We Traded the Culture for Blindness

*Neisseria gonorrhoeae* infects 82 million people per year and has sequentially developed resistance to every antibiotic class used against it over 80 years: sulfonamides, penicillins, tetracyclines, macrolides, and fluoroquinolones. Ceftriaxone resistance — the last-line treatment — rose from 0.8% to 5% globally between 2022 and 2024. Extensively drug-resistant "super-gonorrhea" strains resistant to both ceftriaxone and azithromycin have been reported across multiple continents. Yet the global shift from culture-based to molecular (NAAT) diagnostics, while improving detection sensitivity, has inadvertently destroyed our ability to perform antibiotic susceptibility testing — NAATs do not yield live organisms. Laboratories worldwide are losing the capacity and expertise to perform gonorrhea culture, creating a dangerous surveillance blind spot precisely as resistance accelerates.

Without point-of-care resistance information, clinicians must treat empirically with the most powerful remaining antibiotics, accelerating resistance selection. The WHO/FIND/GARDP collaboration developed two TPPs in 2020: one for a rapid diagnostic test (TPP1, <=30 minutes, <$3) and one for an AMR/susceptibility test (TPP2, <=60 minutes, <$25). Neither exists. The WHO's Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) has limited or no data from Eastern Europe, Central Asia, Latin America, the Eastern Mediterranean, and most of Africa — the regions with the majority of cases. We are losing the ability to track resistance in the pathogen most likely to become completely untreatable.

Culture-based susceptibility testing is the gold standard but requires specialized media, controlled CO2 atmosphere, 24-48 hour incubation, and trained microbiologists — infrastructure that is disappearing even in high-income countries as NAATs take over routine diagnosis. Molecular prediction of resistance is complicated by *N. gonorrhoeae*'s complex resistance mechanisms: cephalosporin resistance involves multiple interacting genes (penA, mtrR, porB, ponA), making genotype-to-phenotype prediction unreliable. ResistancePlus GC (SpeeDx) is FDA-approved for ciprofloxacin susceptibility detection (94.8% sensitivity, 100% specificity) but has limited clinical value since >95% of isolates are already ciprofloxacin-resistant in many regions. No molecular test reliably predicts ceftriaxone susceptibility — the drug that matters most.

Two TPP-aligned approaches are closest: (1) a novel non-molecular lateral flow assay (NG-LFA) for rapid diagnosis meeting TPP1 requirements, recently evaluated with promising results; and (2) a multiplex HRM PCR assay achieving 98.6% sensitivity and 99.2% specificity for AMR determinant detection across four drug classes at <$1/sample, though it still requires molecular infrastructure. The critical unmet need is a test that can predict ceftriaxone susceptibility from clinical specimens without culture — which likely requires either breakthrough genotype-phenotype mapping or a novel rapid phenotypic approach.

A team could develop a microfluidic rapid phenotypic susceptibility test that captures *N. gonorrhoeae* directly from clinical swab specimens, exposes them to ceftriaxone in microchannels, and detects growth/no-growth via fluorescence within 2-4 hours — bypassing the genotype-phenotype problem entirely. The key engineering challenge is viable organism capture from mixed clinical specimens without conventional culture. Alternatively, a team could build a machine learning model trained on whole-genome sequence data to predict ceftriaxone resistance from targeted gene panels, evaluating which minimal set of genetic markers provides clinically useful accuracy. Relevant disciplines: microbiology, microfluidics, bioinformatics, antimicrobial resistance research.