Neisseria gonorrhoeae AMR in Cuba (2009–2013): Ceftriaxone MIC Creep - Bionatura journal

Between 2009 and 2013, Neisseria gonorrhoeae isolates collected across Cuba exhibited consistently high levels of  (AMR), particularly to ciprofloxacin (69.7%), tetracycline (40.1%), and penicillin (36.8%). These findings extend and update previous national surveillance reports that documented high levels of resistance to penicillin and tetracycline in the late 1990s.⁴⁻⁷ Ciprofloxacin was introduced as first-line treatment for gonorrhoea in Cuba in 2002 due to its excellent in vitro activity,⁴ yet resistance subsequently emerged in the early 2000s⁶ and continued to increase, consistent with patterns observed in several regions participating in GASP-LAC.¹² Our data confirm that this trend persisted, aligning with international reports indicating a marked increase in fluoroquinolone resistance across Latin America and the Caribbean (LAC).¹²^,¹³ A recent global meta-analysis further contextualizes these observations, reporting a weighted pooled resistance to ciprofloxacin of 51.6% with substantial geographic variation (Asia 83%, Europe 46%, Oceania 24%).¹⁴

Penicillin resistance in our dataset (36.8%) was markedly lower than earlier Cuban reports (60.8–68%).⁴^,⁷ Similar rates of penicillin susceptibility restoration have been documented in several countries, including Canada¹⁵ and Spain¹¹, although some regions continue to report higher resistance levels, as seen in Argentina¹⁵ and Madagascar.¹⁶ Importantly, over half of our isolates (52.6%) exhibited intermediate susceptibility to penicillin, a pattern also described in studies from Russia, where intermediate MICs (47.6%) were linked to chromosomal mutations in penA, ponA, porA, and mtrR.¹⁷ Such intermediary phenotypes remain epidemiologically relevant because they may evolve toward higher levels of resistance.

Tetracycline resistance also decreased compared with 1995–1998 (83.5%).⁷ This reduction parallels regional dynamics reported through GASP-LAC from 2000 to 2009¹². It aligns with global observations indicating a transition from plasmid-mediated resistance (PPNG, TRNG, PP/TRNG) toward chromosomally mediated mechanisms.¹⁸ In our study, plasmid-mediated resistance phenotypes declined to 16.6%, representing a notable epidemiological shift compared with more than 70% reported in earlier Cuban investigations.⁴^,⁷

Spectinomycin remained highly active against N. gonorrhoeae isolates  (99.3%), consistent with global reports of sustained susceptibility.¹⁴^,¹⁹ Its limited use is typically attributable to factors in clinical practice rather than to microbiological performance.¹⁸ Gentamicin, evaluated for the first time in Cuban gonococcal isolates, also demonstrated favourable in vitro activity, except for two resistant isolates (MICs of 32 and 64 µg/mL). A higher proportion of resistance has been reported in Nigeria and Kenya.¹⁴ Our results of intermediate susceptibility to this aminoglucoside align with the study of Le Van et al. ²⁰ Although gentamicin has been considered a potential alternative in some clinical settings, several studies—including the GToG randomized trial—have shown variable efficacy depending on the anatomical site of infection.⁹

Azithromycin resistance in our dataset (13.8%) exceeds the WHO 5% threshold for empirical treatment of this STI.¹⁴ This value is higher than previously reported in Cuba (9.9%)⁷ and is comparable to increases observed across Europe, North America, Africa, and Asia.¹¹^,¹⁵^,¹⁶^,²² This is the first report in Cuba about HL-AziR isolates.  In Europe, in 2023, these strains were reported by 15 countries, compared to five countries in 2022.¹¹ The global rise in macrolide resistance is multifactorial and underscores the importance of continued susceptibility monitoring, especially in contexts where azithromycin is used in dual therapy of gonococcal infections and for syndrome management of STIs,²³ as in Cuba. An important finding from this study is the identification, for the first time in Cuba, of isolates with decreased susceptibility to ceftriaxone (MIC = 0.5 µg/mL). Similar observations have been reported in France, Spain, and Argentina.¹⁰^,¹¹^,¹³ These Cuban displayed co-resistance to penicillin and tetracycline but remained susceptible to azithromycin, reflecting a resistance profile compatible with early-stage ceftriaxone MIC elevation described in various countries.¹⁵^,¹⁶ These findings are relevant in the global context of “MIC creep,” where gradual increases in cephalosporin MICs have preceded sporadic treatment failures and the emergence of mosaic penA alleles.¹⁵^,¹⁶

Another novel contribution of this study is the detection of six multidrug-resistant isolates (MDR-GC). These MDR-GC strains have been increasingly reported across different regions of the world¹⁰^,¹¹^,²⁴, highlighting the need for surveillance to ensure continued treatment efficacy. Notably, no extensively drug-resistant gonococci (XDR-GC) were identified.

From a regional perspective, the AMR patterns observed in Cuba are broadly consistent with values reported across Latin America in the last two decades, particularly for fluoroquinolones and older antimicrobials.¹²^,²⁵ The present study, which includes isolates from almost all Cuban provinces, provides one of the most geographically comprehensive assessments of gonococcal AMR reported for this country and represents a valuable contribution to regional and global surveillance initiatives.

This study has several limitations.
First, the number of viable isolates available for analysis may not fully capture the diversity of circulating strains.
Second, molecular characterization methods (e.g., penA sequencing, mtrR promoter analysis, NG-MAST, whole-genome sequencing) were not performed, limiting the ability to correlate phenotypes with specific genetic determinants.
Third, detailed epidemiological metadata (clinical presentation, behavioural factors, HIV status, prior treatments, reinfection patterns) were not available, preventing linkage between resistance patterns and transmission dynamics.
Finally, as with many surveillance-based studies, the dataset reflects isolates submitted for laboratory confirmation and may not fully represent all infections occurring in the population.

Despite these considerations, the study provides the most current, geographically broad, and phenotypically detailed dataset on gonococcal AMR in Cuba. It supports the continued value of laboratory surveillance and the progressive integration of molecular tools into future national monitoring efforts.