Implementation considerations for a point-of-care Neisseria gonorrhoeae rapid diagnostic test at primary healthcare level in South Africa: a qualitative study.

BACKGROUND: South Africa maintains an integrated health system where syndromic management of sexually transmitted infections (STI) is the standard of care. An estimated 2 million cases of Neisseria gonorrhoeae (N. gonorrhoeae) occur in South Africa every year. Point-of-care diagnostic tests (POCT) may address existing STI control limitations such as overtreatment and missed cases. Subsequently, a rapid lateral flow assay with fluorescence-based detection (NG-LFA) with a prototype reader was developed for N. gonorrhoeae detection showing excellent performance and high usability; however, a better understanding is needed for device implementation and integration into clinics. METHODS: A qualitative, time-series assessment using 66 in-depth interviews was conducted among 25 trained healthcare workers involved in the implementation of the NG-LFA. Findings were informed by the Normalization Process Theory (NPT) as per relevant contextual (strategic intentions, adaptive execution, and negotiation capacity) and procedural constructs (coherence, cognitive participation, collective action, reflexive monitoring) to examine device implementation within primary healthcare levels. Interviews were audio-recorded, transcribed, and then analyzed using a thematic approach guided by NPT to interpret results. RESULTS: Overall, healthcare workers agreed that STI POCT could guide better STI clinical decision-making, with consideration for clinic integration such as space constraints, patient flow, and workload. Perceived NG-LFA benefits included enhanced patient receptivity and STI knowledge. Further, healthcare workers reflected on the suitability of the NG-LFA given current limitations with integrated primary care. Recommendations included sufficient STI education, and appropriate departments for first points of entry for STI screening. CONCLUSIONS: The collective action and participation by healthcare workers in the implementation of the NG-LFA revealed adaptive execution within the current facility environment including team compositions, facility-staff receptivity, and STI management experiences. User experiences support future clinic service integration, highlighting the importance of further assessing patient-provider communication for STI care, organizational readiness, and identification of relevant departments for STI screening.

Effectiveness of Cefixime for the Treatment of Neisseria gonorrhoeae Infection at 3 Anatomic Sites: A Systematic Review and Meta-Analysis.

BACKGROUND: To treat Neisseria gonorrhoeae infection, the Centers for Disease Control and Prevention recommends a single oral dose of cefixime as an alternative to injectable ceftriaxone. METHODS: We conducted a systematic review and meta-analysis to describe the effectiveness of cefixime in treating N. gonorrhoeae infection at 3 different anatomic sites.We searched PubMed and Embase database to abstract treatment success rates and cefixime dosage/frequency for studies that reported the anatomical site of infection. We included reports published between January 1, 1980, and December 7, 2021. Twenty studies published between 1989 and 2015 were included in our meta-analysis. We calculated pooled treatment success percentages and 95% confidence intervals (CIs) using random-effects models. RESULTS: Of patients who received a 400-mg single dose of cefixime, 824 of 846 (97%; 95% CI, 96%-98%) patients with urogenital infection, 107 of 112 (97%; 95% CI, 84%-100%) patients with rectal infection, and 202 of 242 (89%; 95% CI, 76%-96%) patients with pharyngeal infection were cured. Of patients who received an 800-mg single dose of cefixime, 295 of 301 (98%; 95% CI, 96%-99%) patients with urogenital infection and 21 of 26 (81%; 95% CI, 61%-92%) patients with pharyngeal infection were cured. CONCLUSIONS: Our meta-analysis found that cefixime is highly effective at treating urogenital infections and less effective at treating pharyngeal infections. We recommend more investigation into the effectiveness of cefixime in treating rectal infections and studying multidose therapy for the cefixime treatment of pharyngeal infection.

Resistance-Guided Therapy for Neisseria gonorrhoeae.

Antimicrobial-resistant Neisseria gonorrhoeae infections are a threat to public health. Novel strategies for combating such resistance include the development of molecular assays to facilitate real-time prediction of antimicrobial susceptibility. Resistance to ciprofloxacin is determined by the presence of a single mutation at codon 91 of the gyrase A gene; molecular assays to guide therapy are commercially available. Resistance to cefixime is conferred via 1 of 6 critical mutations in either the mosaic penA gene or specific loci in the nonmosaic region. Resistance to ceftriaxone is conferred through mutations in 1 of 4 genes: penA, ponA, penB, and mtr; however, the ability to predict reduced susceptibility based on those genes varies by geographic region. Here, we highlight the work done toward the development of 3 such assays for ciprofloxacin, cefixime, and ceftriaxone, discuss the status of our current understanding and ongoing challenges, and suggest future directions.

Epidemiology, Treatments, and Vaccine Development for Antimicrobial-Resistant Neisseria gonorrhoeae: Current Strategies and Future Directions.

Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection in the world after Chlamydia trachomatis. The pathogen has developed resistance to every antibiotic currently approved for treatment, and multidrug-resistant strains have been identified globally. The current treatment recommended by the World Health Organization is ceftriaxone and azithromycin dual therapy. However, resistance to azithromycin and ceftriaxone are increasing and treatment failures have been reported. As a result, there is a critical need to develop novel strategies for mitigating the spread of antimicrobial-resistant N. gonorrhoeae through improved diagnosis and treatment of resistant infections. Strategies that are currently being pursued include developing molecular assays to predict resistance, utilizing higher doses of ceftriaxone, repurposing older antibiotics, and developing newer agents. In addition, efforts to discover a vaccine for N. gonorrhoeae have been reignited in recent years with the cross-protectivity provided by the N. meningitidis vaccine, with several new strategies and targets. Despite the significant progress that has been made, there is still much work ahead to combat antimicrobial-resistant N. gonorrhoeae globally.

A Narrative Review of Clinical Treatment Outcomes of Neisseria gonorrhoeae Infection With Ciprofloxacin by Minimum Inhibitory Concentration and Anatomic Site.

BACKGROUND: Neisseria gonorrhoeae infections are becoming increasingly resistant to recommended treatments. Resistance-guided therapy may mitigate the continued emergence of resistance by enabling the use of previously recommended treatments like ciprofloxacin. To describe the effectiveness of ciprofloxacin to treat "susceptible" infections, we estimated the clinical efficacy of ciprofloxacin at various minimum inhibitory concentrations (MICs) and anatomic sites. METHODS: We reviewed publicly available reports using the PubMed.gov database and search terms "gonorrhea/drug therapy"[Mesh] AND "ciprofloxacin". We included clinical treatment studies in which ciprofloxacin was administered alone to treat N. gonorrhoeae, specimens were collected for N. gonorrhoeae culture from each infection, the MIC was determined for ≥90% of infective strains, and individual treatment outcomes were clearly defined. We recorded those data, ciprofloxacin dose and infection site. We calculated the frequency of treatment success and 95% confidence intervals (CIs). RESULTS: Twenty studies from 1985 to 2020 met our inclusion criteria. Ciprofloxacin at commonly used doses eliminated 99.2% (95% CI, 98.5%-99.6%; n = 1439) of gonococcal infections with MICs <0.125 µg/mL, 76.3% (95% CI, 59.8%-88.6%; n = 38) of infections with MICs from 0.125 to 0.5 µg/mL, and 30.1% (95% CI, 20.5%-41.2%; n = 83) of infections with MICs ≥1 µg/mL across anatomic sites. CONCLUSIONS: Ciprofloxacin reliably eliminated gonococcal infections with MICs <0.125 µg/mL across anatomic sites. Molecular assays predicting MICs of ciprofloxacin <0.125 µg/mL of gonococcal strains can allow for reintroduction of ciprofloxacin in gonorrhea treatment. Clinicians can confidently use ciprofloxacin to treat susceptible gonococcal infections.

Resistance-Guided Treatment of Gonorrhea: A Prospective Clinical Study.

BACKGROUND: Novel treatment strategies to slow the continued emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae are urgently needed. A molecular assay that predicts in vitro ciprofloxacin susceptibility is now available but has not been systematically studied in human infections. METHODS: Using a genotypic polymerase chain reaction assay to determine the status of the N. gonorrhoeae gyrase subunit A serine 91 codon, we conducted a multisite prospective clinical study of the efficacy of a single oral dose of ciprofloxacin 500 mg in patients with culture-positive gonorrhea. Follow-up specimens for culture were collected to determine microbiological cure 5-10 days post-treatment. RESULTS: Of the 106 subjects possessing culture-positive infections with wild-type gyrA serine N. gonorrhoeae genotype, the efficacy of single-dose oral ciprofloxacin treatment in the per-protocol population was 100% (95% 1-sided confidence interval, 97.5-100%). CONCLUSIONS: Resistance-guided treatment of N. gonorrhoeae infections with single-dose oral ciprofloxacin was highly efficacious. The widespread introduction and scale-up of gyrA serine 91 genotyping in N. gonorrhoeae infections could have substantial medical and public health benefits in settings where the majority of gonococcal infections are ciprofloxacin susceptible. CLINICAL TRIALS REGISTRATION: NCT02961751.

Trends in antimicrobial resistance in Neisseria gonorrhoeae in Hanoi, Vietnam, 2017-2019.

BACKGROUND: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an emerging global health threat. Surveillance of AMR in N. gonorrhoeae in the Western Pacific Region is important, as resistant strains have typically emerged from this region. There are sparse data regarding antibiotic susceptibility of N. gonorrhoeae from Vietnam. This study aimed to provide updated data on antibiotic susceptibilities in N. gonorrhoeae isolates from Hanoi, Vietnam. METHODS: From 2017 to 2019, 409 N. gonorrhoeae clinical isolates were collected at the National Hospital for Venereology and Dermatology in Hanoi, Vietnam. Antibiotic susceptibility testing was performed by disk diffusion method according to the Clinical and Laboratory Standards Institute (CLSI) protocol. The zone diameters of inhibition were recorded and interpreted according to standard CLSI criteria, except for azithromycin, due to the absence of CLSI interpretation. Categorical variables were analyzed by Chi-square and Fisher's exact tests. Linear regression was used to evaluate zones of inhibition by year. RESULTS: Among the 409 isolates, no isolates were susceptible to penicillin, 98.3% were resistant to ciprofloxacin, and all isolates were susceptible to spectinomycin. There were 122/407 (30.0%) isolates resistant to azithromycin and there was an association between resistance and year (p <  0.01), ranging from 15.3% of isolates in 2017 to 46.7% of the isolates in 2018. Resistance to cefixime was found in 13/406 (3.2%) of isolates and there was no association by year (p = 0.30). Resistance to ceftriaxone occurred in 3/408 (0.7%) of isolates. Linear regression indicated the zone of inhibition diameters decreased by 0.83 mm each year for ceftriaxone (95% CI: - 1.3, - 0.4; p <  0.01) and decreased by 0.83 mm each year (95% CI: - 1.33, - 0.33; p <  0.01) for azithromycin; the association was not significant for cefixime (p = 0.07). CONCLUSIONS: We found decreasing susceptibility of N. gonorrhoeae to ceftriaxone and azithromycin, as well as a high prevalence of resistance to azithromycin, among isolates in Hanoi, Vietnam from 2017 to 2019. The trends of decreasing susceptibility to first-line treatments are concerning and highlight the urgency of addressing antimicrobial resistance in N. gonorrhoeae. Expanded surveillance efforts within the Western Pacific Region are critical to monitoring trends and informing treatment guidelines.

Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections.

Bacterial sexually transmitted infections (STIs) have been increasing over the past 2 decades in gay, bisexual, and other men who have sex with men. With the widespread use of early human immunodeficiency virus (HIV) treatment, which virtually eliminates transmission risk, and the availability of HIV pre-exposure prophylaxis, there have been attitudinal changes regarding HIV infection with resultant increases in sexual contact and declines in condom use. Doxycycline is used for primary prophylaxis in a number of infectious diseases. We conducted a state-of-the-art review to examine the current state of research, knowledge gaps, and challenges around the use of doxycycline prophylaxis to prevent syphilis and other STIs. International academic and government experts met in March 2019 to frame the initial inquiry, which was supplemented by focused literature searches. Two small short-term randomized controlled trials examining doxycycline prophylaxis found high efficacy. Five additional clinical studies are underway or in development. Studies differed in design, population, outcomes, and safety measures. Doxycycline prophylaxis for bacterial STIs shows promise. Better and more robust data are needed on efficacy; target population; community acceptability; behavioral risk compensation; doxycycline dose, regimen, and formulation; long-term safety; antimicrobial resistance; cost-effectiveness; and risk-benefit.

Addressing Neisseria gonorrhoeae Treatment Resistance With the DNA Gyrase A Assay: An Economic Study, United States.

Targeted antibiotics could delay emergence of resistant Neisseria gonorrhoeae. The DNA gyrase subunit A assay predicts susceptibility to ciprofloxacin. A model found that adding a $50 gyrase subunit A test for asymptomatic patients screened for N. gonorrhoeae resulted in cost neutrality. When ciprofloxacin susceptibility was high, a $114 test resulted in savings.

A Cost Analysis of Gyrase A Testing and Targeted Ciprofloxacin Therapy Versus Recommended 2-Drug Therapy for Neisseria gonorrhoeae Infection.

BACKGROUND: Novel approaches to combating drug-resistant Neisseria gonorrhoeae infections are urgently needed. Targeted therapy with ciprofloxacin has been made possible by a rapid assay for genotyping the gyrase A (gyrA) gene; a nonmutated gene reliably predicts susceptibility to ciprofloxacin. METHODS: We determined the costs of running the gyrA assay, 500 mg of ciprofloxacin, 250 mg of ceftriaxone injection, and 1000 mg of azithromycin. Cost estimates for gyrA testing included assay reagents and labor. Cost estimates for ceftriaxone included medication, injection, administration, supplies, and equipment. We measured the cost of using the gyrA assay and treatment based on genotype using previously collected data over a 13-month period between November 2015 and November 2016 for all N. gonorrhoeae cases diagnosed at UCLA. We subsequently developed 3 cost models, varying the frequency of testing and prevalence of N. gonorrhoeae infections with ciprofloxacin-resistant or genotype-indeterminate results. We compared those estimates with the cost of recommended 2-drug therapy (ceftriaxone and azithromycin). RESULTS: Based on a 65.3% prevalence of cases with ciprofloxacin-resistant or genotype indeterminate N. gonorrhoeae infections when running an average of 1.7 tests per day, the per-case cost of gyrA genotyping and targeted therapy was US $197.19. The per-case cost was US $155.16 assuming a 52.6% prevalence of ciprofloxacin-resistant or genotype-indeterminate infections when running an average of 17 tests per day. The per-case cost of 2-drug therapy was US $142.75. CONCLUSIONS: Direct costs of gyrA genotyping and targeted ciprofloxacin therapy depend on the prevalence of ciprofloxacin-resistant or genotype-indeterminate infections and testing frequency.

Implementation of a Rapid Genotypic Assay to Promote Targeted Ciprofloxacin Therapy of Neisseria gonorrhoeae in a Large Health System.

Multidrug-resistant Neisseria gonorrhoeae is a top threat to public health. In November 2015, UCLA Health introduced a rapid gyrase A (gyrA) genotypic assay for prediction of Neisseria gonorrhoeae susceptibility to ciprofloxacin. We found a significant reduction in ceftriaxone use with a concomitant increase in targeted therapy.

Integrating Human Immunodeficiency Virus and Reproductive, Maternal and Child, and Tuberculosis Health Services Within National Health Systems.

Joint United Nations Programme on HIV/AIDS (UNAIDS) established 90-90-90 HIV treatment targets for 2020 including the following: 90 % of HIV-infected people know their HIV status, 90 % of HIV-infected people who know their status are on treatment, and 90 % of people on HIV treatment have a suppressed viral load. Integration of HIV and other programs into the national health system provides an important pathway to reach those targets. We examine the case for integrating HIV and other health services to ensure sustainability and improve health outcomes within national health systems. In this non-systematic review, we examined recent studies on integrating HIV, tuberculosis (TB), maternal-child health (MCH), and sexually transmitted infection (STI) programs. Existing evidence is limited about the effectiveness of integration of HIV and other services. Most studies found that service integration increased uptake of services, but evidence is mixed about the effect on health outcomes or quality of health services. More rigorous studies of different strategies to promote integration over a wider range of services and settings are needed. Research on how best to maximize benefits, including sustainability, of integrated services is necessary to help inform international and national policy. We recommend additional interventions to test how best to integrate HIV and MCH services, HIV and TB services, HIV testing and treatment, and STI testing and treatment.

Stemming the tide of drug-resistant Neisseria gonorrhoeae: the need for an individualized approach to treatment.

Drug-resistant Neisseria gonorrhoeae poses a significant public health challenge. In recent years, gonococci resistant to first- and second-line antibiotics have spread worldwide and new strains have developed that are increasingly resistant to third-generation cephalosporins, which are currently our last line of available treatments. Given the timeline required to develop new drugs or an effective vaccine for N. gonorrhoeae, a top priority is to use the drugs that are available as effectively as possible. Currently, clinical management of gonorrhoea is based upon treatment guidelines informed by international gonococcal antimicrobial susceptibility surveillance programmes. This approach, although currently the most practical, is subject to a number of limitations since surveillance data inherently provide population-level information. As a result, basing treatment guidelines on these data can result in the prescription of more aggressive or broader treatment than is needed by individual patients and hence inadvertently contribute to the development and spread of resistance to important drugs. Clearly, methods are needed that provide patient-specific drug susceptibility information in a time frame that would allow clinicians to prescribe individualized treatment regimens for gonorrhoea. Fortunately, in recent years, there have been a number of advances in the development of rapid methods for characterizing both the genotype and the drug resistance phenotype of N. gonorrhoeae strains. Here, we review these advances and propose additional studies that would help facilitate a transition towards an individualized treatment approach for gonorrhoea.

Integrating clinical services for HIV, tuberculosis, and cryptococcal disease in the developing world: a step forward with 2 novel diagnostic tests.

The success of antiretroviral therapy (ART) programs in the developing world is limited by the lack of adequate diagnostic tests to screen for life-threatening opportunistic infections such as tuberculosis (TB) and cryptococcal disease. Furthermore, there is an increasing need for implementation research in measuring the effectiveness of currently available rapid diagnostic tests. The recently developed lateral flow assays for both cryptococcal disease and TB have the potential to improve care and greatly reduce the time to initiation of ART among individuals who need it the most. However, we caution that the data on feasibility and effectiveness of these assays are limited and such research agendas must be prioritized.

Supporting the massive scale-up of antiretroviral therapy: the evolution of PEPFAR-supported treatment facilities in South Africa, 2005-2009.

BACKGROUND: South Africa has an estimated 1.5 million persons in need of antiretroviral therapy (ART). In 2004, the South African government began collaborating with the United States President's Emergency Plan for AIDS Relief (PEPFAR) to increase access to ART. We determined how PEPFAR treatment support changed from 2005-2009. METHODS: In order to describe the change in number and type of PEPFAR-supported ART facilities, we analyzed routinely collected program-monitoring data from 2005-2009. The collected data included the number, type and province of facilities as well as the number of patients receiving ART at each facility. RESULTS: The number of PEPFAR-supported facilities providing ART increased from 184 facilities in 2005 to 1,469 facilities in 2009. From 2005-2009 the number of PEPFAR-supported government facilities increased 10.1 fold from 54 to 546 while the number of PEPFAR-supported NGO facilities (including general practitioner and NGO facilities) increased 6.2 fold from 114 to 708. In 2009 the total number of persons treated at PEPFAR-supported NGO facilities was 43,577 versus 501,089 persons at PEPFAR-supported government facilities. Overall, the median number of patients receiving ART per site increased from 81 in 2005 to 136 in 2009. CONCLUSIONS: To mitigate the gap between those needing and those receiving ART, more facilities were supported. The proportion of government facilities supported and the median number of persons treated at these facilities increased. This shift could potentially be sustainable as government sites reach more individuals and receive government funding. These results demonstrate that PEPFAR was able to support a massive scale-up of ART services in a short period of time.