Treatment Failure of Nosocomial Pertussis Infection in a Very-Low-Birt
http://www.100md.com
《微生物临床杂志》
Laboratoire d'Etudes de Genetique Bacterienne dans les Infections de l'Enfant (EA 3105), Universite Denis Diderot-Paris 7, Service de Microbiologie
Service de Neonatologie Service de Reanimation, Hpital Robert Debre (AP-HP), 75019 Paris, France
Centre National de Reference de la Coqueluche et autres Bordetelloses, Institut Pasteur, 75015 Paris, France
ABSTRACT
We describe a case of nosocomial maternal transmission of Bordetella pertussis to a very-low-birth-weight (VLBW) neonate in whom treatment was unsuccessful. This case underscores the need for rapid and sensitive PCR diagnosis in VLBW neonates and in parents with clinical signs of pertussis and suggests that standard treatment may not be appropriate for VLBW neonates.
CASE REPORT
A 4-month-old boy born at 26 weeks of pregnancy with a weight of 835 g was hospitalized since birth in a neonatal care unit because of chronic lung disease. His condition worsened abruptly at 4 months of age, with cough, bradycardia, and progressive respiratory failure requiring admission in the neonatal intensive care unit (NICU). Nasopharyngeal washing fluid was negative by immunoassay for respiratory syncytial virus, influenza A and B viruses, adenovirus, and parainfluenza viruses 1, 2, and 3. The same sample was positive for Bordetella pertussis by culture and by a real-time PCR assay based on the IS481 target (11), using an iQ Supermix kit on an iCycler thermal cycler (Bio-Rad, France). Josamycin therapy was started at a dose of 50 mg/kg of body weight/day in two divided doses. The B. pertussis isolate was sent to the the French Pertussis National Reference Center (PNRC) and was found to be susceptible to erythromycin (MIC 0.016 μg/ml). An epidemiological investigation was performed to identify the potential source of B. pertussis. Two patients who were geographically linked to the index case, one NICU staff member with cough, and immediate family members (the parents and two brothers) had nasopharyngeal aspirates to identify B. pertussis. The mother was the only familial contact who complained of mild cough (preceding her infant's onset of disease for 10 days) and was also the only contact positive for B. pertussis by PCR and negative by culture. All members of the immediate family were treated with josamycin for 14 days, and contacts of the parents with their infants were secured by the wear of a procedure mask. It was concluded that the patient, who had never left the hospital, had probably been infected by his mother. After a few days of josamycin treatment, his condition improved, and the patient returned to the neonatal care unit with one or two bouts of paroxystic coughing every 12 h but no apnea or cyanosis.
Two days after the end of this 14-day course of josamycin, the infant received a second injection of a combined diphtheria-tetanus-polyomyelitis-acellular pertussis vaccine. His condition again worsened, with frequent episodes of cough, bradycardia, and progressive respiratory failure, and the boy was again referred to the NICU. A nasopharyngeal specimen taken on the day of the new admission to NICU was positive by IS481 PCR and yielded numerous B. pertussis colonies after 3 days of culture. Intubation was required for acute respiratory distress syndrome and pulmonary hypertension. Cotrimoxazole therapy was chosen to cover the possibility that a macrolide-resistant mutant had been selected during initial josamycin therapy (2). The results of PCR analysis and culture of serial nasopharyngeal specimens are shown in Table 1. The boy's condition started to improve after 1 week of cotrimoxazole therapy. Given that josamycin therapy had failed, that the second B. pertussis isolate was susceptible to erythromycin, and that IS481 PCR was still positive (Table 1), cotrimoxazole was replaced after 17 days by azithromycin, with 10 mg/kg given on the first day followed by 5 mg/kg/day for 4 days. At the end of this treatment, the patient recovered his initial pulmonary condition and was returned to the neonatal ward. IS481 PCR during the second episode showed a gradual decline in the pertussis DNA level but remained positive 31 days after the end of azithromycin therapy (Table 1). There were no further clinical recurrences, and the boy was discharged home at age 8 months with nocturnal oxygen support.
Investigations performed by the PNRC showed that B. pertussis isolates collected during the first and second episodes expressed common adhesins, i.e., filamentous hemagglutinins, pertactins, fimbriae, and toxins (pertussis toxin and adenylate cyclase-hemolysin). It was recently shown that the B. pertussis population is changing and that circulating isolates express different pertussis toxins and pertactins (13). For this reason, we analyzed the isolates collected and compared them with isolates circulating in France and in Europe. The analysis included pulsed-field gel electrophoresis (PFGE) and the genotyping of the genes encoding the pertussis toxin S1 subunit (ptxA) and pertactin (prn). The isolates were indistinguishable from each other by PFGE and belonged to the major group currently circulating in France and Europe, i.e., PFGE group IV (13; data not shown). Furthermore, the isolates express ptxA1 and prn2 alleles as those of the major group circulating in France and Europe. These data and the short time between the end of treatment and the recurrence of pertussis suggest that the recurrence of culture-positive pertussis in this young child was due to treatment failure.
Discussion. Despite a high coverage rate with an effective vaccine for more than 40 years, whooping cough remains endemic in France (1, 6). In recent years, we have shown that, as in the United States and other parts of the world, whooping cough can occur in adolescents and adults who were vaccinated during childhood. Such cases are often diagnosed late, thereby increasing the risk of intrafamilial and nosocomial transmission (1, 3, 8). Infants who are too young to be vaccinated or who have only partially been vaccinated are at the highest risk of severe illness and death.
To our knowledge, this is the first reported case of relapsing nosocomial pertussis infection in a very-low-birth-weight neonate. The source of the child's infection was probably the mother, since she was beginning to cough 15 days before her baby. However, she was culture negative and we could not compare the isolates. The diagnosis was optimized by the use of real-time PCR, which is more sensitive than culture and gives results within a few hours (4). This method could be used to screen all hospital visitors with cough in complement to physical barriers. Although culture is slower and less sensitive than PCR, our report illustrates that the culture must not be abandoned. Here, we could demonstrate that isolates recovered during the infant's initial episode and the recurrence were indistinguishable, were susceptible to all antibiotics used in this setting, and were genetically related to common strains currently circulating in Europe.
Despite standard treatment and the fact that the initial isolate was sensitive to erythromycin, the infection relapsed after an initial clinical improvement. Josamycin has been used in France for more than 20 years and is considered to be as effective as erythromycin on pertussis (12); no treatment failures have previously been reported in this setting. Treatment failure with erythromycin and newer macrolides, such as clarithromycin and azithromycin, is uncommon (7, 9), but previous reports did not genetically compare the initial and recurrent isolates. The reasons for treatment failure in the present case are unclear. The isolate that caused infection is similar to isolates circulating in Europe (7, 9) and harbors no resistance to the antibiotics used. One possible explanation is the infant's immunological immaturity, and this observation may suggest that in such a population, the gold standard duration of treatment with erythromycin or josamycin (the old macrolides) might not be sufficient. Newer macrolides, such as clarithromycin and azithromycin, might be used in such cases, although a 5-day course of azithromycin failed in a 2-month-old boy receiving concomitant steroid therapy (10).
Of particular interest is the observation that B. pertussis DNA may persist for a long time after treatment initiation. The persistence of pertussis DNA after erythromycin therapy in nine infants has already been described by Edelman et al. (5). Pertussis PCR remained positive for 7 days in four patients and for 10 days in two patients. In our patient, PCR was still positive 51 days after the outset of cotrimoxazole treatment and 34 days after azithromycin relay therapy. This underscores the sensitivity of real-time PCR for pertussis diagnosis, even during treatment. Larger studies are needed to determine how long pertussis DNA remains detectable by real-time PCR after treatment initiation. This might help to determine the optimal duration of antimicrobial chemotherapy and of patient isolation for infants with compromised immunity.
In conclusion, our case report underlines the need to protect infants from pertussis exposure. The health care community can limit the spread of pertussis by educating caretakers and the public about preventing the exposure of infants to coughing adolescents or adults, by insisting on the importance of biologically diagnosing pertussis, using culture and PCR, and by carefully following vaccine schedules. This includes a vaccine booster injection given at 11 to 13 years of age in France and also, since this year, a vaccine booster for young parents and health care workers in contact with infants (14).
FOOTNOTES
Corresponding author. Mailing address: Service de Microbiologie, Hpital Robert-Debre, 48 boulevard Serurier, 75395 Paris cedex 19, France. Phone: 33 1 40 03 23 40. Fax: 33 1 40 03 24 50. E-mail: edouard.bingen@rdb.aphp.fr.
REFERENCES
Baron, S., E. Njamkepo, E. Grimprel, P. Begue, J. C. Desenclos, J. Drucker, and N. Guiso. 1998. Epidemiology of pertussis in French hospitals in 1993 and 1994: thirty years after a routine use of vaccination. Pediatr. Infect. Dis. J. 17:412-418.
Bartkus, J. M., B. A. Juni, K. Ehresmann, C. A. Miller, G. N. Sanden, P. K. Cassiday, M. Saubolle, B. Lee, J. Long, A. R. Harrison, Jr., and J. M. Besser. 2003. Identification of a mutation associated with erythromycin resistance in Bordetella pertussis: implications for surveillance of antimicrobial resistance. J. Clin. Microbiol. 41:1167-1172.
Bassinet, L., M. Matrat, E. Njamkepo, S. Aberrane, B. Housset, and N. Guiso. 2004. Nosocomial pertussis outbreak among adult patients and healthcare workers. Infect. Control Hosp. Epidemiol. 25:995-997.
Cherry, J. D., E. Grimprel, N. Guiso, U. Heininger, and J. Mertsola. 2005. Defining pertussis epidemiology: clinical, microbiologic and serologic perspectives. Pediatr. Infect. Dis. J. 24:S25-34.
Edelman, K., S. Nikkari, O. Ruuskanen, Q. He, M. Viljanen, and J. Mertsola. 1996. Detection of Bordetella pertussis by polymerase chain reaction and culture in the nasopharynx of erythromycin-treated infants with pertussis. Pediatr. Infect. Dis. J. 15:54-57.
Gilberg, S., E. Njamkepo, I. P. Du Chatelet, H. Partouche, P. Gueirard, C. Ghasarossian, M. Schlumberger, and N. Guiso. 2002. Evidence of Bordetella pertussis infection in adults presenting with persistent cough in a French area with very high whole-cell vaccine coverage. J. Infect. Dis. 186:415-418.
Langley, J. M., S. A. Halperin, F. D. Boucher, and B. Smith. 2004. Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics 114:e96-101.
Nouvellon, M., J. F. Gehanno, M. Pestel-Caron, C. Weber, J. F. Lemeland, and N. Guiso. 1999. Usefulness of pulsed-field gel electrophoresis in assessing nosocomial transmission of pertussis. Infect. Control Hosp. Epidemiol. 20:758-760.
Pichichero, M. E., W. J. Hoeger, and J. R. Casey. 2003. Azithromycin for the treatment of pertussis. Pediatr. Infect. Dis. J. 22:847-849.
Steinberg, J. M., and I. Srugo. 2002. Reoccurrence of culture-positive pertussis in an infant initially treated with azithromycin and steroids. Arch. Pediatr. Adolesc. Med. 156:1057-1058.
Templeton, K. E., S. A. Scheltinga, A. van der Zee, B. M. Diederen, A. M. van Kruijssen, H. Goossens, E. Kuijper, E. C. Claas, K. Kosters, U. Reischl, J. Schmetz, M. Riffelmann, C. H. Wirsing von Konig, N. Lehn, G. N. Sanden, and M. J. Loeffelholz. 2003. Evaluation of real-time PCR for detection of and discrimination between Bordetella pertussis, Bordetella parapertussis, and Bordetella holmesii for clinical diagnosis. J. Clin. Microbiol. 41:4121-4126.
Torre, D., F. Maggiolo, and C. Sampietro. 1984. Comparative clinical study of josamycin and erythromycin in pertussis. Chemioterapia 3:255-257.
Weber, C., C. Boursaux-Eude, G. Coralie, V. Caro, and N. Guiso. 2001. Polymorphism of Bordetella pertussis isolates circulating for the last 10 years in France, where a single effective whole-cell vaccine has been used for more than 30 years. J. Clin. Microbiol. 39:4396-4403.
Wirsing von Konig, C. H., M. Campins-Marti, A. Finn, N. Guiso, J. Mertsola, and J. Liese. 2005. Pertussis immunization in the global pertussis initiative European region: recommended strategies and implementation considerations. Pediatr. Infect. Dis. J. 24:S87-S92.(Stephane Bonacorsi, Caroline Farnoux, Ph)
Service de Neonatologie Service de Reanimation, Hpital Robert Debre (AP-HP), 75019 Paris, France
Centre National de Reference de la Coqueluche et autres Bordetelloses, Institut Pasteur, 75015 Paris, France
ABSTRACT
We describe a case of nosocomial maternal transmission of Bordetella pertussis to a very-low-birth-weight (VLBW) neonate in whom treatment was unsuccessful. This case underscores the need for rapid and sensitive PCR diagnosis in VLBW neonates and in parents with clinical signs of pertussis and suggests that standard treatment may not be appropriate for VLBW neonates.
CASE REPORT
A 4-month-old boy born at 26 weeks of pregnancy with a weight of 835 g was hospitalized since birth in a neonatal care unit because of chronic lung disease. His condition worsened abruptly at 4 months of age, with cough, bradycardia, and progressive respiratory failure requiring admission in the neonatal intensive care unit (NICU). Nasopharyngeal washing fluid was negative by immunoassay for respiratory syncytial virus, influenza A and B viruses, adenovirus, and parainfluenza viruses 1, 2, and 3. The same sample was positive for Bordetella pertussis by culture and by a real-time PCR assay based on the IS481 target (11), using an iQ Supermix kit on an iCycler thermal cycler (Bio-Rad, France). Josamycin therapy was started at a dose of 50 mg/kg of body weight/day in two divided doses. The B. pertussis isolate was sent to the the French Pertussis National Reference Center (PNRC) and was found to be susceptible to erythromycin (MIC 0.016 μg/ml). An epidemiological investigation was performed to identify the potential source of B. pertussis. Two patients who were geographically linked to the index case, one NICU staff member with cough, and immediate family members (the parents and two brothers) had nasopharyngeal aspirates to identify B. pertussis. The mother was the only familial contact who complained of mild cough (preceding her infant's onset of disease for 10 days) and was also the only contact positive for B. pertussis by PCR and negative by culture. All members of the immediate family were treated with josamycin for 14 days, and contacts of the parents with their infants were secured by the wear of a procedure mask. It was concluded that the patient, who had never left the hospital, had probably been infected by his mother. After a few days of josamycin treatment, his condition improved, and the patient returned to the neonatal care unit with one or two bouts of paroxystic coughing every 12 h but no apnea or cyanosis.
Two days after the end of this 14-day course of josamycin, the infant received a second injection of a combined diphtheria-tetanus-polyomyelitis-acellular pertussis vaccine. His condition again worsened, with frequent episodes of cough, bradycardia, and progressive respiratory failure, and the boy was again referred to the NICU. A nasopharyngeal specimen taken on the day of the new admission to NICU was positive by IS481 PCR and yielded numerous B. pertussis colonies after 3 days of culture. Intubation was required for acute respiratory distress syndrome and pulmonary hypertension. Cotrimoxazole therapy was chosen to cover the possibility that a macrolide-resistant mutant had been selected during initial josamycin therapy (2). The results of PCR analysis and culture of serial nasopharyngeal specimens are shown in Table 1. The boy's condition started to improve after 1 week of cotrimoxazole therapy. Given that josamycin therapy had failed, that the second B. pertussis isolate was susceptible to erythromycin, and that IS481 PCR was still positive (Table 1), cotrimoxazole was replaced after 17 days by azithromycin, with 10 mg/kg given on the first day followed by 5 mg/kg/day for 4 days. At the end of this treatment, the patient recovered his initial pulmonary condition and was returned to the neonatal ward. IS481 PCR during the second episode showed a gradual decline in the pertussis DNA level but remained positive 31 days after the end of azithromycin therapy (Table 1). There were no further clinical recurrences, and the boy was discharged home at age 8 months with nocturnal oxygen support.
Investigations performed by the PNRC showed that B. pertussis isolates collected during the first and second episodes expressed common adhesins, i.e., filamentous hemagglutinins, pertactins, fimbriae, and toxins (pertussis toxin and adenylate cyclase-hemolysin). It was recently shown that the B. pertussis population is changing and that circulating isolates express different pertussis toxins and pertactins (13). For this reason, we analyzed the isolates collected and compared them with isolates circulating in France and in Europe. The analysis included pulsed-field gel electrophoresis (PFGE) and the genotyping of the genes encoding the pertussis toxin S1 subunit (ptxA) and pertactin (prn). The isolates were indistinguishable from each other by PFGE and belonged to the major group currently circulating in France and Europe, i.e., PFGE group IV (13; data not shown). Furthermore, the isolates express ptxA1 and prn2 alleles as those of the major group circulating in France and Europe. These data and the short time between the end of treatment and the recurrence of pertussis suggest that the recurrence of culture-positive pertussis in this young child was due to treatment failure.
Discussion. Despite a high coverage rate with an effective vaccine for more than 40 years, whooping cough remains endemic in France (1, 6). In recent years, we have shown that, as in the United States and other parts of the world, whooping cough can occur in adolescents and adults who were vaccinated during childhood. Such cases are often diagnosed late, thereby increasing the risk of intrafamilial and nosocomial transmission (1, 3, 8). Infants who are too young to be vaccinated or who have only partially been vaccinated are at the highest risk of severe illness and death.
To our knowledge, this is the first reported case of relapsing nosocomial pertussis infection in a very-low-birth-weight neonate. The source of the child's infection was probably the mother, since she was beginning to cough 15 days before her baby. However, she was culture negative and we could not compare the isolates. The diagnosis was optimized by the use of real-time PCR, which is more sensitive than culture and gives results within a few hours (4). This method could be used to screen all hospital visitors with cough in complement to physical barriers. Although culture is slower and less sensitive than PCR, our report illustrates that the culture must not be abandoned. Here, we could demonstrate that isolates recovered during the infant's initial episode and the recurrence were indistinguishable, were susceptible to all antibiotics used in this setting, and were genetically related to common strains currently circulating in Europe.
Despite standard treatment and the fact that the initial isolate was sensitive to erythromycin, the infection relapsed after an initial clinical improvement. Josamycin has been used in France for more than 20 years and is considered to be as effective as erythromycin on pertussis (12); no treatment failures have previously been reported in this setting. Treatment failure with erythromycin and newer macrolides, such as clarithromycin and azithromycin, is uncommon (7, 9), but previous reports did not genetically compare the initial and recurrent isolates. The reasons for treatment failure in the present case are unclear. The isolate that caused infection is similar to isolates circulating in Europe (7, 9) and harbors no resistance to the antibiotics used. One possible explanation is the infant's immunological immaturity, and this observation may suggest that in such a population, the gold standard duration of treatment with erythromycin or josamycin (the old macrolides) might not be sufficient. Newer macrolides, such as clarithromycin and azithromycin, might be used in such cases, although a 5-day course of azithromycin failed in a 2-month-old boy receiving concomitant steroid therapy (10).
Of particular interest is the observation that B. pertussis DNA may persist for a long time after treatment initiation. The persistence of pertussis DNA after erythromycin therapy in nine infants has already been described by Edelman et al. (5). Pertussis PCR remained positive for 7 days in four patients and for 10 days in two patients. In our patient, PCR was still positive 51 days after the outset of cotrimoxazole treatment and 34 days after azithromycin relay therapy. This underscores the sensitivity of real-time PCR for pertussis diagnosis, even during treatment. Larger studies are needed to determine how long pertussis DNA remains detectable by real-time PCR after treatment initiation. This might help to determine the optimal duration of antimicrobial chemotherapy and of patient isolation for infants with compromised immunity.
In conclusion, our case report underlines the need to protect infants from pertussis exposure. The health care community can limit the spread of pertussis by educating caretakers and the public about preventing the exposure of infants to coughing adolescents or adults, by insisting on the importance of biologically diagnosing pertussis, using culture and PCR, and by carefully following vaccine schedules. This includes a vaccine booster injection given at 11 to 13 years of age in France and also, since this year, a vaccine booster for young parents and health care workers in contact with infants (14).
FOOTNOTES
Corresponding author. Mailing address: Service de Microbiologie, Hpital Robert-Debre, 48 boulevard Serurier, 75395 Paris cedex 19, France. Phone: 33 1 40 03 23 40. Fax: 33 1 40 03 24 50. E-mail: edouard.bingen@rdb.aphp.fr.
REFERENCES
Baron, S., E. Njamkepo, E. Grimprel, P. Begue, J. C. Desenclos, J. Drucker, and N. Guiso. 1998. Epidemiology of pertussis in French hospitals in 1993 and 1994: thirty years after a routine use of vaccination. Pediatr. Infect. Dis. J. 17:412-418.
Bartkus, J. M., B. A. Juni, K. Ehresmann, C. A. Miller, G. N. Sanden, P. K. Cassiday, M. Saubolle, B. Lee, J. Long, A. R. Harrison, Jr., and J. M. Besser. 2003. Identification of a mutation associated with erythromycin resistance in Bordetella pertussis: implications for surveillance of antimicrobial resistance. J. Clin. Microbiol. 41:1167-1172.
Bassinet, L., M. Matrat, E. Njamkepo, S. Aberrane, B. Housset, and N. Guiso. 2004. Nosocomial pertussis outbreak among adult patients and healthcare workers. Infect. Control Hosp. Epidemiol. 25:995-997.
Cherry, J. D., E. Grimprel, N. Guiso, U. Heininger, and J. Mertsola. 2005. Defining pertussis epidemiology: clinical, microbiologic and serologic perspectives. Pediatr. Infect. Dis. J. 24:S25-34.
Edelman, K., S. Nikkari, O. Ruuskanen, Q. He, M. Viljanen, and J. Mertsola. 1996. Detection of Bordetella pertussis by polymerase chain reaction and culture in the nasopharynx of erythromycin-treated infants with pertussis. Pediatr. Infect. Dis. J. 15:54-57.
Gilberg, S., E. Njamkepo, I. P. Du Chatelet, H. Partouche, P. Gueirard, C. Ghasarossian, M. Schlumberger, and N. Guiso. 2002. Evidence of Bordetella pertussis infection in adults presenting with persistent cough in a French area with very high whole-cell vaccine coverage. J. Infect. Dis. 186:415-418.
Langley, J. M., S. A. Halperin, F. D. Boucher, and B. Smith. 2004. Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics 114:e96-101.
Nouvellon, M., J. F. Gehanno, M. Pestel-Caron, C. Weber, J. F. Lemeland, and N. Guiso. 1999. Usefulness of pulsed-field gel electrophoresis in assessing nosocomial transmission of pertussis. Infect. Control Hosp. Epidemiol. 20:758-760.
Pichichero, M. E., W. J. Hoeger, and J. R. Casey. 2003. Azithromycin for the treatment of pertussis. Pediatr. Infect. Dis. J. 22:847-849.
Steinberg, J. M., and I. Srugo. 2002. Reoccurrence of culture-positive pertussis in an infant initially treated with azithromycin and steroids. Arch. Pediatr. Adolesc. Med. 156:1057-1058.
Templeton, K. E., S. A. Scheltinga, A. van der Zee, B. M. Diederen, A. M. van Kruijssen, H. Goossens, E. Kuijper, E. C. Claas, K. Kosters, U. Reischl, J. Schmetz, M. Riffelmann, C. H. Wirsing von Konig, N. Lehn, G. N. Sanden, and M. J. Loeffelholz. 2003. Evaluation of real-time PCR for detection of and discrimination between Bordetella pertussis, Bordetella parapertussis, and Bordetella holmesii for clinical diagnosis. J. Clin. Microbiol. 41:4121-4126.
Torre, D., F. Maggiolo, and C. Sampietro. 1984. Comparative clinical study of josamycin and erythromycin in pertussis. Chemioterapia 3:255-257.
Weber, C., C. Boursaux-Eude, G. Coralie, V. Caro, and N. Guiso. 2001. Polymorphism of Bordetella pertussis isolates circulating for the last 10 years in France, where a single effective whole-cell vaccine has been used for more than 30 years. J. Clin. Microbiol. 39:4396-4403.
Wirsing von Konig, C. H., M. Campins-Marti, A. Finn, N. Guiso, J. Mertsola, and J. Liese. 2005. Pertussis immunization in the global pertussis initiative European region: recommended strategies and implementation considerations. Pediatr. Infect. Dis. J. 24:S87-S92.(Stephane Bonacorsi, Caroline Farnoux, Ph)