guidelines. MMWR Recomm Rep. 2005;54:1-16.
  12. Langley JM, Halperin SA, Boucher FD, Smith B. Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics. 2004;114:e96-e101.
  13. Bettiol S, Thompson MJ, Roberts NW, et al. Symptomatic treatment of the cough in whooping cough. Cochrane Database Syst Rev. 2010;(1):CD003257.
  14. Halperin SA, Vaudry W, Boucher FD, et al. Is pertussis immune globulin efficacious for the treatment of hospitalized infants with pertussis? No answer yet. Pediatr Infect Dis J. 2007;26:79-81.
  15. Berbers GA, de Greeff SC, Mooi FR. Improving pertussis vaccination. Hum Vaccin. 2009;5:497-503.
  16. Guiso N. Bordetella pertussis and pertussis vaccines. Clin Infect Dis. 2009;49:1565-1569.
  17. Atkinson W, Wolfe S, Hamborsky J, McIntyre L, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 11th ed. Washington DC: Public Health Foundation; 2009.
  18. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010. MMWR Morb Mortal Wkly Rep. 2011;60:13-15.
  19. Murphy TV, Slade BA, Broder KR, et al. Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57:1-51.
  20. Institute for Safe Medication Practices. DTaP-Tdap mix-ups now affecting hundreds of patients. July 1, 2010. www.ismp.org/Newsletters/acutecare/articles/20100701.asp. Accessed December 13, 2010.
  21. Plotkin S. The global pertussis initiative: process overview. Pediatr Infect Dis J. 2005;24:S7-S9.

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