Our data demonstrate the importance of pneumococcus and Hib in the aetiology of meningitis in PNG; with the serotype distribution of pathogenic pneumococci and age of infection having implications for vaccine efficacy. Potential changes in serotype distribution (post-vaccine) and antimicrobial susceptibility dictate the need for ongoing surveillance.
Hib accounts for the vast majority of pathogenic H. influenzae isolated in this setting (and other settings), enabling the Hib vaccine to have a significant impact on disease. In contrast, non-PCV13 serogroups/types 2, 8, 12, 18A, 19B, 24 and 46 were amongst the most commonly isolated strains of S. pneumoniae, accounting for >40 % of all pneumococcal isolates in this study. The broad range of serotypes observed in this study is in keeping with our earlier study in which Lehmann et al found so-called ‘adult’ serogroups of pneumococci were more commonly isolated from CSF of children than ‘paediatric’ serotypes (i.e. 6, 14) [17].
Serotype 2, the most commonly isolated serotype in this study, has recently been described as a “newly recognised pneumococcal infection threat” [19]; however, it has been noted as a major cause of pneumococcal meningitis in PNG for the past 30 years with no obvious temporal clustering [6, 17]. Saha and colleagues noted that serotype 2 affected younger children relative to other serotypes [19]. In contrast, in our study the age distribution of serotype 2 reflected the pneumococcal isolation rate over the age groups (Table 2 and Additional file 2: Table S2). Our study provides evidence that serotype 2 presents a threat to this region. PCV13 does not include serotype 2, and upper respiratory tract carriage of other non-vaccine serotypes of pneumococcus is common in infants in this setting [20]. Thus, there may be the potential for an increase in disease due to non-vaccine serotypes post pneumococcal vaccine introduction in PNG, as was seen after the introduction of PCV7 in other settings [21].
Despite the potential for serotype replacement, the overall impact of PCVs has been positive, particularly in high income settings and with broader spectrum (PCV10 and PCV13) vaccines. It is difficult to make direct comparisons due to lack of meningitis-specific data, but in high-income settings PCVs have reduced overall IPD rates by up to 80 % as a result of the better match between serotypes in PCVs and serotypes causing disease [13]. Even with lower serotype coverage (relative to high income settings) and the potential for serotype replacement, a vaccine that offers 40–50 % coverage in a high burden setting will save lives. When consideration is given to the roll of pneumococcus in pneumonia, the case for immediate PCV rollout in high-burden settings becomes even stronger.
Our data demonstrate differences in age distribution and CFR between Hib meningitis and pneumococcal meningitis (Table 2). The CFRs for laboratory-confirmed bacterial meningitis was higher than the CFR for patients in whom no bacterial pathogen was isolated, and there was a trend towards a higher CFR in patients with pneumococcal meningitis than in those with H. influenzae meningitis (though not statistically significant). The CFRs observed in the current surveillance are a considerable improvement on those observed previously in the same setting, when approximately one-third of children with probable or confirmed bacterial meningitis died [17]. It is difficult to ascertain the reasons for this decrease in CFR over the two study periods; though better overall health of the population resulting in less severe disease, and/or improved management, may be contributing factors.
We observed high and increasing rates of antimicrobial resistance in Hib isolates. An increase in resistance relative to our previous study was observed, in which all Hib were susceptible to ampicillin and chloramphenicol [17]. A recent study in the lowlands of PNG found all H. influenzae CSF isolates tested (n = 14) were chloramphenicol-resistant [22]. Until recently chloramphenicol was the first-line treatment for meningitis in children in PNG: due to increasing resistance of Hib to chloramphenicol, ceftriaxone has now replaced it as the treatment of choice [23]. The observation that four Hib isolates were non-susceptible to ceftriaxone using the disk-diffusion method is of concern; however MICs were not conducted to confirm non-susceptibility (due to loss of viability of the isolates). Resistance to ceftriaxone in Hib remains uncommon in other settings [24, 25]; nonetheless, ongoing monitoring of ceftriaxone susceptibility of Hib is imperative given its current use for treatment of meningitis in PNG.
Penicillin-resistant pneumococci have long been recognised in PNG. In this study 21.5 % of isolates were penicillin resistant: a similar proportion of isolates (7/31; 22.6 %) had an MIC ≥0.125 μg/ml in the previous study conducted in this setting [17]. Thus, on the basis of current and previous findings [17, 22], there is no evidence of increasing prevalence of antimicrobial resistant pneumococci in PNG.
Tetracycline and erythromycin are not well suited for the treatment of meningitis; however, monitoring resistance to these antibiotics in pneumococcal isoaltes is of value. With limited routine diagnostic culture and sensitivity conducted in PNG, it is important to gain an insight into resistance patterns for a wide range of antimicrobial agents from relatively few clinical isolates. Moreover, baseline data on macrolide resistance in malaria endemic settings is of value as trials are conducted on malaria prophylaxis [26].
Our study provides important data leading up to the introduction of Hib and PCV vaccines. The Hib vaccine (introduced in 2008) and the PCV13 (rollout commenced in 2014) should reduce the number of cases of bacterial meningitis. The predominance of pneumococcal meningitis in the first 6 months of life highlights the need for early protection. In PNG both an accelerated 1-2-3-month PCV schedule (which ties in with PNG’s standard EPI schedule) and a schedule including a neonatal dose (0,1 and 2 months) have been shown to be safe and immunogenic [27] and should assist in protecting young children from disease caused by vaccine serotypes. Recent data from GGH show the benefit of the introduction of Hib vaccination into the national EPI program. Analysis conducted by our research team [28] reveal that the isolation rate of Hib from CSF fell significantly from 6.0 % pre-introduction (2004–7) to 0.94 % following introduction (2009–13) (χ2, P < 0.001). There was no change in the isolation rate of S. pneumoniae over the same period [28].
We acknowledge that there are some limitations of the study and resulting data. We isolated higher numbers of S. aureus than expected. Further investigation indicated that CSF collection methods were inadequate and likely to have contributed to high isolation rate of S. aureus in 2004–2005. Some of these isolates, and some or all of those in previous years (in which no more than 6 were isolated in any given year between 1997 and 2003) may have been the causative agent of meningitis. Of the 68 S. aureus isolates, 11 corresponding CSF specimens were observed to have elevated PMN counts. However, even in samples with high PMN counts we cannot discount the possibility of another undetected bacterial pathogen being the causative agent of meningitis. This cautious supposition is supported by the fact that elevated PMN counts were detected in some specimens from which no bacteria were isolated (Additional file 2: Tables S2 and Additional file 3: Table S3). Given that S. aureus is rarely a cause of paediatric meningitis, and is generally associated with pre-existing abnormalities of the central nervous system or recent surgery (which were not present in our patients) [29, 30], we concluded that S. aureus were most likely contaminants.
Our isolation rate of other contaminants (aside from S. aureus) was <2 %, which is consistent with other CSF culture studies (e.g. Dunbar et al. [31]). One additional limitation of our study is that we obtained data from only one site within PNG, which may not be representative of the whole country.
The benefits of ongoing multi-site surveillance of bacterial diseases in high-burden settings are well recognised; however, conducting such surveillance is costly and the level of expertise required is in short supply. At regional sites non-culture based methods could be applied. However, antigen detection assays have short-comings, and currently available culture-independent nucleic acid detection methods appear to lack the robustness and user-friendliness required for resource-poor regional settings [32]. Moreover, neither method enables antimicrobial susceptibility testing to be conducting (though resistance can be inferred through the detection of genes). Concerted efforts are required to develop expertise and methods to enable more widespread and sustainable surveillance of S. pneumoniae and H. influenzae disease and upper respiratory tract carriage, as vaccines that reduce the impact of these pathogens are introduced globally.
