Ampicillin and Chloramphenicol Resistance in Systemic Haemophilus influenzae Disease

In late August 1983, a 19-month-old girl was transferred from the Dominican Republic to a hospital in Houston, Texas, with a diagnosis of relapsing Haemophilus influenzae type b (Hib) meningitis.

Her initial cerebrospinal fluid (CSF) examination in the Dominican Republic contained 800 white blood cells (WBC), predominantly polymorphonuclear leukocytes, and a glucose concentration of 7 mg/dl. She was treated with ampicillin and chloramphenicol for 72 hours and then changed to chloramphenicol alone for 9 more days after the initial Hib isolate was demonstrated to be B-lactamase positive.

At the end of a 12-day course of antibiotic treatment, the patient was reported well and afebrile. Lumbar puncture after completion of treatment was sterile, showed five lymphocytes, and reportedly had normal glucose and protein values.

Three days later, she developed vomiting and fever up to 40.5 C (105 F). She was again started on chloramphenicol and was given three doses of ceftazidime before arrival in Houston. Her CFS at this time had 300 WBC/mm((3)), with 39% polys, a glucose of 50 mg/dl, and a protein concentration of 52 mg/dl. CSF culture was sterile, but counterimmunoelectrophoresis (CIE) was positive for Hib polyribosylribitol phosphate (PRP) antigen. She received a 12-day course of moxalactam (200 mg/kg/day), remained afebrile from the second day, and had normal neurologic examinations throughout hospitalization. At completion of therapy, the CSF was sterile and CIE-negative and contained 99 WBC, 2% polys, 98% monocytes, protein 22 mg/dl, and glucose 39 mg/dl. The original CSF isolate from the Dominican Republic was confirmed as H. influenzae type b, B-lactamase positive. On testing in Houston, the organism had a minimum inhibitory concentration (MIC) of 12.5 ug/ml and a minimum bactericidal concentration (MBC) of 25 ug/ml to chloramphenicol and produced chloramphenicol acetyltransferase. The MIC and MBC to moxalactam were both 0.016 ug/ml. Reported by JN Walterspiel, MD, SL Kaplan, MD, Baylor College of Medicine, MJ Kessler, MD, Houston, Texas; LF Reid, MD, Clinica Gomez Patino, Santo Domingo, Dominican Republic; Respiratory and Special Pathogens Epidemiology Br, Div of Bacterial Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Resistance of H. influenzae strains to ampicillin or chloramphenicol, conventional antimicrobial therapy for systemic (bacteremic) H. influenzae disease, is of growing concern among medical practitioners. An estimated 15,000-20,000 cases of systemic disease caused by H. influenzae, including meningitis, sepsis, pneumonia, epiglottitis, cellulitis, septic arthritis, and osteomyelitis, occur annually in the United States. Most such systemic infections occur among children under 5 years of age and are caused by serotype b organisms.

Since ampicillin-resistant isolates of Hib were first recognized in 1974, resistant strains have become increasingly prevalent. In 1975-1976, a national survey of pediatric centers in the United States found the prevalence of ampicillin-resistant H. influenzae isolates from cultures of blood and CSF was 4.5% (1). Since then, several reports have documented a steady trend of increasing prevalence of ampicillin resistance (2-3). By 1980-1981, ampicillin resistance rates of 17% to 28% were reported (2-5). Nationwide data on this trend are available for 1978-1982 from CDC's passive surveillance system for bacterial meningitis maintained in collaboration with the Conference of State and Territorial Epidemiologists (Table 2). These data are based on hospital reporting of resistance from 20 states that (1) participated in all years from 1978 to 1982, (2) reported ampicillin-testing results on at least 50 isolates, and (3) had over 75% of all isolates from reported cases tested for ampicillin susceptibility. Ampicillin resistance among HI isolates from reported cases of bacterial meningitis varied from 19% in 1978 to 24% in 1981-1982. Geographic differences emerged when the frequency of resistance was analyzed by individual reporting states (Figure 2).

The primary mechanism of ampicillin resistance is by production of the TEM B-lactamase enzyme, mediated by a plasmid that contains a gene coding for this enzyme. Similar plasmids mediating resistance to penicillin and ampicillin have been found in Enterobacteriaceae and in Neisseria gonorrhoeae strains, and such genes are transferable between species.

Resistance of Hib strains to chloramphenicol has remained at a low prevalence rate of under 1% since the first report appeared in 1972 (6). Most chloramphenicol-resistant (MIC greater than 2 ug/ml) strains produce chloramphenicol acetyltransferase, an enzyme capable of inactivating chloramphenicol, and resistance is often plasmid-mediated (7).

Resistance of Hib strains to both ampicillin and chloramphenicol, first reported in 1980 (8-10) and seen in the case described above, is rare. Presently, there are no indications that any change in the initial therapy for suspected systemic disease caused by H. influenzae--ampicillin and chloramphenicol--is warranted. However, the substantial rise in prevalence of ampicillin resistance in the past decade, and similarities in mechanisms mediating ampicillin and chloramphenicol resistance, suggest the possibility that chloramphenicol resistance alone or combined with ampicillin resistance could emerge as a more prevalent problem. Through the existing meningitis surveillance system, CDC plans to begin monitoring reported cases of H. influenzae meningitis for the prevalence of chloramphenicol resistance.

References

1. Ward JI, Tsai TF, Filice GA, Fraser DW. Prevalence of ampicillin- and chloramphenicol-resistant strains of Haemophilus influenzae causing meningitis and bacteremia: national survey of hospital laboratories. J Infect Dis 1978;138:421-4.

2. Nelson JD. The increasing frequency of beta-lactamase-producing Haemophilus influenzae B. JAMA (letter) 1980;244:239.

3. Schwartz RH, Goldenberg RI, Park C, Keim D. The increasing prevalence of bacteremic ampicillin-resistant Haemophilus influenzae infections in a community hospital. Ped Infect Dis 1982;1:242-4.

4. Schlech WF, Band JD, Hightower AW, Broome CV. Bacterial meningitis in the United States (Abstract). 22nd Interscience Conference on Antimicrobial Agents and Chemotherapy. Miami, Florida: American Society for Microbiology, 1982.

5. Gustafson TL, Kelley RA, Hutcheson RH, Schaffner W, Sell SH. Statewide survey of the antimicrobial susceptibilities of Haemophilus influenzae producing invasive disease in Tennessee. Ped Infect Dis 1983;2:119-22.

6. Barrett FF, Taber LH, Morris CR, Stephenson WB, Clark DJ, Yow MD. A 12 year review of the antibiotic management of Hemophilus influenzae meningitis. Comparison of ampicillin and conventional therapy including chloramphenicol. J Pediatr 1972;81:370-7.

7. Roberts MC, Swenson CD, Owens LM, Smith AL. Characterization of chloramphenicol-resistant Haemophilus influenzae. Antimicrob Agents Chemother 1980;18:610-5.

8. Kenny JF, Isburg CD, Michaels RH. Meningitis due to Haemophilus influenzae type b resistant to both ampicillin and chloramphenicol. Pediatrics 1980;66:14-6.

9. Uchiyama N, Greene GR, Kitts DR, Thrupp LD. Meningitis due to Haemophilus influenzae type b resistant to ampicillin and chloramphenicol. J Pediatr 1980;97:421-4.

10. Simasathien S, Dnangmani C, Echeverria P. Haemophilus influenzae type b resistant to ampicillin and chloramphenicol in an orphanage in Thailand. Lancet 1980;2:1214-7.

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