September /978
394
TheJournalojPEDIATRICS
Effect of TMP-SMX on nasopharyngeal carriage of ampicillin-sensitive and ampicillin-resistant Hemophilus influenzae type B The carriage rate of ampictlltn-resistant Hemophilus infiuenzae type B in a chronic care facfli~y was investigated. Up to 48% of the children carried this strain. Of interest was the finding of sim ultaneous carriage of ampicillin-resistant and ampicillin-sensitive HITB. a phenomenon which was detected by
using both chocolate agar and chocolate agar containing 2 p.glml of ampicillin. A trial of sulfamethoxazote-tnm ethoprim successfull y eradicated the ampicillin-sensitive H1TB. but had no effect on the ampicilli n-resistant HITB .
Ram Yogev, M.D., Herman B. Lander, M.D., and A Todd Davis, M.D., Chicago, Ill.
AMPICILLI N-RESISTANT Hemophilus infiuenzae type B bas emerged as clinically important pathogens within the last decade.' As many as 10% of RITB isolates are ampicillin resistant. ' Although there has been intensive study of host bactericidal mechanisms' and the mechanisms of antibiotic resistance," the epidemiology of HITB is incompletely understood, Carriage rates of 10 to 58% in healthy children have been reported for RITB presumed to be sensitive to ampicillin.s" One study noted carriage of ampicillin-resistant RITB in 35% of children at a day-care center following three cases of ampicillin-resistant H. influenzae meningitis." Following recognition of ampicillin-resistant HITB as the etiologic agent of a subgaleal abscess in a child in a chronic care facility, ' we studied the ' carriage rates of ampicillin-sensitive and ampicillin-resistant RITB, and investigated the efficacy of sulfamethoxazole-trimethoprim therapy in eradicating HITB from the children.
From the Division of Infe ctious Disease, Children's Memorial Hospital. Presented. in part, at the 481h Annual Meeting of The Society for Pediatric Research April 26 to 28, 19 78. in New York. N. Y. "Reprint address: DMsi M of I nfectious Disease, Children 's Memorial Hospl tal; 2300 Children's Plaza, Chicago. IL
60614.
.
Vol, 93, No.3, pp. 394-397
PATIENTS, SUBJECT , AND METHODS The index case was admitted to Children's Memorial Hospital from a children's chronic care facility with an ampicillin-resistant HITB subgaleal abscess. As man y as 41 infants I to 3 years of age residing on the same ward were cultured multiple times. Abbreviations used HITB: Hemophilus tnfiuenzae type B TMP-SMX: trirnerhcprim-sulfamethoxazole
Nasopharyngeal swabs were plated directly on two med ia, chocolate agar and selective medium consisting of chocolate agar containing 2 J,lg/ml amp icillin . After incubation overnight at 36°C in an atmosphere supplemented with 5% CO ., the plates were examined for growth of Hemophilus species. Negative plates were re-incubated for another 24 hours and, ifstill negative, discarded. Colonies suspected to be Hemophilus were identified as H. infiuenzae by their Gram stain and nu trit ional requirements (V and X). Typing was done by slide agglutination using the H. infiuen zae typing sera supplied by Difco (Detroit, Mich.); !" The antibiotic susceptibility of the RITB was tested against standard discs of ampicillin, and the combination of trimethoprim-sulfamethoxazole in a ratio of 1.25 to 23.75 /lg." Production of ,B-lactamase was assessed by the rapid test" and contirmed by Dr. Clyde Thornsberry,
0022·3476178/0393-0394$00,40/0 It> 1978 The C. V. Mosby Co.
Effect of TMP-SMX on nasopharyngeal carriage of H . influenzae type B
Volume 93 Number 3
395
Table I. Carrier rate of H. influenzae type B during the first three surveys
Patients with amp icillinsensitiveH. influenzae typ e
Patients with ampicillinresistan t H. influenzae type
B
B
Patients with both ampicillin-sensitive and ampicillin-resistant H. inlluenzae type B
Date
No. patients cultured
11/76 12/76
32
21
8
2
30
10
8
1/77
27
20 22
13
8
Table II. Carrier rate of H. infiuenzae type B during treatment with trimethoprim-sulfamethoxazole (8 mg TMP + 40 mg SMX/kg/day)
Date Before TMP-SMX started 2 days after treatment started 3 days after treatment completed
Patients with ampicillinresistant H . in fluenzae type B
No. patients cultured
Patients with amp icillinsensitive H. influenz ae type B
41 41
22
8
0
2
41
5
8
National Center for Diseas e Control. Minimal inhibitory con centration determinations for TMP-SMX were performed by Dr. Thornsberry and by Dr. S. Bushby, Burroughs-Welcome Co.• utilizing 10' colony-forming units on Mueller-Hinton agar supplemented with S% lysed horse blood and NAD .13 End points were determined by the concentration of TMP·SMX causing more than 80% reduction of growth . RESULTS Three culture surveys were done over a three-month period (Table 1). The number of children harboring ampicillin-resistant HlTB ranged from eight to 13 (2548%). Sixty-five to 81% of the children carried ampicillinsensitive RITB during the culture surveys. An intri guing finding was the simultaneous carriage of both am picillin-sensitive and ampicillin-resistant strains. Two such children were found on the first survey. and eight in each of the two subseq uent surveys. Therefore,.2S to 80% of the children carrying ampicillin-resistant strains also carried ampicillin-sensitive strains. After the third culture surve y, two infants harboring resistant organisms died . One died at home of unknown causes; unfortunately, no a utopsy was performed. The other child was hospitalized with pneumonia. su bseq uently died , and amp icillin-resistant RITB were cultured from postmortem lung specimens. On the basis of this observation, an attempt to reduce or eradicate HITB carriage in these children was undertaken. At this time, 41 children
Patients with both ampicillin-sensitive and amp icillin-resistant H. influenzae type B
4 0
were again cultured (Table II) . Eight children had ampicillin-resistant HITB and 22 had am picillin-sensitive BITB. Four children had both ampicillin-sensitive and ampi cillin-resistant strains. All of the ampicillin-sensitive and ampicillin-resistant isola tes were sens itive in vitro by disc susceptibility testing to TMP-SMX. Treatment was instituted for all 41 children for five days with 8 mg trimethoprim and 40 mg sulfarnethoxazole/kg/day. The children were cultured two days after initiation of therapy and three days after it was completed. After two days of therapy, no ampicillin-sensitive organisms were recovered. Two of the eight patients who had the ampicillinresistant organisms were positive at this time. Three days after therapy had been completed, five of the 22 who originally carried the a mpicillin -sensitive strain continued to carry ampicillin-sensitive HITB. All eight who had carried ampicillin-resist ant strains continued to be colonized. One of the eight children also grew ampicillinsensitive HITB. The zone sizes for TMP-SMX were identical for pre- and post-treatment BITB isolates. Three weeks later, another child who carried ampi cillin-resistant HITB developed severe pneumonia, which responded to administration of chloram p henicol. This prompted one more attempt to eradicate the ampicillinresistant HITB from the eight carriers, three of whom also carried ampicillin-sen sitive HITB. Both the dose ofTMPSMX and the duration of th era py were doubled (16 mg trimethoprim and 80 mg sulfamethoxazole/kg/day for ten days). At the end of treatment. no ampicillin-sensitive
396
Yogev. Lander, and Davis
HITB were recovered. Cultures from aU eight infants remained positive for ampicillin-resistant HITB. All eight isolates continued to be susceptible by disc susceptibility testing to TMP-SMX. The discrepancy between in vivo results and disc susceptibility testing led to further in vitro susceptibility studies. Utilizing agar dilution, 93 nasopharyngeal isolates of HITB obtained during the various culture surveys showed at least an 80% reduction in growth in concentrations less than or equal to 9.5 Ilg/ml SMX in combination with 0.5 Ilg/ml of TMP. On 'this basis, all the isolates were judged to be susceptible. Forty-three of 51 ampicillin-resistant isolates had as much as 20% of the original inoculum persisting in TMP-SMX concentrations above 9.5 /Lg/ml SMX and 0,5 j.lg/ml TMP (trailing end points). In contrast, only two of 42 ampicillin-sensitive isolates showed this phenomenon.
DISCUSSION High carriage rates of ampicillin-resistant HITB had been detected in one previous study.' Three cases of meningitis with HITB occurred in members of a day-care center. Eight of 23 (35%) of children attending the same day-care center were subsequently found to harbor ampicillin-resistant HITB. In our study, 25 to 48% of the children harbored the resistant strain. Simultaneous carriage of ampicillin-resistant and ampicillin-sensitive strains has not been previously reported. This phenomenon was detected by simultaneously culturing specimens on both chocolate agar and chocolate agar containing 2 j.lg/ml of ampicillin. More ampicillinresistant strains were recovered from selective media (chocolate agar with ampicillin) than from plain chocolate agar. For example, in the third survey, all 13 ampicillinresistant HITB were detected on the selective media, while only five were found on the plain chocolate agar. The other eight plain chocolate agar plates yielded only ampicillin-sensitive HITB. Previous clinical experience with TMP-SMX in patients with infections caused by ampicillin-sensitive HITB suggested this to be a useful drug combination." .. In addition, in vitro studies have shown little difference in the susceptibility of ampicillin-sensitive and ampicillinresistant HITB to this drug combination.": 18 Therefore, the persistence of ampicillin-resistant HITB in the face of TMP-SMX therapy was unexpected. After a five-day course, there was a 76% reduction in the carriage rate of ampicillin-sensitive strains. The ampicillin-resistant strain was not eradicated from any carrier. Failure to obtain or absorb the medication is not a likely explanation. These
The Journal of Pediatrics September 1978
patients were given the medication while inpatients at the chronic care facility. Also, four of the eight carriers of the ampicillin-resistant RITB strains simultaneously had an ampicillin-sensitive strain prior to treatment. Three became culture negative for the ampicillin-sensitive strain after therapy. Doubling the dose of TMP-SMX and extending therapy for ten days were equally ineffective in eradicating the ampicillin-resistant strains. In fact, by the conclusion of this therapy, only ampicillin-resistant HITB were cultured from the nasopharynx; all the ampicillin-sensitive HITB had been eradicated. All the ampicillin-sensitive and ampicillin-resistant HITB were thought to he susceptible to SMX-TMP by disc susceptibility studies. The majority of the ampicillinresistant isolates showed trailing end points when agar dilution susceptibility studies were done. This phenomenon was also noted in two of the ampicillin-sensitive strains. Further clinical experience is needed to determine if trailing end points are indicative of in vivo resistance to TM~-SMX. Unfortunately. technical problems precluded assessing the mean bacteriocidal concentration of TMPSMX. Previous reports of intrafamilial disease secondary to HITB," outbreaks of disease due to HITB in day-care centers," , and our observation of three children becoming severely ill with this organism, suggest the occasional spread of this organism in closed populations. Previous investigators have attempted to reduce HITB carriage rates by vaccination or administration of antibiotics. H. infiuenzae type B vaccine has been used without success." Ampicillin has had variable effects in eliminating ampicillin-sensitive HITB from the nasopharynx of carriers." IS Our study shows that TMP-SMX was effective against the ampicillin-sensitive strain but not against ampicillinresistant strain. Further studies will be required to determine the frequency of in vivo resistance to TMP-SMX of ampicillin-resistant HITB. If chemoprophylaxis for ampicillin-resistant HITB is undertaken, and failure with TMP-SMX occurs, clinical trials with other antibiotics such as rifampin, tetracycline, and chloramphenicol could be considered. At present, it is not known if ampicillin-resistant HlTB strains found to be susceptible in vitro would be eliminated from the nasopharynx by one of those three drugs. From our study TMP-SMX appears to be useful in eradicating ampicillinsensitive HITB. The authors acknowledge the nursing staff at the Children's Institute for Developmental Diseases, the technical assistance of Sandra Marubio, and the helpfuladvice provided by Dr. John V. Bennett.
Volume 93 Number 3
Effect of TMP-SMX on nasopharyngeal carriage of H, infJuenzae type B
REFERENCES I.
2, 1
4. 5.
6.
7.
8.
9,
Jacobson JA, McCormick JB, Hayes P, Thornsberry C, and Kirven L: Epidemiologic characteristics of infections caused by ampicillin-resistant Hamophilus influenzae, Pediatrics 58:388, 1976. Kahn W. Ross S, and Rodriguez W: Haemopnilus influcnzae type B resistant to ampicillin, JAMA 229:298, 1974. Shaw S, Smith AL, Anderson P, and Smith DH: The paradox of Haemophilus influenzae type B bacteremia in the presence of serum bactericidal activity, J Clin Invest 58:1019, 1976. Smith AL: Antibiotics and invasive Haemophilus influenzae, N Engl J Med 294: 1329, 1976, Hable KA, Washington JA, and Herrmann EC: Bacterial and viral throat flora: Comparison of findings in children with acute upper respiratory tract disease and in healthy controls during winter, Clin Pediatr to: 199, 1971. Wald ER, and Levine NM: Frequency of detection of Haemophilus influenzae type B capsular polysaccharide in infants and children with pneumonia, Pediatrics 57:266, 1976, Kilian M, Heine-Jensen J, and Bulow P: Haemophilus in the upper respiratory tract of children, Acta Path Microbiol Scand Section B 80:571, 1972. Ginsburg CM, McCracken GH, Rae S, and Parke JC: Haemophilus influenzae type B disease: Incidence in a daycare center, JAM A 238:604, 1977. Schiffer MS, Maclowry J, Schneerson R, and Robbins JB: Clinical, bacteriological and immunological characterization of ampicillin-resistant Haemophilus influenzae type B, Lancet 2:257, 1974.
397
10. Smith DT, Conant NF, Overman JR, and Zinsser H: Microbiology, ed 13, New York, 1964, Meredith Publishing Co. 11. Thornsberry C, and Kirven LA: Antimicrobial susceptibility of Haemophilus intluenzae, Antlmicrob Agents Chemother 6:620. 1974. 12. Escamilla J: Susceptibility of Haemophilus intluenzae to ampicillin as determined by use of a modified, one minute beta lactarnase test, Aruimicrob Agents Chemother 9: 196, 1976. 13. Kirven LA, and Thornsberry C: In vitro susceptibility of Haemophilus influenzae to trimethoprim-sulfarnethoxazole, Antimicrob Agents Chemother 6:869, 1974. 14. Quick CA, and Wagner D: Trirnethoprim-sulfamethoxazole in the treatment of the ear, nose and throat, J Infec Dis 128:S696, 1973. 15. Hughes DTD: Use of combination of trimethoprim-sulfamethoxazole in the treatment of chest infections, J Infect Dis 128:S701, 1973. 16. McGowan JE, Terry PM, and Nahmias AJ: Susceptibility of Haemophilus influenzae isolates from blood and cerebrospinal fluid to ampicillin, chloramphenicol and trimethoprim-sulfarnethoxazole, Antimicrob Agents Chernother 9: 137, 1976. 17. Ginsburg CM: Epiglottitis, meningitis, and arthritis due to Haernophilus influenzae type B presenting almost simultaneously in siblings, J PEDIATR 87:492, 1975. 18, Globe, MP, Schiffer MS, and Robbins JB: An outbreak of Haemophilus influenzae type B meningitis in an enclosed hospital population, J PEDIATR 88:36, 1976.
Information for authors Most of the provisions of the Copyright Act of 1976 became effective on January I. 1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: "The undersigned authm(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. y, Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not und~r consideration by another journal, and has not been previously published." Authors will be consulted, when possible, regarding republication of their material.
394
TheJournalojPEDIATRICS
Effect of TMP-SMX on nasopharyngeal carriage of ampicillin-sensitive and ampicillin-resistant Hemophilus influenzae type B The carriage rate of ampictlltn-resistant Hemophilus infiuenzae type B in a chronic care facfli~y was investigated. Up to 48% of the children carried this strain. Of interest was the finding of sim ultaneous carriage of ampicillin-resistant and ampicillin-sensitive HITB. a phenomenon which was detected by
using both chocolate agar and chocolate agar containing 2 p.glml of ampicillin. A trial of sulfamethoxazote-tnm ethoprim successfull y eradicated the ampicillin-sensitive H1TB. but had no effect on the ampicilli n-resistant HITB .
Ram Yogev, M.D., Herman B. Lander, M.D., and A Todd Davis, M.D., Chicago, Ill.
AMPICILLI N-RESISTANT Hemophilus infiuenzae type B bas emerged as clinically important pathogens within the last decade.' As many as 10% of RITB isolates are ampicillin resistant. ' Although there has been intensive study of host bactericidal mechanisms' and the mechanisms of antibiotic resistance," the epidemiology of HITB is incompletely understood, Carriage rates of 10 to 58% in healthy children have been reported for RITB presumed to be sensitive to ampicillin.s" One study noted carriage of ampicillin-resistant RITB in 35% of children at a day-care center following three cases of ampicillin-resistant H. influenzae meningitis." Following recognition of ampicillin-resistant HITB as the etiologic agent of a subgaleal abscess in a child in a chronic care facility, ' we studied the ' carriage rates of ampicillin-sensitive and ampicillin-resistant RITB, and investigated the efficacy of sulfamethoxazole-trimethoprim therapy in eradicating HITB from the children.
From the Division of Infe ctious Disease, Children's Memorial Hospital. Presented. in part, at the 481h Annual Meeting of The Society for Pediatric Research April 26 to 28, 19 78. in New York. N. Y. "Reprint address: DMsi M of I nfectious Disease, Children 's Memorial Hospl tal; 2300 Children's Plaza, Chicago. IL
60614.
.
Vol, 93, No.3, pp. 394-397
PATIENTS, SUBJECT , AND METHODS The index case was admitted to Children's Memorial Hospital from a children's chronic care facility with an ampicillin-resistant HITB subgaleal abscess. As man y as 41 infants I to 3 years of age residing on the same ward were cultured multiple times. Abbreviations used HITB: Hemophilus tnfiuenzae type B TMP-SMX: trirnerhcprim-sulfamethoxazole
Nasopharyngeal swabs were plated directly on two med ia, chocolate agar and selective medium consisting of chocolate agar containing 2 J,lg/ml amp icillin . After incubation overnight at 36°C in an atmosphere supplemented with 5% CO ., the plates were examined for growth of Hemophilus species. Negative plates were re-incubated for another 24 hours and, ifstill negative, discarded. Colonies suspected to be Hemophilus were identified as H. infiuenzae by their Gram stain and nu trit ional requirements (V and X). Typing was done by slide agglutination using the H. infiuen zae typing sera supplied by Difco (Detroit, Mich.); !" The antibiotic susceptibility of the RITB was tested against standard discs of ampicillin, and the combination of trimethoprim-sulfamethoxazole in a ratio of 1.25 to 23.75 /lg." Production of ,B-lactamase was assessed by the rapid test" and contirmed by Dr. Clyde Thornsberry,
0022·3476178/0393-0394$00,40/0 It> 1978 The C. V. Mosby Co.
Effect of TMP-SMX on nasopharyngeal carriage of H . influenzae type B
Volume 93 Number 3
395
Table I. Carrier rate of H. influenzae type B during the first three surveys
Patients with amp icillinsensitiveH. influenzae typ e
Patients with ampicillinresistan t H. influenzae type
B
B
Patients with both ampicillin-sensitive and ampicillin-resistant H. inlluenzae type B
Date
No. patients cultured
11/76 12/76
32
21
8
2
30
10
8
1/77
27
20 22
13
8
Table II. Carrier rate of H. infiuenzae type B during treatment with trimethoprim-sulfamethoxazole (8 mg TMP + 40 mg SMX/kg/day)
Date Before TMP-SMX started 2 days after treatment started 3 days after treatment completed
Patients with ampicillinresistant H . in fluenzae type B
No. patients cultured
Patients with amp icillinsensitive H. influenz ae type B
41 41
22
8
0
2
41
5
8
National Center for Diseas e Control. Minimal inhibitory con centration determinations for TMP-SMX were performed by Dr. Thornsberry and by Dr. S. Bushby, Burroughs-Welcome Co.• utilizing 10' colony-forming units on Mueller-Hinton agar supplemented with S% lysed horse blood and NAD .13 End points were determined by the concentration of TMP·SMX causing more than 80% reduction of growth . RESULTS Three culture surveys were done over a three-month period (Table 1). The number of children harboring ampicillin-resistant HlTB ranged from eight to 13 (2548%). Sixty-five to 81% of the children carried ampicillinsensitive RITB during the culture surveys. An intri guing finding was the simultaneous carriage of both am picillin-sensitive and ampicillin-resistant strains. Two such children were found on the first survey. and eight in each of the two subseq uent surveys. Therefore,.2S to 80% of the children carrying ampicillin-resistant strains also carried ampicillin-sensitive strains. After the third culture surve y, two infants harboring resistant organisms died . One died at home of unknown causes; unfortunately, no a utopsy was performed. The other child was hospitalized with pneumonia. su bseq uently died , and amp icillin-resistant RITB were cultured from postmortem lung specimens. On the basis of this observation, an attempt to reduce or eradicate HITB carriage in these children was undertaken. At this time, 41 children
Patients with both ampicillin-sensitive and amp icillin-resistant H. influenzae type B
4 0
were again cultured (Table II) . Eight children had ampicillin-resistant HITB and 22 had am picillin-sensitive BITB. Four children had both ampicillin-sensitive and ampi cillin-resistant strains. All of the ampicillin-sensitive and ampicillin-resistant isola tes were sens itive in vitro by disc susceptibility testing to TMP-SMX. Treatment was instituted for all 41 children for five days with 8 mg trimethoprim and 40 mg sulfarnethoxazole/kg/day. The children were cultured two days after initiation of therapy and three days after it was completed. After two days of therapy, no ampicillin-sensitive organisms were recovered. Two of the eight patients who had the ampicillinresistant organisms were positive at this time. Three days after therapy had been completed, five of the 22 who originally carried the a mpicillin -sensitive strain continued to carry ampicillin-sensitive HITB. All eight who had carried ampicillin-resist ant strains continued to be colonized. One of the eight children also grew ampicillinsensitive HITB. The zone sizes for TMP-SMX were identical for pre- and post-treatment BITB isolates. Three weeks later, another child who carried ampi cillin-resistant HITB developed severe pneumonia, which responded to administration of chloram p henicol. This prompted one more attempt to eradicate the ampicillinresistant HITB from the eight carriers, three of whom also carried ampicillin-sen sitive HITB. Both the dose ofTMPSMX and the duration of th era py were doubled (16 mg trimethoprim and 80 mg sulfamethoxazole/kg/day for ten days). At the end of treatment. no ampicillin-sensitive
396
Yogev. Lander, and Davis
HITB were recovered. Cultures from aU eight infants remained positive for ampicillin-resistant HITB. All eight isolates continued to be susceptible by disc susceptibility testing to TMP-SMX. The discrepancy between in vivo results and disc susceptibility testing led to further in vitro susceptibility studies. Utilizing agar dilution, 93 nasopharyngeal isolates of HITB obtained during the various culture surveys showed at least an 80% reduction in growth in concentrations less than or equal to 9.5 Ilg/ml SMX in combination with 0.5 Ilg/ml of TMP. On 'this basis, all the isolates were judged to be susceptible. Forty-three of 51 ampicillin-resistant isolates had as much as 20% of the original inoculum persisting in TMP-SMX concentrations above 9.5 /Lg/ml SMX and 0,5 j.lg/ml TMP (trailing end points). In contrast, only two of 42 ampicillin-sensitive isolates showed this phenomenon.
DISCUSSION High carriage rates of ampicillin-resistant HITB had been detected in one previous study.' Three cases of meningitis with HITB occurred in members of a day-care center. Eight of 23 (35%) of children attending the same day-care center were subsequently found to harbor ampicillin-resistant HITB. In our study, 25 to 48% of the children harbored the resistant strain. Simultaneous carriage of ampicillin-resistant and ampicillin-sensitive strains has not been previously reported. This phenomenon was detected by simultaneously culturing specimens on both chocolate agar and chocolate agar containing 2 j.lg/ml of ampicillin. More ampicillinresistant strains were recovered from selective media (chocolate agar with ampicillin) than from plain chocolate agar. For example, in the third survey, all 13 ampicillinresistant HITB were detected on the selective media, while only five were found on the plain chocolate agar. The other eight plain chocolate agar plates yielded only ampicillin-sensitive HITB. Previous clinical experience with TMP-SMX in patients with infections caused by ampicillin-sensitive HITB suggested this to be a useful drug combination." .. In addition, in vitro studies have shown little difference in the susceptibility of ampicillin-sensitive and ampicillinresistant HITB to this drug combination.": 18 Therefore, the persistence of ampicillin-resistant HITB in the face of TMP-SMX therapy was unexpected. After a five-day course, there was a 76% reduction in the carriage rate of ampicillin-sensitive strains. The ampicillin-resistant strain was not eradicated from any carrier. Failure to obtain or absorb the medication is not a likely explanation. These
The Journal of Pediatrics September 1978
patients were given the medication while inpatients at the chronic care facility. Also, four of the eight carriers of the ampicillin-resistant RITB strains simultaneously had an ampicillin-sensitive strain prior to treatment. Three became culture negative for the ampicillin-sensitive strain after therapy. Doubling the dose of TMP-SMX and extending therapy for ten days were equally ineffective in eradicating the ampicillin-resistant strains. In fact, by the conclusion of this therapy, only ampicillin-resistant HITB were cultured from the nasopharynx; all the ampicillin-sensitive HITB had been eradicated. All the ampicillin-sensitive and ampicillin-resistant HITB were thought to he susceptible to SMX-TMP by disc susceptibility studies. The majority of the ampicillinresistant isolates showed trailing end points when agar dilution susceptibility studies were done. This phenomenon was also noted in two of the ampicillin-sensitive strains. Further clinical experience is needed to determine if trailing end points are indicative of in vivo resistance to TM~-SMX. Unfortunately. technical problems precluded assessing the mean bacteriocidal concentration of TMPSMX. Previous reports of intrafamilial disease secondary to HITB," outbreaks of disease due to HITB in day-care centers," , and our observation of three children becoming severely ill with this organism, suggest the occasional spread of this organism in closed populations. Previous investigators have attempted to reduce HITB carriage rates by vaccination or administration of antibiotics. H. infiuenzae type B vaccine has been used without success." Ampicillin has had variable effects in eliminating ampicillin-sensitive HITB from the nasopharynx of carriers." IS Our study shows that TMP-SMX was effective against the ampicillin-sensitive strain but not against ampicillinresistant strain. Further studies will be required to determine the frequency of in vivo resistance to TMP-SMX of ampicillin-resistant HITB. If chemoprophylaxis for ampicillin-resistant HITB is undertaken, and failure with TMP-SMX occurs, clinical trials with other antibiotics such as rifampin, tetracycline, and chloramphenicol could be considered. At present, it is not known if ampicillin-resistant HlTB strains found to be susceptible in vitro would be eliminated from the nasopharynx by one of those three drugs. From our study TMP-SMX appears to be useful in eradicating ampicillinsensitive HITB. The authors acknowledge the nursing staff at the Children's Institute for Developmental Diseases, the technical assistance of Sandra Marubio, and the helpfuladvice provided by Dr. John V. Bennett.
Volume 93 Number 3
Effect of TMP-SMX on nasopharyngeal carriage of H, infJuenzae type B
REFERENCES I.
2, 1
4. 5.
6.
7.
8.
9,
Jacobson JA, McCormick JB, Hayes P, Thornsberry C, and Kirven L: Epidemiologic characteristics of infections caused by ampicillin-resistant Hamophilus influenzae, Pediatrics 58:388, 1976. Kahn W. Ross S, and Rodriguez W: Haemopnilus influcnzae type B resistant to ampicillin, JAMA 229:298, 1974. Shaw S, Smith AL, Anderson P, and Smith DH: The paradox of Haemophilus influenzae type B bacteremia in the presence of serum bactericidal activity, J Clin Invest 58:1019, 1976. Smith AL: Antibiotics and invasive Haemophilus influenzae, N Engl J Med 294: 1329, 1976, Hable KA, Washington JA, and Herrmann EC: Bacterial and viral throat flora: Comparison of findings in children with acute upper respiratory tract disease and in healthy controls during winter, Clin Pediatr to: 199, 1971. Wald ER, and Levine NM: Frequency of detection of Haemophilus influenzae type B capsular polysaccharide in infants and children with pneumonia, Pediatrics 57:266, 1976, Kilian M, Heine-Jensen J, and Bulow P: Haemophilus in the upper respiratory tract of children, Acta Path Microbiol Scand Section B 80:571, 1972. Ginsburg CM, McCracken GH, Rae S, and Parke JC: Haemophilus influenzae type B disease: Incidence in a daycare center, JAM A 238:604, 1977. Schiffer MS, Maclowry J, Schneerson R, and Robbins JB: Clinical, bacteriological and immunological characterization of ampicillin-resistant Haemophilus influenzae type B, Lancet 2:257, 1974.
397
10. Smith DT, Conant NF, Overman JR, and Zinsser H: Microbiology, ed 13, New York, 1964, Meredith Publishing Co. 11. Thornsberry C, and Kirven LA: Antimicrobial susceptibility of Haemophilus intluenzae, Antlmicrob Agents Chemother 6:620. 1974. 12. Escamilla J: Susceptibility of Haemophilus intluenzae to ampicillin as determined by use of a modified, one minute beta lactarnase test, Aruimicrob Agents Chemother 9: 196, 1976. 13. Kirven LA, and Thornsberry C: In vitro susceptibility of Haemophilus influenzae to trimethoprim-sulfarnethoxazole, Antimicrob Agents Chemother 6:869, 1974. 14. Quick CA, and Wagner D: Trirnethoprim-sulfamethoxazole in the treatment of the ear, nose and throat, J Infec Dis 128:S696, 1973. 15. Hughes DTD: Use of combination of trimethoprim-sulfamethoxazole in the treatment of chest infections, J Infect Dis 128:S701, 1973. 16. McGowan JE, Terry PM, and Nahmias AJ: Susceptibility of Haemophilus influenzae isolates from blood and cerebrospinal fluid to ampicillin, chloramphenicol and trimethoprim-sulfarnethoxazole, Antimicrob Agents Chernother 9: 137, 1976. 17. Ginsburg CM: Epiglottitis, meningitis, and arthritis due to Haernophilus influenzae type B presenting almost simultaneously in siblings, J PEDIATR 87:492, 1975. 18, Globe, MP, Schiffer MS, and Robbins JB: An outbreak of Haemophilus influenzae type B meningitis in an enclosed hospital population, J PEDIATR 88:36, 1976.
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