Susan A. Wang

Multidrug-Resistant Neisseria gonorrhoeae with Decreased Susceptibility to Cefixime—Hawaii, 2001

We report 4 urogenital Neisseria gonorrhoeae isolates recovered from 3 patients that demonstrated resistance to penicillin, tetracycline, and ciprofloxacin and reduced susceptibility to cefixime. This report of the first 3 patients in the United States identified with this multidrug-resistant strain may portend an emerging problem for clinicians and public health officials.

Evaluation of Antimicrobial Resistance and Treatment Failures for Chlamydia trachomatis: A Meeting Report

Each year, Chlamydia trachomatis causes ~3 million new infections and results in more than 1 billion dollars in medical costs in the United States. Repeat or persistent infection occurs in 10%-15% of women who are treated for C. trachomatis infection. However, the role played by antimicrobial resistance in C. trachomatis treatment failures or persistent infection is unclear. With researchers in the field, we reviewed current knowledge and available approaches for evaluating antimicrobial resistance and potential clinical treatment failures for C. trachomatis. We identified key research questions that require further investigation. To date, there have been no reports of clinical C. trachomatis isolates displaying in vitro homotypic resistance to antimicrobials, but in vitro heterotypic resistance in C. trachomatis has been described. Correlation between the results of existing in vitro antimicrobial susceptibility tests and clinical outcome after treatment for C. trachomatis infection is unknown. Animal models may provide insight into chlamydial persistence, since homotypic resistance against tetracycline has been described for Chlamydia suis in pigs. Evaluating C. trachomatis clinical treatment failures, interpreting laboratory findings, and correlating the 2 clearly remain extremely challenging undertakings.

Prevalence of and Associated Risk Factors for Fluoroquinolone-Resistant Neisseria gonorrhoeae in California, 2000–2003

BACKGROUND Rates of fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) are increasing worldwide and in California. METHODS As a supplement to established surveillance, the investigation of QRNG in California included expanded surveillance in southern California, with in-depth interviews of patients (who had QRNG during the period of January 2001-June 2002) and a cross-sectional study of patients at 4 sexually transmitted diseases clinics with gonococcal isolates that underwent susceptibility testing (for the period of July 2001-June 2002). RESULTS The rate of QRNG increased from <1% in 1999 to 20.2% in the second half of 2003. The 2001-2002 expanded surveillance demonstrated that 66 (4.9%) of 1355 isolates were resistant to fluoroquinolones; the majority of these infections occurred after August 2001. Cross-sectional analysis of 952 patients with gonorrhea revealed that the prevalence of QRNG varied geographically during 2001-2002, with the highest rate being in southern California (8.9%) and the lowest being in San Francisco (3.6%). The QRNG prevalence was 8.6% among men who have sex with men (MSM), 5.1% among heterosexual men, and 4.3% among women. Although risk factors for QRNG varied by clinic, multivariate analysis demonstrated independent associations with race/ethnicity, recent antibiotic use, and MSM. CONCLUSIONS The emergence and spread of QRNG in California appeared to evolve from sporadic importation to endemic transmission among both MSM and heterosexuals. Monitoring of both the prevalence of and risk factors for QRNG infections is critical for making treatment recommendations and for developing interventions to interrupt transmission.

Antimicrobial resistance for Neisseria gonorrhoeae in the United States, 1988 to 2003: the spread of fluoroquinolone resistance.

Context Antimicrobial resistance of Neisseria gonorrhoeae isolates is changing. Contribution This surveillance study from the Gonococcal Isolate Surveillance Project (GISP) reports gonococcal isolate susceptibility among a large sample of male patients with urethral gonorrhea in the United States. In this sample, resistance to ciprofloxacin did not occur until 1995 but occurred in 4.1% of isolates in 2003. In 2003, 14.4% and 6.5% of isolates were resistant to tetracycline and penicillin, respectively. Resistance to ceftriaxone, cefixime, spectinomycin, and azithromycin is rare. Cautions The GISP obtains isolates only from men attending public clinics and tests fewer than 2% of gonococcal infections reported in the United States annually. Implication The number of fluoroquinolone-resistant gonococcal isolates is increasing in the United States. The Editors Annually, Neisseria gonorrhoeae infects approximately 800000 people in the United States, at an estimated cost of

The emergence of Neisseria gonorrhoeae with decreased susceptibility to Azithromycin in Kansas City, Missouri, 1999 to 2000.

1 billion (1). Besides causing urethritis, cervicitis, and pharyngitis, gonorrhea remains an important cause of pelvic inflammatory disease (2) and increases the risk for HIV transmission (3). Gonorrhea incidence in the United States declined from 467.7 cases per 100000 persons in 1975 to 116.2 cases per 100000 persons in 2003, but it is still 3- to 25-fold higher than rates in other developed countries (4, 5). Gonorrhea rates in the United States remain high in the southeastern states and among minorities, adolescents of all racial and ethnic groups, and men who have sex with men (4). Gonorrhea control strategies have relied on highly effective, single-dose therapy to rapidly cure the infection and eliminate transmission to others. However, antimicrobial resistance has repeatedly compromised such strategies. In 1936, sulfonamides effectively treated gonorrhea, but within 9 years, one third of strains were sulfonamide-resistant and 50000 units of penicillin became the recommended treatment (6). By 1972, the required penicillin dose had increased 96-fold to 4.8 million units. The spread of penicillin- and tetracycline-resistant N. gonorrhoeae eventually led to the abandonment of these drugs as gonorrhea therapies in the United States in the 1980s (7). Cephalosporins (ceftriaxone and cefixime) and fluoroquinolones (ciprofloxacin, ofloxacin, and levofloxacin) became the primary gonorrhea therapies recommended by the Centers for Disease Control and Prevention (CDC) (811). However, in the 1990s, fluoroquinolone-resistant N. gonorrhoeae strains were routinely identified in Asia (12) and were sporadically identified elsewhere (13, 14). Ongoing spread of fluoroquinolone-resistant N. gonorrhoeae threatens the continued use of inexpensive, oral fluoroquinolones and necessitates the increased use of expensive, and often injectable, cephalosporins. To monitor national trends in gonococcal resistance, the CDC established the Gonococcal Isolate Surveillance Project (GISP) in 1986 (15). We describe GISP trends from 1988 to 2003. Methods Surveillance Design The GISP is a national sentinel surveillance system (15, 16) that includes selected sexually transmitted disease clinics in 25 to 30 cities each year, 5 regional laboratories, and the CDC. Each month, the first 25 gonococcal urethral isolates were collected from men attending the clinics and were submitted to regional laboratories for antimicrobial susceptibility testing. Patient data were abstracted from medical records. For simplicity and to avoid overrepresenting any individual city, we limited analyses to no more than 300 infections per city per year. Human Subjects As a disease control and surveillance activity, GISP was determined to be a nonresearch, public health activity. Laboratory Methods Methods used to isolate N. gonorrhoeae and to determine minimum inhibitory concentrations (MICs) by inoculating 104 organisms on GC II agar base medium (Becton Dickinson, Sparks, Maryland) containing 1% IsoVitaleX (Becton Dickinson) have been described previously (15, 16). Control strains (ATCC 49226, F-28, P681E, CDC 10328, CDC 10329, SPJ-15, and SPL-4) (17) were included with each susceptibility run. Periodically, the CDC provided a panel of unidentified strains to each laboratory for testing, and results were compared to evaluate interlaboratory consistency. Resistance Phenotypes For most antimicrobials, we interpreted susceptibility results according to criteria for N. gonorrhoeae recommended by the Clinical Laboratory Standards Institute (CLSI) (1618): resistance to penicillin (MIC 2.0 g/mL), resistance to tetracycline (MIC 2.0 g/mL), resistance to spectinomycin (MIC 128.0 g/mL), intermediate resistance to ciprofloxacin (MIC, 0.125 to 0.5 g/mL), and resistance to ciprofloxacin (MIC 1.0 g/mL). The CLSI has defined susceptibility categories for ceftriaxone and cefixime (MICs 0.25 g/mL) but has not defined resistance; thus, isolates with ceftriaxone or cefixime MIC of 0.5 g/mL or more are categorized as having decreased susceptibility. Susceptibility or resistance categories for azithromycin have not been defined. Correlation of azithromycin MICs of 0.5 g/mL or more with clinical treatment failure when azithromycin, 2.0 g, is used to treat gonorrhea is not known. Clinical treatment failures with azithromycin, 1.0 g, have been reported for strains with MICs of 0.125 to 0.5 g/mL (19). For these analyses, we categorized isolates with azithromycin MIC of 1.0 g/mL or more as having decreased susceptibility to azithromycin. We defined penicillinase-producing N. gonorrhoeae by positive results on a -lactamase test, and we assumed that isolates with tetracycline MICs of 16 g/mL or more contained the tetM determinant (plasmid-mediated, tetracycline-resistant N. gonorrhoeae). We categorized resistant strains that lacked these criteria for plasmid-mediated resistance as chromosomally resistant according to previously described criteria (16). Statistical Analysis We used the chi-square statistic to compare the frequency distributions of different categorical variables. We used the CochranArmitage trend test to assess trends in binomial proportions across levels of a single factor for demographic and clinical characteristics and prevalences of resistance phenotypes. We performed logarithmic transformation on MICs to make treatment effects linear and to stabilize the variances. We fitted regression lines to calculate trends over time. We analyzed data from clinics that participated for the entire 16-year period separately from those that participated for shorter periods and compared results by using the chi-square test for trend. We calculated 95% CIs for the percentage of ciprofloxacin-resistant isolates by using a log-based transformation of that percentage and assumed that a random sample was obtained from the population of all reported gonorrhea cases. For locations where the percentage of ciprofloxacin-resistant isolates was 0%, we calculated the upper limit of the intervals by using the formula 3.5/N (20). Role of the Funding Source The GISP is funded by the CDC, an agency of the U.S. Department of Health and Human Services. Representatives of the CDC were involved in the design and conduct of this surveillance activity; the collection, management, analysis, and interpretation of GISP data; and the review of all GISP publications. Results From 1988 to 2003, GISP collected 82064 isolates from men with urethral gonorrhea who attended sexually transmitted disease clinics in 37 cities (range, 21 to 30 cities per year). A median of 5088 isolates were collected each year (range, 4544 to 6552 isolates per year) (Table 1). Clinics in 16 cities participated for all 16 years and contributed 53593 (65.3%) of the isolates. When we restricted analyses to these clinics, demographic or antimicrobial resistance trends were not affected. Table 1. Cities that Participated in the Gonococcal Isolate Surveillance Project, 1988 to 2003 The GISP specimens represented 8% to 100% of all male urethral gonococcal infections identified in each sexually transmitted disease clinic for a given year. Among all GISP patients, 42.0% were from the West, 21.7% from the Midwest, 7.7% from the Northeast, and 28.6% from the South. In comparison, among the distribution of nationally reported male patients with gonorrhea from 1988 to 2003 (21), 11.3% were from the West, 22.7% from the Midwest, 15.3% from the Northeast, and 50.7% from the South. Regional distributions of GISP cases compared with nationally reported male gonorrhea cases significantly differed (P< 0.001). Demographic Characteristics of Patients The median age of patients was 26 years (range during the 16-year period, 24 to 27 years), with a significant increase in age from 1988 to 2003 (P< 0.001 for trend). Patients younger than 25 years of age were underrepresented in GISP compared with the nationally reported number of male patients with gonorrhea from 1988 to 2003 (for example, 39.3% vs. 48.1% in 2003, respectively [21]) (P< 0.001). This difference increased over time (P< 0.001). Of all GISP patients for all years, 74.1% were African American, 12.6% were white, 11.2% were Hispanic, 1.3% were Asian or Pacific Islander, and 0.8% were American Indian. Nationally reported percentages of male patients with gonorrhea for this period were 83.0% African American, 10.9% white, 5.3% Hispanic, 0.4% Asian or Pacific Islander, and 0.4% American Indian (21). African-American men were underrepresented in GISP compared with their proportion among nationally reported male patients with gonorrhea during each of the 16 years (for example, 68.2% vs. 75.3% in 2003, respectively; P< 0.001). The proportion of GISP isolates from men who have sex with men (that is, homosexual or bisexual men) increased from 4.0% in 1988 to 19.6% in 2003 (P< 0.001 for trend). Annually, the proportion of men identified as bisexual ranged from 0.7% in 1989 to 4.4% in 2002, with more patients identified as bisexual after 1997. No data ex

Mutations causing in vitro resistance to azithromycin in Neisseria gonorrhoeae

Background and Objectives We describe the first cluster of persons with Neisseria gonorrhoeae with decreased susceptibility to azithromycin (AziDS; minimum inhibitory concentration ≥1.0 &mgr;g/mL) in the United States. Goal The goal of this study was to identify risk factors for AziDS N. gonorrhoeae and to describe isolate microbiology. Study Design Persons with AziDS N. gonorrhoeae (cases) were identified in Kansas City, Missouri, through the Gonococcal Isolate Surveillance Project (GISP) in 1999 and expanded surveillance, January 2000 to June 2001. A case-control study using 1999 GISP participants was conducted; control subjects had azithromycin-susceptible N. gonorrhoeae. Results Thirty-three persons with AziDS N. gonorrhoeae were identified. Case patients were older than control patients (median age, 33 years vs. 23 years; P <0.001). Fifty percent of cases and 13% of control subjects had a history of sex with a female commercial sex worker (odds ratio, 7.0; 95% confidence interval, 1.3–36.0); 50% of cases and 4% of control subjects met sex partners on street A (P <0.01). AziDS N. gonorrhoeae isolates were phenotypically and genotypically similar and contained an mtrR gene mutation. Conclusions With few treatment options remaining, surveillance for antimicrobial-resistant N. gonorrhoeae is increasingly important, especially among persons at high risk.

Fluoroquinolone resistance among Neisseria gonorrhoeae isolates in Hawaii, 1990-2000: role of foreign importation and increasing endemic spread.

In 1999, a cluster of gonococcal isolates exhibiting high Minimal Inhibitory Concentrations (MICs), to azithromycin (2.0-4.0 mg/l) were identified in Kansas City, MO. Isolates were characterized by auxotype/serovar class, lipoprotein (Lip) subtyping and sequencing of the mtrR gene, which has been implicated in decreased azithromycin susceptibility in the gonococcus. Isolates were Pro/IB-3 and contained the 17c Lip subtype. Molecular characterization of the mtrR gene revealed a 153 base pair insertion sequence located between the mtrR/mtrC promoter and the mtrC gene. Some isolates also contained a frame shift within the mtrR gene. Transformation of these mutations into an azithromycin-sensitive recipient strain resulted in transformants with MICs as high as 2.0 mg/l and inactivation of the mtrD gene reduced azithromycin MICs 270-fold. These results demonstrated that the mtr mutations were responsible for the increased MICs in these isolates.

Emergence and Continuous Evolution of Genotype 1E Rubella Viruses in China

Objectives: In 1999, an increase in ciprofloxacin-resistant Neisseria gonorrhoeae isolates was identified in Hawaii, prompting initiation of investigative studies. Goals: The goal of this study was epidemiologic evaluation of this increase. Study: The authors conducted a review of laboratory data; case-series and case-control studies based on medical record review; and a prospective case-control study based on patient interviews. Results: A total of 10.4% (21 of 201) of gonococcal isolates from Hawaii in 2000 were ciprofloxacin-resistant compared with <1.5% per year from 1990 to 1997. From medical record review for patients diagnosed with ciprofloxacin-resistant N. gonorrhoeae infection from 1990 to 1999, 59% were Asian/Pacific Islanders and 91% were heterosexual. From review of 1998 and 1999 sexually transmitted disease (STD) clinic medical records, patients with ciprofloxacin-resistant N. gonorrhoeae were more likely to report recent foreign travel or a sex partner with recent foreign travel than patients with ciprofloxacin-susceptible N. gonorrhoeae (6 of 12 vs. 10 of 117, P <0.001), but 50% (6 of 12) acquired a ciprofloxacin-resistant strain locally from a partner with no recent travel. In 2000, 70% (7 of 10) of STD clinic patients with ciprofloxacin-resistant N. gonorrhoeae acquired their infection locally from partners with no reported recent travel. Conclusions: Infections with ciprofloxacin-resistant N. gonorrhoeae are increasing and evolving in Hawaii.

Using strain typing to characterise a fluoroquinolone-resistant Neisseria gonorrhoeae transmission network in southern California

ABSTRACT In China, rubella vaccination was introduced into the national immunization program in 2008, and a rubella epidemic occurred in the same year. In order to know whether changes in the genotypic distribution of rubella viruses have occurred in the postvaccination era, we investigate in detail the epidemiological profile of rubella in China and estimate the evolutionary rate, molecular clock phylogeny, and demographic history of the predominant rubella virus genotypes circulating in China using Bayesian Markov chain Monte Carlo phylodynamic analyses. 1E was found to be the predominant rubella virus genotype since its initial isolation in China in 2001, and no genotypic shift has occurred since then. The results suggest that the global 1E genotype may have diverged in 1995 and that it has evolved at a mutation rate of 1.65 × 10−3 per site per year. The Chinese 1E rubella virus isolates were grouped into either cluster 1 or cluster 2, which likely originated in 1997 and 2006, respectively. Cluster 1 viruses were found in all provinces examined in this study and had a mutation rate of 1.90 × 10−3 per site per year. The effective number of infections remained constant until 2007, and along with the introduction of rubella vaccine into the national immunization program, although the circulation of cluster 1 viruses has not been interrupted, some viral lineages have disappeared, and the epidemic started a decline that led to a decrease in the effective population size. Cluster 2 viruses were found only in Hainan Province, likely because of importation.

The Epidemiology of Fluoroquinolone-Resistant Neisseria gonorrhoeae in Hawaii, 2001

Objective: We investigated the initial outbreak of fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) in southern California with analysis of transmission using strain typing. Methods: Surveillance for QRNG was conducted between 2000 and 2002 in southern California, including epidemiology and strain typing by a combination of antibiogram, auxotype, serovar, Lip type and amino acid alteration patterns in the quinolone-resistance determining region of GyrA and ParC. Combining epidemiological data with strain typing, we describe the emergence of QRNG outbreak strains using risk factor analysis and transmission networks. Results: Two outbreak strains accounted for 82% of isolates. Both strains required proline, were Lip type 17c, had amino acid alterations 91> Phe in GyrA and 87> Arg in ParC, but they differed by their serovar, IB-3C8 versus IB-2H7, 2G2. Outbreak strains were positively associated with men who have sex with men (MSM), adjusted odds ratio (AOR) 23.9 (95% confidence interval (CI) 2.2 to 261) and negatively associated with travel history: AOR 0.05, (95% CI 0.0 to 0.6). Network analysis demonstrated that 17 cases were connected by sexual contacts and/or public venues including bars, bathhouses/sex clubs, and internet sites. Conclusions: QRNG may have become established among Californian MSM through an identified transmission network of southern Californian bars, bathhouses and internet sites.