International Journal of Antimicrobial Agents 31S (2008) S35 S39 Trends of sexually transmitted diseases and antimicrobial resistance in Neisseria gonorrhoeae T. Matsumoto Department of Urology, School of Medicine, University of Occupational and Environmental Health, Japan Abstract Sexually transmitted diseases (STDs), especially HIV infection, gonococcal infection and genital chlamydial infections are increasing all over the world. UNAIDS recently reported that the number of HIV/AIDS patients had been increasing and the highest prevalence was found in African countries, followed by Caribbean, Asian and Eastern European countries. HIV infection has also been gradually increasing in Japan. In non-hiv STDs, genital chlamydial infections are increasing worldwide also. On the contrary, gonococcal infections have been decreasing in many countries except Asian countries. N. gonorrhoeae has been changing in its infecting sites. The pharynx is the most important infecting site, because gonococcal infection in the pharynx may be one of the causes of the wide spread of N. gonorrhoeae. Antimicrobial-resistant N. gonorrhoeae has wide distribution throughout the world. For example, penicillin-resistant N. gonorrhoeae is prevalent in various part of the world, and fluoroquinolone-resistant N. gonorrhoeae is prevalent mainly in Asia. In addition to penicillin, tetracycline and fluoroquinolone resistance, N. gonorrhoeae acquired resistance to almost all of the cephalosporins except for ceftriaxone and cefodizime in Japan. Although there is no resistant strain to ceftriaxone, cefodizime and spectinomycin, 1.0 g single dose of ceftriaxone is considered to be the most suitable regimen for the treatment of gonococcal infection including the pharyngeal infection, because of the 100% elimination rate of N. gonorrhoeae from the urethra, cervix and pharynx obtained in a recent study. 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: STD; N. gonorhoeae; Resistance; Pharyngeal infection 1. Introduction Over 30 kinds of micro-organisms are known to be transmittable through sexual contact. Sexually transmitted diseases (STDs), especially HIV infection, gonococcal infection and genital chlamydial infection have been increasing in various regions of the world. As the increasing incidence of STDs is now becoming a serious concern in various countries, combined socioeconomic and medical approaches are essential to solve the complicated problem of STD prevalence. UNAIDS recently reported that the number of HIV/AIDS patients had been increasing worldwide and that the highest prevalence was found in African countries, followed by Caribbean, Asian and Eastern European countries. In this report, it was estimated in December 2005 that the number of people with HIV was 40.3 million in total, 38.0 million Tel.: +81 93 691 7446; fax: +81 93 603 8724. E-mail address: t-matsu@med.uoeh-u.ac.jp. in adults, 17.5 million in women and 2.3 million in children under 15 years old. People who were newly infected with HIV were also estimated to be 4.9 million in total, 4.2 million in adults and 700 000 in children. Death from AIDS was 3.1 million in total, 2.6 million in adults and 570 000 in children in 2005. The incidence rates of adults were also estimated to be 7.2 in Sub-Saharan Africa, followed by 1.6 in Caribbean, 0.9 in Eastern Europe and Central Asia, 0.7 in South and South-East Asia and 0.7 in North America. About 14 000 people were newly infected with HIV infections per day in 2005. More than 95% of newly infected patients were in low- and middle-income countries, and almost 2000 were children. In addition, around 12 000 patients were in the age group between 15 and 49 years old, of whom almost 50% were women [1]. Although HIV incidence has been declining in a few countries, overall HIV infection has been increasing and is still a big concern in many countries, such as African, Asian, Eastern European and Caribbean countries. In the non-hiv STDs, genital chlamydial infection has been also increasing worldwide. On the contrary, gonococcal 0924-8579/$ see front matter 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2007.08.029
S36 T. Matsumoto / International Journal of Antimicrobial Agents 31S (2008) S35 S39 Fig. 1. Chronological changes of HIV/AIDS cases in Japan except for foreigners and infection from blood derivatives. infection has been decreasing in many countries except in Asia. Genital chlamydial and gonococcal infection are other targets for STD surveillance, preventive actions and clinical care. 2. Trends of STDs in Japan 2.1. HIV and non-hiv infections in Japan HIV infection has been gradually increasing in Japan. Total number of infected people is relatively low and is estimated to be around 10 000. Although the number of AIDS patients manifested from unknown HIV infection has been increasing, those from known HIV infection has been decreasing [2]. This difference seems to be based on the good patient control using newer treatment regimens, and well-controlled patient care in reported HIV-infected patients (Fig. 1). Epidemiological studies in Japan revealed that chlamydial infections are continuously increasing in both sexes during several decades, and gonococcal infections are increasing again in both sexes after a temporary decrease due to the AIDS shock in 1993 and 1994, which meant first notice of HIV infection (Fig. 2) [3]. Increase in genital chlamydial and gonococcal infections in Japan is considered to be due to several reasons such as a change in sexual behaviours in the young, decrease in condom use at the sexual contact, change in sexual service by commercial sex workers (CSWs), inappropriate diagnosis and treatment for infected patients and poor educational approach to the young. In addition, an increase in gonococcal infection may be due to an increase in antimicrobial-resistant strains and change of its infecting sites. 2.2. Gonococcal infection in Japan Neisseria gonorrhoeae is a causative bacteria of various infections such as urethritis, epididymitis, cervicitis, pelvic inflammatory disease, pharyngitis, conjunctivitis, proctitis and disseminated infection. Recently, we experienced many patients with gonococcal infection other than urethritis and Fig. 2. Chronological changes of infection rate in symptomatic cases of chlamydial and gonococcal infection in males and females.
T. Matsumoto / International Journal of Antimicrobial Agents 31S (2008) S35 S39 S37 Table 1 Mechanisms of antimicrobial-resistance in N. gonorrhoeae β-lactam resistance PPNG (penicillinase-producing Neisseria gonorrhoeae): plasmid-mediated β-lactamase (TEM-1) CMRNG (chromosomally mediated resistant Neisseria gonorrhoeae) CZRNG (cefozopran-resistant Neisseria gonorrhoeae): most new resistant mechanism to penicillins and cephalosporins Tetracycline resistance (chromosomal, plasmid) Change of outer membrane Efflux pump Quinolone resistance (chromosomal) Point mutation of DNA gyrase and/or Topo-isomerase IV Change of outer membrane Efflux pump Fig. 3. Positive rate of gonococcal pharyngeal infection. CSW; commercial sex worker. cervicitis. N. gonorrhoeae has been changing in its infecting sites and the pharynx has been the most important infecting site in Japan. In our experience, pharyngeal infection was found in 58% of females and 11% of males, who visited our clinics suffering from gonococcal urethritis or cervicitis (Fig. 3) [4]. Chlamydia trachomatis is also detected in the pharynx in around 30% of patients who had genital chlamydial infection. Therefore, the pharynx could be one of the reservoirs or infecting sites of N. gonorrhoeae and C. trachomatis. Almost all patients had no symptom or sign of pharyngitis in patients whose N. gonorrhoeae and/or C. trachomatis were detected in pharyngeal swabs. In Japan, CSWs provide oral sex at a less expensive price and young people misunderstand that oral sex is safer for STD transmission rather than vaginal sex. These two factors may have led to the increase and wide spread of N. gonorrhoeae and C. trachomatis. There are several problems in the diagnosis and treatment of pharyngeal infection of N. gonorrhoeae. In the diagnosis of gonococcal pharyngeal infection, PCR method is not useful, because it has cross-reactivity with some Nesseria species such as N. meningitides, N. flavescens and so on, which are residents of the oral cavity or pharynx. Culture or gene amplification methods other than PCR should be used for the diagnosis of gonococcal pharyngeal infection. 2.3. Antimicrobial-resistant N. gonorrhoeae Several kinds of resistance mechanisms in N. gonorrhoeae against antimicrobial agents are known. For example, penicillinase-producing N. gonorrhoeae (PPNG), chromosomally mediated resistant N. gonorrhoeae (CMRNG), and cefozopran-resistant N. gonorrhoeae (CZRNG) are -lactam resistant. PPNG which is mediated by TEM-1 type -lactamase has been decreasing in Japan. However, the incidence of CMRNG is now 100%. CZRNG, which is the novel resistant mechanism against penicillins and cephalosporins, emerged several years ago and is increasing in Japan [5]. Other types of resistance mechanisms such as tetracycline-, macrolides- and fluoroquinolone-resistant N. gonorrhoeae (QRNG) have been also increasing (Table 1). Antimicrobial-resistant N. gonorrhoeae is distributed worldwide. For example, penicillin- and tetracycline- Table 2 Quinolone resistance in N. gonorrhoeae in WP region, 2004 Country Tested Less susceptible Resistant All QRNG n n % n % n % Australia 3542 68 1.9 757 21.4 825 23.3 Brunei 113 15 13.3 46 40.7 61 54.0 China 1203 60 4.9 1,135 94.3 1195 99.2 Hong Kong SAR 2811 144 5.1 2,647 94.2 2627 99.3 Japan 261 16 6.1 213 81.6 239 91.6 Korea 93 17 18.2 65 70.0 82 88.2 Lao PDR 48 4 8.0 42 88.0 46 96.0 New Caledonia 43 0 0.0 1 2.3 New Zealand 773 14 1.8 148 19.1 162 20.9 Papua New Guinea 92 1 1.0 1 1.0 2 2.0 Philippines 175 2 1.1 83 47.4 85 48.5 Singapore 160 10 6.2 80 50.0 90 56.2 Vietnam 156 49 31.4 82 52.5 131 83.9
S38 T. Matsumoto / International Journal of Antimicrobial Agents 31S (2008) S35 S39 125 mg intramuscular dose of ceftriaxone for the treatment of uncomplicated gonococcal infection. Although there is no study comparing 125 mg intramuscular and 1.0 g intravenous dose of ceftriaxone, 1.0 g intravenous dose of ceftriaxone is recommended rather than 125 mg intramuscular regimen for the treatment of gonococcal infection in Japan, because MIC distribution of N. gonorrhoeae to cefriaxone has been gradually shifting to higher MIC level (data not presented). 3.2. Treatment of pharyngeal gonococcal infection Fig. 4. Incidence of drug-resistant strains of N. gonorrhoeae in 4 areas of Japan and in Korea. resistant N. gonorrhoeae was distributed in various part of the world, and QRNG was mainly distributed in Asian countries. QRNG is the most serious concern in Asia, because the incidence rate of QRNG is quite high in this region. For example, the incidence of QRNG was reported to be 99.3% in Hong Kong, 99.2% in China, 96.9% in Lao PDR, 91.6% in Japan, 88.2% in Korea and 83.9% in Vietnam (Table 2) [6]. In Japan, N. gonorrhoeae is resistant to penicillins, fluoroquinolones, tetracyclines and macrolides in the rate of 100%, 70%, 60%, 80%, respectively. In addition to penicillin-, macrolide-, tetracycline- and fluoroquinoloneresistance, N. gonorrhoeae acquired resistance to almost all of the oral and parenteral cephalosporins except for ceftriaxone and cefodizime, and was named CZRNG. The incidence rate of CZRNG is now 40% and CZRNG is simultaneously resistant to fluoroquinolones, tetracyclines and macrolides. Therefore, 40% of N. gonorrhoeae is considered to be so-called multi-drug-resistant strains and this type of resistant strain was distributed in various parts of Japan (Fig. 4). In addition, similar strains were found in Hawaii in 2002, which were isolated from 3 male patients who may have been infected by Japanese women [7]. There are few resistant strains to 3 parenteral drugs, ceftriaxone, cefodime and spectinomycin in Japan. In the treatment of gonococcal pharyngeal infection, spectinomycin is not recommended because of low permeability into pharyngeal tissue. In addition, 1.0 g or 2.0 g single dose of cefodizime was not effective for the pharyngeal infection of N. gonorrhoeae in our experience. Two studies were recently performed to find suitability of cefodizime for the treatment of gonococcal pharyngeal infection. Although a 100% elimination rate of N. gonorrhoeae from the urethra and cervix was obtained in 103 patients with genital gonococcal infection, the elimination rate from the pharynx was 63% in 38 patients with pharyngeal infection among 103 genitally infected patients [9]. A following study using 2.0 g single dose of cefodizime also revealed a 55% elimination rate of N. gonorrhoeae from the pharynx in 11 patients who had pharyngeal infection. However, two to three times of additional dose of cefodizime completely eliminated N. gonorrhoae even from the pharynx [10]. In addition, another study using 1.0 g single intravenous dose of ceftriaxone revealed a 100% elimination rate from the urethra, cervix and pharynx in 57 patients with gonococcal urethritis and 28 patients who had pharyngeal infection among them [4]. Therefore, we conclude that single 1.0 g intravenous dose of ceftriaxone is the most suitable for the treatment of gonococcal infection including pharyngeal infection. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required. 3. Treatment of gonococcal infection 3.1. Recommended regimen CDC recommended cefixime, ceftriaxone, ciprofloxacin, ofloxacin or levofloxacin for the treatment of uncomplicated gonococcal infection of the cervix, urethra and rectum, and also recommended ceftriaxone or ciprofloxacin for uncomplicated gonococcal infection of the pharynx [8]. Because QRNG is widely distributed and around 40% of N. gonorrhoeae are resistant to cefixime in Japan, fluroquinolones and cefixime are not recommended for the treatment of gonococcal infection. CDC also recommended References [1] UNAIDS/WHO. 2006 Report on the global AIDS epidemic. http://www.unaids.org/. [2] Hashimoto S, Kawado M, Murakami Y, Ichikawa S, Kimura H, Nakamura Y, et al. Numbers of people with HIV/AIDS reported and not reported to surveillance in Japan. J Epidemiol 2004;14:182 6. [3] Kumamoto Y, Tsukamoto T, Sugiyama T, Akaza H, Noguchi M, Naya T, et al. National surveillance of sexually transmitted diseases of Japan in 2002. Jap J STD 2004;15:17 45. [4] Matsumoto T. Unpublished data. [5] Muratani T, Akasaka S, Kobayashi T, Yamada Y, Inatomi H, Takahashi K, et al. Outbreak of cefozopran (penicillin, oral cephems, and aztreonam)-resistant Neisseria gonorrhoeae in Japan. Antimicrob Agents Chemother 2001;45:3603 6.
T. Matsumoto / International Journal of Antimicrobial Agents 31S (2008) S35 S39 S39 [6] The WHO Western Pacific Gonococcal Surveillance Programme. Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific Region, 2004. Commun Dis Intell 2006;30:129 32. [7] Wang S, Lee MV, O Conner N, Iverson CJ, Ohye RG, Whiticar PM, et al. Multidrug-resistant Neisseria gonorrhoeae susceptibility to cefixime Hawaii, 2001. Clin Infect Dis 2003;37:849 52. [8] Workowski KA, Levine WC. Sexually transmitted disease treatment guidelines 2002. MMWR 2002;51:1 80. [9] Mtasumoto T, Muratani T, Takahashi K, Ando Y, Sato Y, Kurashima M, et al. Single dose of cefodizime completely eradicated multi-drug resistant strains of Neisseria gonorrhoeae in urethritis and cervicitis. J Infect Chemother 2006;12:97 9. [10] Matsumoto T, Muratani T, Takahashi K, Yokoo D, AndoY, Sato Y, et al. Multiple doses of cefodizime are necessary for the treatment of Neisseria gonorrhoeae pharyngeal infection. J Infect Chemother 2006;12:145 7.