Clonal Evolution Leading to Maintenance of Antibiotic Resistance Rates among Colonizing Pneumococci in the PCV7 Era in Portugal

Abstract

The introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in Portugal led to extensive serotype replacement among carriers of pneumococci, with a marked decrease of PCV7 types. Although antimicrobial resistance was traditionally associated with PCV7 types, no significant changes in the rates of nonsusceptibility to penicillin, resistance to macrolides, or multidrug resistance were observed. This study aimed to investigate the mechanisms leading to maintenance of antimicrobial resistance, despite marked serotype replacement. We compared, through molecular typing, 252 antibiotic-resistant pneumococci recovered from young carriers in 2006 and 2007 (era of high PCV7 uptake) with collections of isolates from 2002 and 2003 (n ‫؍‬ 374; low-PCV7-uptake era) and 1996 to 2001 (n ‫؍‬ 805; pre-PCV7 era). We observed that the group of clones that has accounted for antimicrobial resistance since 1996 is essentially the same as the one identified in the PCV7 era. The relative proportions of such clones have, however, evolved substantially overtime. Notably, widespread use of PCV7 led to an expansion of two Pneumococcal Molecular Epidemiology Network (PMEN) clones expressing non-PCV7 capsular variants of the original strains: Sweden 15A ST63 (serotypes 15A and 19A) and Denmark 14 ST230 (serotypes 19A and 24F). These variants were already in circulation in the pre-PCV7 era, although they have now become increasingly abundant. Emergence of novel clones and de novo acquisition of resistance contributed little to the observed scenario. No evidence of capsular switch events occurring after PCV7 introduction was found. In the era of PCVs, antimicrobial resistance remains a problem among the carried pneumococci. Continuous surveillance is warranted to evaluate serotype and clonal shifts leading to maintenance of antimicrobial resistance.Streptococcus pneumoniae is a Gram-positive bacterium that frequently colonizes asymptomatically the nasopharynx of young children. However, it is also an important human pathogen that can cause a wide range of diseases, from otitis media to pneumonia and meningitis. Worldwide, it has been estimated that 14.5 million episodes of serious pneumococcal disease and 826,000 deaths per year occur in children aged less than 5 years (23).In 2000, a seven-valent pneumococcal conjugate vaccine (PCV7) targeting the seven most common serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) causing invasive disease among young children in the United States became available. Since then, in countries where the vaccine has been introduced in the universal vaccination plan, a dramatic reduction in the incidence of invasive disease caused by PCV7 serotypes has been observed in all age groups (11,17,35). This extended phenomenon beyond the target group, known as herd immunity, has been attributed to decreased transmission of pneumococci from children to other age groups. Indeed, the nasopharynx of children is the main reservoir of pneumococci, and a decrease in carriage of PCV7 serotypes has been observed in vaccina...

Serotype and Clonal Evolution of Penicillin-Nonsusceptible Invasive Streptococcus pneumoniae in the 7-Valent Pneumococcal Conjugate Vaccine Era in Italy

“…Two clones, Sweden 15A -25/ST63/CC63, expressing multiple VS and NVS serotypes, and Denmark 14 -32/ST230/CC230, expressing NVS 19A and 24F, expanded in the PCV7 era, ranking second and third, respectively. The increase of these two clones, associated with both carriage and disease, has been reported in several countries (1,8,17,22). Denmark 14 -32/ST230/CC230 was detected in Italy as far back as 1997, in association with serotype 24F isolates (19).…”

“…The presence of the same antibiotic-resistant clones in the periods before and after PCV7 implementation, and also of an evolution in their proportions leading to persistence of antimicrobial resistance, has already been documented in a colonization study from Portugal (22).…”

Noninvasive Pneumococcal Clones Associated with Antimicrobial Nonsusceptibility Isolated from Children in the Era of Conjugate Vaccines

“…However, by the end of the study Sweden 15A -25 and its variants mostly expressed NVT serotype 15A. The occurrence of Sweden 15A -25 expressing different capsular serotypes is well documented (21,30). Importantly, NVT expressed by Sweden 15A -25 variants, including those not traditionally associated with antimicrobial nonsusceptibility, could lead to antimicrobial nonsusceptibility rates similar to those of the pre-PCV7 era (21,30).…”

“…The rapid decline of Spain 9V -3 and its variants in our population within a short period of PCV7/13 introduction differs from previous studies where Spain 9V -3 persisted (20, 21). The high vaccination coverage (92%) of PCV7/13 among Irish children may have contributed to a rapid decline in Spain 9V -3 compared to a lower coverage (30.7% to 55%) in regions where this clone persisted (20)(21)(22). Furthermore, we mostly included children born after universal conjugate vaccine introduction, whereas in the study by Gherardi et al where Spain 9V -3 persisted, isolates were also obtained from adults likely not to be directly protected by conjugate vaccines (20).…”

“…The PI-1 locus has been associated with the spread of antimicrobial-nonsusceptible clones, including Spain 9V -3 and England 14 -9 and CC320 (5,21,31). Moreover, nonsusceptible piliated clones have spread in countries with low antibiotic use (5).…”