Emergence of Fluoroquinolone-Resistant Neisseria meningitidis --- Minnesota and North Dakota, 2007--2008

Meningoccocal disease causes substantial morbidity and mortality; approximately 10% of cases are fatal. Among those who survive, 10%--15% have long-term sequelae. Nasopharyngeal carriage of Neisseria meningitidis is a precursor to disease; however, the majority of carriers do not develop disease. Household and other close contacts of persons with meningococcal disease have a higher risk for carriage and therefore invasive disease. These persons should receive antibiotic chemoprophylaxis to eliminate nasopharyngeal carriage of N. meningitidis as soon as possible (1). The rate of secondary disease for close contacts is highest immediately after onset of disease in the index patient; secondary cases rarely occur after 14 days (1). Ciprofloxacin, a second-generation fluoroquinolone, is an effective single-dose oral chemoprophylaxis agent. Although isolated cases of ciprofloxacin-resistant meningoccocal disease have been described in Argentina, Australia, China, France, India, and Spain, resistance has not been reported in North America (2--4). This report describes a cluster of three cases of fluoroquinolone-resistant meningococcal disease that occurred among residents of the border area of North Dakota and Minnesota during January 2007--January 2008. The first of these cases was epidemiologically linked and had closely related molecular features to a 2006 case of fluoroquinolone-susceptible meningococcal disease that occurred in the same geographic region. Until further notice, ciprofloxacin should not be used for chemoprophylaxis of close contacts of persons with meningococcal disease in selected counties in North Dakota and Minnesota. Ceftriaxone, rifampin, and azithromycin are alternative agents.

Case Reports

In August 2006, a worker in a day care center in eastern North Dakota became ill with fever, rash, headache, and abdominal pain. The patient had a precipitous clinical decline and died on the first day of hospitalization. N. meningitidis was not isolated from postmortem samples of cerebrospinal fluid (CSF), but polymerase chain reaction (PCR) results were positive for serogroup B N. meningitidis (5). DNA sequencing of the gyrA gene revealed none of the mutations previously associated with fluoroquinolone resistance, consistent with fluoroquinolone susceptibility (3). The majority of children at the day care center received rifampin, and staff members received ciprofloxacin for antibiotic prophylaxis.

Case 1. A child from eastern North Dakota, who was a student in the same classroom in the day care center of the worker who died, received rifampin prophylaxis in 2006. In January 2007, the child was hospitalized with meningitis and treated with ceftriaxone; the patient made a full recovery. Serogroup B N. meningitidis was isolated from CSF culture. Subsequently, the isolate was determined to be resistant to ciprofloxacin by epsilometer test (E-test), an agar diffusion method, with a minimum inhibitory concentration (MIC) of 0.19 µg/mL at the North Dakota Department of Health (NDDH). Broth microdilution testing at the Minnesota Department of Health (MDH) laboratory indicated an MIC of 0.25 µg/mL for ciprofloxacin and levofloxacin, indicating fluoroquinolone resistance (6). The isolate was susceptible to ceftriaxone, rifampin, and azithromycin by broth microdilution at the MDH laboratory. Sequencing of the gyrA gene revealed a threonine to isoleucine change at amino acid 91, which had been associated previously with fluoroquinolone resistance in N. meningitidis (3). Except for differences in the gyrA gene, isolates from this patient and the worker who died in 2006 were indistinguishable on further molecular characterization, including multilocus sequence typing (MLST) and porA and porB typing. Day care attendants and staff members and household contacts of the child were administered antibiotic prophylaxis with rifampin (for children) and ciprofloxacin (for adults) before antibiotic susceptibility results were available.

Case 2. On January 7, 2008, an adult resident of western Minnesota had meningococcal disease and died. Serogroup B N. meningitidis was isolated from CSF culture. Antibiotic susceptibility testing by broth microdilution on the isolate at the MDH laboratory revealed identical results to the isolate in case 1, and results of MLST and pulsed-field gel electrophoresis (PFGE) testing were indistinguishable from the isolate in case 1. DNA sequencing revealed the same gyrA sequence detected in the isolate in case 1. Household contacts were administered ciprofloxacin or rifampin for chemoprophylaxis. When antibiotic susceptibility results were available, more than 2 weeks had passed, and adults were not offered chemoprophylaxis with another agent.

Case 3. On January 24, 2008, a college senior from western Minnesota had headache, fever, and rash; the student recovered completely. Serogroup B N. meningitidis was isolated from CSF culture. Antibiotic susceptibility of the isolate was identical to that in cases 1 and 2 by broth microdilution at the MDH laboratory. MLST, porA and porB typing, and PFGE of this isolate were indistinguishable from the isolates in cases 1 and 2. DNA sequencing revealed the same gyrA sequence detected in isolates from cases 1 and 2. Close contacts initially received ciprofloxacin but were offered azithromycin after the isolate was determined to be fluoroquinolone resistant.

Reported by: J Rainbow, D Boxrud, A Glennen, R Danila, B Juni, J Mariotti, R Lynfield, Minnesota Dept of Health. J Baird, K Kruger, M Sander, T Miller, S Lovelace, J Sletteland, T Dwelle, L Elijah, L Well, North Dakota Dept of Health. TA Clark, A Cohn, B Harcourt, C Hatcher, R Mair, L Mayer, N Messonnier, R Novak, S Schmink, J Theodore, Div of Bacterial Diseases, National Center for Immunization and Respiratory Diseases; S Wei, H Wu, EIS officers, CDC.

Editorial Note:

This report describes three cases of fluoroquinolone-resistant serogroup B meningococcal disease among residents of the North Dakota--Minnesota border during 2007--2008. Case 1 was epidemiologically linked to a 2006 case in the same geographical region and had closely related molecular features to that case. However, the 2006 case lacked the gyrA mutation that confers fluoroquinolone resistance.

This report is the first description of ciprofloxacin-resistant meningococcal disease reported in North America. The three fluoroquinolone-resistant cases were caused by serogroup B N. meningitidis. Serogroup B accounts for 35% of meningococcal disease cases in the United States. No licensed vaccine against serogroup B N. meningitidis is available in the United States. Many public health laboratories do not routinely test N. meningitidis isolates for antibiotic susceptibility. Therefore, other cases of fluoroquinolone-resistant meningococcal disease might have occurred in the United States that have not been detected. Neisseria gonorrhoeae and N. meningitidis are closely related pathogens; fluoroquinolone-resistant gonoccocal disease emerged rapidly in North America and now accounts for 13.6% of clinical isolates (7).

Ciprofloxacin is 95% effective in eliminating nasopharyngeal carriage of N. meningitidis, but the effectiveness of 500 mg of ciprofloxacin in eliminating carriage of fluoroquinolone-resistant N. meningitidis is unknown. Ciprofloxacin should not be used in areas where resistant strains have been identified; effective alternative antimicrobial chemoprophylaxis agents are available (Table). Of 142 isolates tested at MDH from cases that occurred during 2002--2007, all were sensitive to ceftriaxone and azithromycin, and one isolate in 2002 was resistant to rifampin (8). Azithromycin is not recommended routinely for chemoprophylaxis, but one study determined that azithromycin was equivalent to rifampin for chemoprophylaxis (9). In decisions regarding prophylaxis of close contacts, all antibiotics should be used cautiously because of possible resistance resulting from widespread use.

A survey of pharyngeal carriage to determine the extent of fluoroquinolone-resistant meningococcus among residents of the North Dakota--Minnesota border area is being conducted jointly by NDDH, MDH, and CDC. Additionally, susceptibility testing of existing isolates from other regions of the United States and prospective surveillance are under way at CDC. The following are interim recommendations to state and local health departments and public health laboratories.

Until further notice, ciprofloxacin should no longer be prescribed for empiric antimicrobial chemoprophylaxis of meningococcal disease in the North Dakota counties of Barnes, Cass, Cavalier, Grand Forks, Nelson, Pembina, Ramsey, Ransom, Richland, Sargent, Steele, Traill, and Walsh, and in the Minnesota counties of Becker, Beltrami, Clay, Clearwater, Douglas, Grant, Hubbard, Kittson, Lake of the Woods, Mahnomen, Marshall, Norman, Otter Trail, Pennington, Polk, Pope, Red Lake, Roseau, Stevens, Traverse, and Wilkin. Ceftriaxone, rifampin, and azithromycin are alternative agents (Table). Ciprofloxacin may continue to be used for chemoprophylaxis of adults outside this region (1). If an isolate is tested and determined to be resistant to ciprofloxacin within 2 weeks of illness onset in the index patient, close contacts should be offered an alternative agent for antibiotic chemoprophylaxis.

Laboratories are encouraged to conduct surveillance for antibiotic-resistant isolates of meningococcal disease, especially in serogroup B isolates. Laboratories that seek support for such testing should contact CDC. Health departments should enhance surveillance for chemoprophylaxis failure among reported cases of meningococcal disease.

All cases of ciprofloxacin-resistant meningococcal disease and ciprofloxacin prophylaxis failures should be reported to local and state health authorities and to CDC. Laboratories that routinely test meningococcal isolates for resistance to ciprofloxacin should report any ciprofloxacin-resistant isolates identified retrospectively to the Meningitis and Vaccine Preventable Diseases Branch at 404-639-3158.

References

1. CDC. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005;54(No. RR-7).
2. Jorgensen JH, Crawford SA, Fiebelkorn KR. Susceptibility of Neisseria meningitidis to 16 antimicrobial agents and characterization of resistance mechanisms affecting some agents. J Clin Microbiol 2005;43: 3162--71.
3. Singhal S, Purnapatre K, Kalia V, et al. Ciprofloxacin-resistant Neisseria meningitidis, Delhi, India. Emerg Infect Dis 2007;13:614--6.
4. Chu YW, Cheung TK, Tung V, et al. A blood isolate of Neisseria meningitidis showing reduced susceptibility to quinolones in Hong Kong. Int J Antimicrob Agents 2007;30:94--5.
5. Mothershed EA, Sacchi C, Whitney A, et al. Use of real-time PCR to resolve slide agglutination discrepancies in serogroup identification of Neisseria meningitidis. J Clin Microbiol 2004;42:320--8.
6. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Wayne, PA: Clinical and Laboratory Standards Institute; 2005(Suppl M100-S15).
7. CDC. Update to CDC's sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR 2007;56:332--6.
8. Rainbow J, Cebelinski E, Bartkus J, Glennen A, Boxrud D, Lynfield R. Rifampin-resistant meningococcal disease. Emerg Infect Dis 2005;11:977--9.
9. Girgis N, Sultan Y, Frenck RW Jr, El-Gendy A, Farid Z, Mateczun A. Azithromycin compared with rifampin for eradication of nasopharyngeal colonization by Neisseria meningitidis. Pediatr Infect Dis J 1998;17:816--9.

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Date last reviewed: 2/20/2008