Resistance of Streptococcus pneumoniae to Fluoroquinolones -- United States, 1995-1999.
ABCs is an ongoing, active, population-based surveillance system for invasive pneumococcal disease conducted in selected areas of the United States. This analysis includes ABCs areas with continuous surveillance during 1995-1999. These areas include selected counties in California, Connecticut, Georgia, Maryland, Minnesota, Oregon, and Tennessee (aggregate population: 17.3 million). A case of invasive pneumococcal disease was defined as isolation of pneumococcus from blood or other normally sterile site from a resident of one of the surveillance areas. Isolates were tested for antimicrobial susceptibility to ofloxacin (1995-1997) or levofloxacin and trovafloxacin (1998-1999) using the broth microdilution method, as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (7). Definitions for interpretation of susceptible, intermediate, and resistant isolates also were from NCCLS (8); isolates that were either intermediate or resistant were considered nonsusceptible. Pulsed field gel el ectrophoresis (PFGE) was performed on levofloxacin-nonsusceptible isolates. All pneumococci isolated in 1998 and 1999 were serotyped using the quellung reaction.
NHAMCS collects data on the use and provision of ambulatory care services in hospital emergency and outpatient departments on a representative national sample. U.S. Bureau of the Census data were used to determine population denominators for fluoroquinolone use. The chi-square test for comparison of proportions and chi-square for linear trends were used for analysis. Statistical significance was defined as p[less than]0.05.
During 1995-1997, susceptibility testing was performed on 8763 isolates from persons with pneumococcal invasive disease, representing 81.5% of cases identified through ABCs. During 1998-1999, susceptibility testing was available for 6529 cases of pneumococcal invasive disease, representing 84.9% of all identified cases. Overall, the prevalence of ofloxacin-nonsusceptible isolates (minimum inhibitory concentration [MIC]: [greater than or equal to]4 [micro]g/mL) increased from 2.6% (65 of 2508) in 1995 to 3.8% (119 of 3108) in 1997 (chi-square for linear trend=5.24; p=0.02). Levofloxacin-nonsusceptible isolates (MIC: [greater than or equal to]4 [micro]g/mL) were 0.2% of isolates in 1998 (seven of 3120) and in 1999 (eight of 3432) (Figure 1). Of 15 levofloxacin-nonsusceptible isolates, 13 also were nonsusceptible to trovafloxacin.
Isolates that were not susceptible to ofloxacin were more common among persons aged [greater than or equal to] 18 years (225 [3.6%] of 6317) than among persons aged [less than]18 years (64 [2.6%] of 2446) (p=0.02). Among adults, the prevalence of ofloxacin-nonsusceptible pneumococcal isolates increased from 3.1% (55 of 1791) in 1995 to 4.5% (103 of 2276) in 1997 (chi-square for linear trend=5.33; p=0.02). The proportion of ofloxacin-resistant isolates (MIC: [greater than or equal to]8 [micro]g/mL) did not increase significantly (0.3% in 1995, 0.2% in 1996, and 0.4% in 1997). Of the 225 ofloxacin-nonsusceptible isolates from adults, 62.2% were from whites and 51.6% were from males. These proportions were similar for ofloxacin-susceptible isolates (57.7% from whites and 52.9% from males). Ofloxacin-nonsusceptible isolates were from patients residing in six of the seven surveillance areas.
All levofloxacin-nonsusceptible isolates were from adults (median age: 77 years; range: 44-89 years). Among adults, 0.2% (seven of 2340) of pneumococci were nonsusceptible (MIC: [greater than or equal to]4 [micro]g/mL) to levofloxacin in 1998 and 0.3% (eight of 2451) in 1999. Of the 15 levofloxacin-nonsusceptible isolates, one was intermediately resistant. Fourteen (93.3%) of the levofloxacin-nonsusceptible isolates were from whites, and nine (60%) were from males. The proportion of levofloxacin-nonsusceptible isolates was significantly higher among isolates from persons aged [greater than or equal to]65 years (p[less than]0.001) and among whites (p[less than]0.001), as compared with levofloxacin-susceptible isolates. Ten serotypes were identified among the 15 levofloxacin-nonsusceptible isolates: 6A, 6B, 9V, 14, 16, 18C, 19F, 22F, 23F, and 35B. Eight of the 15 isolates were obtained from residents residing in one surveillance area (Connecticut). In this area, 0.9% of invasive pneumococcal isolates were nons usceptible to levofloxacin, compared with 0.2% for all other areas. Examination of the isolates from Connecticut using PFGE showed eight unrelated patterns.
Fluoroquinolone resistance was associated with resistance to other antimicrobials. Among the 225 isolates that were nonsusceptible to ofloxacin, 44 (19.6%) also were nonsusceptible to penicillin (MIC:[greater than or equal to]0.12 [micro]g/mL), 23 (10.2%) to cefotaxime (MIC: [greater than or equal to]1 pg/mL), 20 (8.9%) to erythromycin (MIC: [greater than or equal to]0.5 [micro]g/mL), and 68 (30.2%) to trimethoprimsulfamethoxazole (MIC:[greater than or equal to]1/19 [micro]g/mL). Among the 15 isolates nonsusceptible to levofloxacin, nine (60%) had decreased susceptibility to penicillin, eight (53.3%) were nonsusceptible to cefotaxime, five (33.3%) to erythromycin, and nine (60%) to trimethoprim-sulfamethoxazole. In comparison, among the 4623 levofloxacin-susceptible isolates, 1018(22%) were nonsusceptible to penicillin, 594(12.8%) were nonsusceptible to cefotaxime, 650 (14%) to erythromycin, and 1229 (26.6%) to trimethoprimsulfamethoxazole.
During 1993-1998, fluoroquinolone prescriptions in the United States increased from 3.1 to 4.6 per 100 persons per year. The frequency of fluoroquinolone prescriptions was highest among persons aged 65 years and increased in this age group from 8.2 to 12.4 per 100 persons per year (Figure 2). Prescriptions written in the United States for all antibiotics decreased from 53.5 to 51.5 per 100 persons per year for all ages during this period.
Reported by: P Daily, MPH, L Gelling, MPH, G Rothrock, MPH, A Reingold, MD, California Emerging Infections Program, San Francisco; D Vugia, MD, Acting State Epidemiologist, California Dept of Health Svcs. NL Barrett, MS, J Hadler, MD, State Epidemiologist, Connecticut Dept of Public Health. W Baughman, MSPH, M Farley, MD, Veterans Administration Medical Center and Emory Univ School of Medicine, Atlanta; PA Blake, MD, State Epidemiologist, Georgia Dept of Health. MA Pass, J Roche, MD, LH Harrison, MD, Johns Hopkins Univ, Baltimore; J Roche, MD, Acting State Epidemiologist, Maryland State Dept of Health and Mental Hygiene. SK Johnson, MT. CA Lexau, MPH, R Lynfield, MD, R Danila, MD, Assistant State Epidemiologist, Minnesota Dept of Health. K Stefonek, MPH, PR Cieslak, MD, MA Kohn, MD, State Epidemiologist, Oregon Health Div. B Barnes, W Schaffner, A Craig, MD, State Epidemiologist, Tennessee Dept of Health. JH Jorgensen, PhD, L McElmeel, S Crawford, Univ of Texas Health Sciences Center, San Antonio, Texas. Resp iratory Diseases Br, Div of Bacterial and Mycotic Diseases and Active Bacterial Core Surveillance/Emerging Infections Program Network, National Center for Infectious Diseases; and an EIS Officer, CDC.
Editorial Note: The findings in this report indicate that fluoroquinolone-nonsusceptible pneumococci are present in the United States; however, it is unclear whether resistance is increasing with the newer fluoroquinolones. The proportion of isolates that were ofloxacin-nonsusceptible isolates increased during 1995-1997. The main mechanisms of resistance to fluoroquinolone agents are alterations on DNA gyrase subunits and reduced penetration associated with decreased outer membrane protein production. These mechanisms are common between ofloxacin and the newer fluoroquinolone agents, although ofloxacin-resistant strains may be seen with a single mutation to DNA gyrase and newer fluoroquinolones and require mutations in both mechanisms for resistance (9,10). Therefore, trends in ofloxacin susceptibility may predict what will occur for other fluoroquinolone agents.
The growing use of fluoroquinolones probably contributes to the emergence of fluoroquinolone-resistant pneumococci. Fluoroquinolone-resistant isolates were more common among persons aged [greater than or equal to]65 years, who have the highest density of fluoroquinolone use. In comparison, penicillin-resistant strains are more common among isolates from young children, who have the highest rate of beta-lactam use. Fluoroquinolones are not licensed for use in children, a factor that may be helping to slow the rate of emerging fluoroquinolone resistance. PEGE results suggest that the emergence of resistant isolates does not result from spread of a single resistant clone.
Levofloxacin-nonsusceptible isolates had reduced susceptibility to other antimicrobials used for the treatment of pneumococcal pneumonia, notably penicillin, trimethoprimsulfamethoxazole, erythromycin, and cefotaxime. Most levofloxacin-nonsusceptible isolates also were nonsusceptible to trovafloxacin. These findings have important implications given that fluoroquinolones are recommended for the treatment of pneumococcal infections when penicillin resistance or resistance to other antimicrobials is suspected. Few therapeutic options exist for invasive disease attributable to pneumococci resistant to quinolones and other agents.
Susceptibility testing for ofloxacin and levofloxacin at ABCs started in 1995 and 1998, respectively. Therefore, results presented in this report are limited by the short time that systematic testing for levofloxacin susceptibility has been available and by the lack of continuity for testing of a single fluoroquinolone agent during this period. Identification of decreased susceptibility to fluoroquinolones in ABCs sites is population based and representative of the areas under surveillance. ABCs does not provide comprehensive national surveillance, but provides a good approximation of national trends.
Fluoroquinolones are important agents for treating pneumococcal infections and community-acquired pneumonia. Appropriate use of antibiotics is crucial for slowing the emergence of fluoroquinolone resistance. Principles for appropriate use of antibiotics in adults are available at [less than]http://www.cdc.gov/antibioticresistance/technical.htm[greater than]. Continuous prospective surveillance for antimicrobial resistance in pneumococci is needed to determine whether increases in fluoroquinolone resistance will occur in the United States. If fluoroquinolone resistance becomes more common, clinical laboratories should consider routine susceptibility testing of fluoroquinolones on invasive pneumococcal isolates. Several state health departments have established surveillance for cases of invasive drug-resistant S. pneumoniae. Because fluoroquinolone-resistant isolates have been rare, clinicians and microbiology personnel are encouraged to report episodes of suspected fluoroquinolone resistance in pneumococcal isolates collected from blood or cerebrospinal fluid to their state or local health department.
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|Publication:||Morbidity and Mortality Weekly Report|
|Date:||Sep 21, 2001|
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