Streptococcus pneumoniae is a transient colonizer of the nasopharynx, with colonization peaking in the early years of life and declining into adulthood. It is associated with both invasive and non-invasive pneumococcal diseases. The incidence of invasive pneumococcal diseases is most prominent at the extremes of age, as well as in immunocompromised hosts and people with chronic respiratory tract diseases. People living with HIV are particularly vulnerable to severe pneumococcal disease [1] Globally, Streptococcus pneumoniae is estimated to have caused as many as 515,000 deaths (95% uncertainty interval, UI 302,000–609,000) in children aged < 5 years in 2015, and approximately 50% of those deaths occurred in four countries in Africa (Nigeria, Democratic republic of Congo) and Asia (India, Pakistan) [2]. Globally, Streptococcus pneumoniae is estimated to cause 1,189,937 deaths (UI 690,445-1,770,660) [3].
Before 1970, pneumococci were readily susceptible to nearly all relevant antibiotics, and penicillin was the antibiotic of choice. In the late 1970s, pneumococci with non-susceptibility to penicillin emerged, resulting in treatment failures [4, 5]. The discovery of pneumococci resistant to penicillin shifted empirical treatment for suspected bacterial respiratory tract infection to macrolides and tetracycline. In Tanzania, standard treatment guidelines recommend macrolides and tetracyclines as first and second line treatments, respectively, for mild to moderate community acquired pneumonia caused by Streptococcus pneumoniae [6]. However, the recommendation is not based on current evidence of susceptibility patterns, as surveillance of the trend of antibiotic resistance in Streptococcus pneumoniae is limited in Tanzania. Data from the Network for Surveillance of Pneumococcal Disease in the East African Region in the pre-pneumococcal vaccination era reported a low rate of Streptococcus pneumoniae resistant to erythromycin and other antibiotics in Tanzania [7]. Furthermore, a meta-analysis of childhood pneumococcal diseases in Africa prior to the widespread use of the pneumococcal capsular vaccine (PCV) reported a low rate of resistance to erythromycin, but a substantially higher rate of resistance to tetracycline [8].
However, post-PCV surveillance studies conducted in well-organized settings have shown increased pneumococcal resistance to erythromycin and other antibiotics, partly attributed to increased consumption of macrolides [9,10,11].
Pneumococcal resistance to macrolides is mediated by erythromycin ribosomal methylase B (erm(B)) encoding enzymes that methylate the 23S rRNA, thereby inhibiting macrolide binding [12]. The erm(B) confers resistance to macrolides, lincosamides, and Streptogramin B, producing MLSB phenotypes [13, 14]. Macrolide efflux protein A and E, efflux pumps encoded by the mef(A) and mef(E) genes, and ribosomal mutations (23S rRNA), are other common causes of macrolide resistance in Streptococcus pneumoniae [13]. The mef(A/E) genes confer the M phenotype, exhibiting low level resistance to macrolides, but not resistance to lincosamides and streptogramin B. The macrolide resistance genes are commonly carried on mobile genetic elements, facilitating their easy intra- and interspecies dissemination [15, 16]. The Tn916 transposon family that contains the tetracycline resistance determinant tet(M), has frequently been reported to harbor macrolide resistance determinant genes [17].
Macrolide resistance determinants vary with geographical locations [13]. In Tanzania, where macrolides and tetracyclines are commonly used and easily accessible over the counter without prescriptions, the mechanisms of resistance to these antibiotics in Streptococcus pneumoniae has not been studied. Therefore, we performed this study using whole genome sequencing to determine mechanisms of antibiotic resistance among penicillin non-susceptible Streptococcus pneumoniae isolated from Tanzania.
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