Gonorrhea, caused by Neisseria gonorrhoeae, has become one of the prevalent bacterial sexually transmitted infections (STIs) worldwide. According to the most recent estimation of World Health Organization (WHO), there were an estimated 78 million new cases or 27 million prevalent cases of gonorrhea among 15- to 49-year-olds worldwide in 2012.1 The WHO Western Pacific Region to which China belongs has had the highest disease burden of the infections. Data from the national STI surveillance program in China indicate a 14.3% increase in reported incidence of gonorrhea from 2015 to 2016 (unpublished data from the National Center for Sexually Transmitted Disease [STD] Control in China). Untreated gonorrhea can lead to sequelae including chronic pelvic pain, pelvic inflammatory disease, ectopic pregnancy, and infertility in women2 and increase the risk of infection with HIV.3 Because a vaccine for gonorrhea is not yet available, timely diagnosis and effective treatment with antimicrobials remain the cornerstone for control of the infection and further prevention of its spread.
However, current treatment measures are seriously threatened by the rapid emergence of antimicrobial resistance (AMR).4 Gonococcal AMR was usually first documented in Asia. Emergence of resistance to penicillin and tetracycline was identified in Asia during the 1970s and became more widespread in multiple regions in early 1980s.5 In the mid-2000s, high level of resistance to fluoroquinolone emerged.6 Only third-generation cephalosporins, either cefixime or ceftriaxone, now remain recommended as the first-line treatment regimen for gonococcal infections in most countries. However, available data have indicated an increasing gonococcal resistance to, and treatment failures with, the last-line oral extended-spectrum cephalosporins currently used for the treatment of gonorrhea, and a decreasing susceptibility of N. gonorrhoeae to injectable extended-spectrum cephalosporin ceftriaxone.6–8 In China, the prevalence of azithromycin resistance was 18.6% and the percentage of decreased susceptibility of ceftriaxone fluctuated between 9.7% and 12.2% over the period from 2013 to 2016.9
There are various factors that may influence occurrence and spread of gonococcal AMR. Several reports have shown that gonococcal AMR is significantly associated with demographic characteristics, place of residence, sexual orientation, and previous gonorrhea infection.9–13 Another important factor that may facilitate emergence of the resistance in China is inappropriate use of antibiotics, including no adherence to the treatment regimens recommended by the National STD Treatment Guidelines (the National STD Guidelines).14 The Guidelines align with the 2016 WHO's recommendations for single therapy (ceftriaxone 250 mg intramuscular [IM] as a single dose and spectinomycin 2 g IM as a single dose). However, dual therapy (ceftriaxone plus azithromycin), which is recommended by the WHO and other countries,15–17 has not been recommended in China. The current study was aimed to investigate beliefs and clinical practices of physicians from across China, and to examine the determinants associated to inappropriate use of antibiotics to treatment of gonorrhea.
MATERIALS AND METHODS
Study Population and Locations
The survey was a cross-sectional study to investigate physicians' beliefs and practices in diagnosis and treatment of gonorrhea at health sectors. Geographically, 31 provinces (provinces, province-level municipalities, and province-level autonomous regions) in China can be grouped into 6 regions, including Northern China, Northeastern China, Eastern China, Southern China, Southwestern China, and Northwestern China. Provinces were sampled to ensure inclusion of at least 1 province for each region. In each selected province, cities with elevated incidence of reporting gonorrhea cases were purposively selected. In the selected cities, general hospitals (GHs) and/or dermatology hospitals were recruited for the survey. A multistage sampling frame was used to select hospitals and recruit participants for the survey (Fig. 1).
The study questionnaire was piloted among 5 physicians in a hospital in Nanjing to optimize contents and comprehensibility. Based on the comments and feedbacks from the pilot survey, the questionnaire was further improved and finalized before it was used at a nationwide scale. The final questionnaire comprised 4 sections regarding (1) sociodemographic information and affiliation information, (2) routine practice in diagnosis of gonorrhea, (3) prescribing behaviors in treatment of uncomplicated gonorrhea, and (4) explanations on prescribing behaviors. Questionnaire having inconsistent responses to the 2 intercorrected questions (department and patient natures, respectively) and/or having less than 50% of questions to be answered were considered as invalid questionnaires and excluded from the data set for analyses. The study protocol including the questionnaire was reviewed and approved by the Medical Ethics Committee of the Chinese Academy of Medical Sciences Institute of Dermatology and National Center for STD Control in Nanjing (approval number: 2017-LS-003).
The survey was conducted from July to September 2017. Physicians who were working in a health sector randomly recruited for the survey and those had clinical experience in diagnosis and treatments of gonorrhea in the last year were eligible for participating in the survey. The eligible physician was asked to independently finish the survey by filling out an anonymous paper-format questionnaire after taking a verbal consent in the working place. The survey in each of study areas was organized by the local coordinator(s) through the Chinese Medical Association, the Chinese Preventive Medicine Association, the provincial institutes of dermatology, or the provincial centers for diseases control and prevention.
Questionnaires were double entered and validated using the following criteria: (1) relevant responses to the 2 interconnected questions, (2) more than 50% of questions answered, and (3) provision of information on previous practice of diagnosis or treatment of gonorrhea. The Excel-format data set was subsequently transferred to the IBM SPSS Statistics for Windows Version 22.0 (IBM Corp, Armonk, NY) for descriptive and inferential analyses. The numbers of reported cases with gonorrhea in different regions and the national total came from the National STD Surveillance Programme. General hospitals were classified into primary, secondary, and tertiary hospitals according to a 3-tier system,18 and dermatology or dermatovenereology hospitals were not included into the classification but designed as specialized STI hospitals (SHs). Traditionally, to clinically manage STIs is one of the services in department of dermatology or dermatovenerology, but this service has been expanded to other departments including departments of urology and gynecology. According to the nature of medical services primarily provided, the hospitals were categorized into GHs, SHs, and other specialized hospitals (OHs) including infectious diseases, maternal care, urology, or gynecology hospitals.
Adherence with the recommendations in the National STD Guidelines for treatment of uncomplicated gonorrhea was defined as prescribing ceftriaxone 250 mg, spectinomycin 2 or 4 g, or cefotaxime 1 g IM as a single dose.14 Any prescription of antibiotic therapy against the regimen recommended by the National Treatment Guidelines for treatment of gonorrhea was classified into “nonadherence.”
Categorical variables were compared using the χ2 test. Univariate analysis was used to determine the association between variable and specific outcome, and odds ratio (OR) and 95% confidence intervals (CIs) were calculated. Variables with significance level of P ≤ 0.10 in univariate analyses were included in multivariate logistic regression model to explore the association of variables with a specific outcome. Interactions between the independent variables were applied into the model analyses. Adjusted OR (AOR,) and its 95% CIs were estimated. Values of P < 0.05 were considered statistically significant. All statistical analyses were conducted in SPSS (IBM Corp, Armonk, NY).
The study was participated by 512 hospitals located in 126 cities from 22 provinces in China. Among a total of 2923 eligible physicians who were invited to participate in the survey, 118 refused to participate in the survey. An additional 684 questionnaires were defined as invalid questionnaires. The final analysis sample included 2121 questionnaires (Table 1). The ratio of sample size to the number of physicians who reported cases with gonorrhea to the national surveillance program in 2015 is 8.8%, ranging from 6.5% in Northeastern China to 11.0% in Southern China (Table 1). The ratio of sample size (2121) to the number of reported cases of gonorrhea in 2015 (100,245) is 2.1%, ranging from 1.2% in Northeastern China to 2.9% in Southwestern China. The number of reported cases of gonorrhea in the participated provinces accounts for 86.8% of the national reports in 2015.
The participants were from 512 hospitals located in 126 cities, including 2092 from 500 public hospitals and 29 from 12 private hospitals. As shown in Table 1, half of the participants (50.1%; 1062/2121) worked at the tertiary GHs, whereas approximately 10% (195/2121) at the SHs. However, more than half (55.7%; 1182/2121) were those from departments of dermatovenereology. The participants with professional titles of chief, attending, and resident (or trainee) doctors each accounted for approximately one third (30.8%, 41.8%, and 27.4%) and most of them (89.7%; 1902/2121) received either an internal or an external training on treatment of gonorrhea in the past 3 years. However, there were still almost half of the participants (47.9%; 1015/2121) who were not familiar with the National STD Guidelines.
Clinical Practice in Diagnosis of Gonorrhea
Of the 2113 respondent participants, more than half (56.6%) diagnosed less than 5 cases with gonorrhea in the past 6 months, and less than one tenth (7.3%) diagnosed more than 30 cases in which most (80.5%) were physicians from the departments of dermatovenereology (χ2 = 53.04, P < 0.001). All of the participants diagnosed gonorrhea in women using the laboratory tests of Gram stain (31.1%), culture (54.5%), nucleic acid amplification test (13.0%), or other tests (1.3%). Gram stain was more likely used by physicians in department of urology (46.6%) than those in department of dermatovenereology (25.9%) or department of gynecology (28.2%; χ2 = 72.17, P < 0.001). Gram stain was also more likely used for diagnosis by the physicians who did not receive training in the past 3 years (42.9%) than those received the training (29.8%; χ2 = 14.97, P < 0.001). For diagnosis in men, less than 1% of the participants used syndromic screening to make the diagnosis. Gram stain was chosen by 61.0% of the participants as their laboratory test for diagnosis in men, particularly by those in department of urology (68.6%; χ2 = 60.03, P < 0.001). Nucleic acid amplification test was more likely used by the physicians in GHs (11.1% and 13.6%) or OHs (18.3% and 19.7%) than in SHs (3.1% and 3.1%) for diagnosis in men and women, respectively (χ2 = 19.43 and 23.21, both P < 0.001). In GHs, nucleic acid amplification test was used by more physicians in secondary or tertiary hospitals (16.4%) than those in primary hospitals (5.2%; χ2 = 6.06, P = 0.001).
Antibiotic Use for Treatment of Gonorrhea
Among the 2121 participants, 1890 (89.1%) responded to the questions related to treatment prescriptions. Of the 1890 respondent participants, 1479 (78.3%), 150 (7.9%), 36 (1.9%), and 225 (11.9%) participants chose ceftriaxone, spectinomycin, cefotaxime, and other antibiotics as the first choice for treatment of gonorrhea, respectively. Physicians in department of urology (21.6%) were more likely to choose antibiotics rather than ceftriaxone, spectinomycin, or cefotaxime as their first choice therapy as compared with those in other departments (9.3%; χ2 = 45.77, P < 0.001). Up to 95% (182/192) of the physicians from the SHs chose ceftriaxone, spectinomycin, or cefotaxime as their first choicefor treatment of gonorrhea, but this proportion fell to 86.8% in the GHs (1372/1580; χ2 = 10.04, P = 0.001). Among the physicians in the GHs who chose the antibiotics rather than ceftriaxone, spectinomycin, or cefotaxime, 18.7% chose oral cefixime and 18.2% chose oral azithromycin as their first choice.
Among the 1449 physicians chose ceftriaxone with definite dosage as the first choice for treatment, the dosage was prescribed as 250 mg by 38.0%, 500 mg by 3.2%, 1.0 g by 32.4%, and 2.0 g or greater by 26.3%. High dosage (≥1.0 g) of ceftriaxone was more likely prescribed by the physicians in department of urology (65.7%) than in other departments (57.9%; χ2 = 6.74, P = 0.009).
Regarding the therapy for treatment of gonorrhea, 62.2% (1176/1890) of the physicians preferred to use regimens that were not adherent to those recommended by the National Guidelines in terms of antibiotic agents and their corresponding dosages, and this rate ranged from 44.8% (86/192) in the SHs to 65.4% (1037/1580) in the GHs.
Determinants Associated With the Nonadherence
Nine variables were identified in the univariate analyses to be associated with nonadherence to the National STD Guidelines at P ≤ 0.10 (Table 2). In the multivariate analyses with these 9 variables as independent variables and potential interactions between these variables, the following factors were found to be significantly associated with the nonadherence after adjusting for potential confounding factors: working in the areas located in the Northern China (AOR, 3.06 [95% CIs, 1.77–5.31], as compared with those in the Southern China; P < 0.001); in a GH (AOR, 1.54 [95% CIs, 1.08–2.19], as compared with a SH; P = 0.017), or in a department of urology (AOR, 1.44 [95% CIs, 1.08–1.93], as compared with the department of dermatovenereology; P = 0.0014); diagnosing more cases (11–30 cases) in the past 6 months (AOR, 1.82 [95% CIs, 1.25–2.67], as compared with diagnosis of <5 cases; P = 0.002); and unknowing the regimens for treatment of gonorrhea in the National STD Guidelines (AOR, 3.48 [95% CIs, 2.76–4.37], as compared with knowing about the National STD Guidelines; P < 0.001).
To our knowledge, the current study is the first nationwide cross-sectional survey on clinical practices of diagnosis and treatment of gonorrhea among physicians recruited from different categories and different levels of of health facilities in 22 provinces, municipalities, or autonomous regions in China. Our study found a high proportion of physicians who were not adherent to the recommendations for treating uncomplicated gonorrhea in the National STD Guidelines.14 Regarding the prescription for treatment of gonorrhea, there were still up to 12% of physicians chose those antibiotics, including oral azithromycin, oral cephalosporin, or oral ciprofloxacin, which had been no longer recommended by the National STD Guidelines in China as monotherapy because of the high prevalence rates of resistances.7,19,20 Persistent infections due to treatment failure resulting from treatment with these ineffective antibiotics may make a further transmission. Our study found that although 89.1% of the physicians chose ceftriaxone, spectinomycin, or cefotaxime as the first option for treatment of gonorrhea, the proportion of physicians who were not exactly adherent to the National STD Guidelines in terms of recommended antibiotic agents or their corresponding dosages was as high as 62.2%. These rates are hard to compare with those reported from the previous studies because the time frames and methodologies used in these studies are different.21–23 A study in Massachusetts in 2010 indicated that providers who treated gonorrhea differently from the guidelines in Massachusetts accounted for approximately 4% of cases and were associated with private practice/health maintenance organization settings and lower-incidence locations.21 The STD Surveillance Network data from 6 city and state health departments in the United States in 2010 to 2012 indicated that 76.8% of the cases reported to the system received ceftriaxone and 16.4% received an oral cephalosporin.22 A study based on surveillance data originating from Chicago Department of Public Health (CDPH) or non-CDPH providers showed 71.3% to 80.8% of adherence the Centers for Disease Control and Prevention gonococcal treatment guidelines among CDPH providers and 63.5% to 68.9% among non-CDPH providers.23
Inappropriate prescribing of ceftriaxone for treatment of uncomplicated gonorrhea is another important issue which was highlighted by our findings. In our surveyed subpopulation who chose ceftriaxone as the first option, nearly two thirds indicated a preferred dosage at 500 mg or greater. No clinical data exist to support use of doses of ceftriaxone of greater than 250 mg.15 However, given the propensity of gonorrhea to develop antibiotic resistance, impact to the wide application of high-dose ceftriaxone on development of resistance should be carefully investigated. Although a high prevalence (>10%) of decreased susceptibility to ceftriaxone has been reported in China,9 treatment failure of ceftriaxone has not been documented in China. It is not quite clear whether no reporting of the treatment failure in China is primarily because many of the patients were treated with a high dose (usually at 1.0 g or greater) of ceftriaxone or the current surveillance system was not sensitive to capture the treatment failure. It should be noted that there were still up to 18% of physicians who chose oral azithromycin as their first choice for treatment. Regarding the high rate of AMR to azithromycin in China, the frequent use of azithromycin monotherapy is a concern. Further training on the updated treatment recommendations and further monitoring of the treatment practice are needed in China.
In multivariable-adjusted analyses, our study found that entities located in Northern China had 3 times the prevalence of nonadherence to the National STD Guidelines than the areas in the Southern China. One possible explanation for associations between practice location and nonadherence may be relative familiarity with gonorrhea among physicians in each region. Incidence of reported cases with gonorrhea in the Northern China is lower than that in the Southern China or the Eastern China.24 This explanation is also supported by our findings that significantly less nonadherence occurred in the dermatovenereology specialty clinic settings (i.e., specialized dermatovenereology hospital and department of dermatovenereology) where gonorrhea is seen more often. However, the physicians who had experience in diagnosing more cases in the past 6 months were less likely to be adherent to the National STD Guidelines. This association is not quite clear, but it may be related to the nature of department where the physicians were working and/or the inertia of previous practice in the department.25 More importantly, nonadherence to the National STD Guidelines was lower among the physicians who were aware of the National STD Guidelines than those who were not (50.0% vs. 77.6%), indicating that the awareness could not be automatically translated into practice. This is not surprising given that 65% of the physicians who knew originated from the departments of dermatovenereology in which more physicians exposed to the training program. Based on these findings, it may be suggested that evaluation of the current training programs and continuous audit of clinical practice are needed. It is of note, though, that nonadherence was still suboptimal for those physicians who were familiar with the National STD Guidelines, largely as a result of overdosage in prescription. Interestingly, the nonadherence was not significantly different between those with and without participation of a training program in the recent 3 years. These findings further highlight the needs not only for developing the tailored training curriculums to meet the specific needs of physicians in different facilities and scaling up the training programs to improve coverage of health facilities, but also for strengthening the training effects through more innovative strategies. In addition, in the context of rapidly changing recommendations for treatment of uncomplicated, timely and frequent training on the updated recommendations is particularly critical.
The strengths of this study include (1) use of an anonymous questionnaire to gather information to ensure the truthfulness and confidentiality, (2) inclusion of 2 interconnected questions in questionnaire designed to validate the questionnaires, and (3) coverage of more than 500 health facilities from more than two thirds of provinces in the country. The study has several limitations. First, the surveyed hospitals were restricted to urban areas and mostly to the public health sectors (the numbers of the surveyed private health sectors and the participants from these facilities were relatively small); therefore, the results may not fully represent the clinical practices in diagnosis and treatment of gonorrhea of all hospitals in China. Second, around 20% of the invited physicians were not included because of study refusal or invalid questionnaires. The study results could be changed by these selection biases. Third, our results may also be affected by a self-reporting, recall, or social response bias, particularly those related to the sensitivity of prescribing behaviors. Further studies on validation of the self-reporting data against actual treatment prescriptions are needed. Finally, the study was not able to use a random sampling method to recruit the health facilities and/or physicians, likely resulting in the sample bias. Although a multistage sampling frame was used for recruiting the participants, the sampling strategy was not exactly based on the procedure that assures an equal probability of different units (province, city, hospital, or physician) to be chosen.
Although there are some limitations, to the best of our knowledge, the current study is the first nationwide survey to describe the clinical practices in diagnosis and treatment of uncomplicated gonorrhea across types and levels of health care in China. We identified a high proportion of physicians who were not adherent to the National STD Guidelines and factors associated with nonadherence. Our findings underscore the need for improved practices in the treatment of uncomplicated gonorrhea in China. In addition, further studies on clinical practice and its associations in providing care to patients with gonorrhea and other STIs in the era of health system reforms in China are urgently needed.
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