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Invasive Pneumococcal Disease in Neonates Prior to Pneumococcal Conjugate Vaccine Use in South Africa

2003–2008

Moodley, Krishnee, MBChB, FCPath, MMed*,†; Coovadia, Yacoob Mahomed, MBChB, FCPathSA; Cohen, Cheryl, MBChB, PhD§,¶; Meiring, Susan, MBChB, DTM&H; Lengana, Sarona, MBChB, DipHIVManSA; De Gouveia, Linda, NDMed Tech; von Mollendorf, Claire, MBChB, MSc, PhD§,¶; Crowther-Gibson, Penny, MSc, MSc; Quan, Vanessa, MBChB, MPH; Eley, Brian, MBChB**; Reubenson, Gary, MBBCh, FCPaed††; Nana, Trusha, MBChB, FCPath, MMed‡‡; von Gottberg, Anne, MBChB, PhD¶,§§

The Pediatric Infectious Disease Journal: April 2019 - Volume 38 - Issue 4 - p 424–430
doi: 10.1097/INF.0000000000002096
Maternal-Neonatal Reports
Free

Background: Neonatal invasive pneumococcal disease (IPD) in developing countries is poorly described. We provide a baseline description of neonatal IPD in South Africa, before implementation of the 7-valent pneumococcal conjugate vaccine (PCV7) in 2009.

Methods: Data from children (age ≤ 2 years) with IPD (pneumococcus identified from a normally sterile specimen) from January 2003 to December 2008 were extracted from a national laboratory-based surveillance database. Clinical and laboratory characteristics of IPD among neonates (0–27 days old) was compared with IPD among young children (≥ 28 days ≤ 2 years). Early-onset IPD (0–6 days old) was compared with late-onset IPD (≥ 7–27 days old). Isolates were serotyped using the Quellung reaction.

Results: Overall 27,630 IPD cases were reported. Of the 26,277 (95%) with known ages, 6583 (25%) were ≤ 2 years of age, of which 4.5% (294/6583) were neonates. The estimated annual incidence of neonatal IPD in 2008 was 5 per 100,000 live births. Fifty-one percent of neonates with IPD presented with early-onset IPD. Case fatality ratios (CFRs) were high in both groups, 31% (28/89) in neonatal IPD versus 26% (614/2383) in non-neonatal IPD (P = 0.18). Among neonates, the meningitis cases (15/37, 41%) were associated with the highest CFR. The 13-valent pneumococcal conjugate vaccine (PCV13) serotypes accounted for 69% (134/194) of neonatal IPD isolates.

Conclusions: Pneumococcal neonatal disease in South Africa was not uncommon before PCV introduction and is associated with a high CFR. The indirect effect on neonatal IPD of PCV rollout requires further evaluation.

From the *Microbiology, Lancet Laboratories, Kwa-Zulu Natal

Antimicrobial Research Unit, College of Health Sciences, University of Kwa-Zulu-Natal, Durban

Department of Medical Microbiology, Nelson R Mandela School of Medicine, University of Kwa-Zulu Natal, Durban

§School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg

Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg

Division of Public Health Surveillance and Response, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg

**Pediatric Infectious Diseases Unit, Red Cross War Memorial Children’s Hospital, Department of Pediatrics and Child Health, University of Cape Town, Cape Town

††Rahima Moosa Mother and Child Hospital, Department of Pediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng

‡‡Department of Microbiology, Charlotte Maxeke Johannesburg Academic Hospital, National Health Laboratory Services, Johannesburg

§§School of Pathology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.

Accepted for publication April 15, 2018.

Dr. Cohen was supported by the National Institute for Communicable Diseases of the National Health Laboratory Service and the US Centers for Disease Control and Prevention (co-operative agreement number: 5U51IP000155). In addition, Dr. Cohen has received grants from Sanofi and Parexel, unrelated to the current article. Dr. Mollendorf has received speaker funding from Pfizer in the last 3 years, unrelated to the current article. Dr. Anne von Gottberg received grant funds to institution from Pfizer and Sanofi, and travel expenses reimbursed from Pfizer, Sanofi, and Novartis.

This study received funding from the NICD/NHLS and was supported in part by funds from the United States Agency for International Development’s Antimicrobial Resistance Initiative, transferred via a cooperative agreement (number U60/CCU022088) from the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia; and cooperative agreement U62/CCU022901 from the CDC. (The contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC.)

The rest of the authors have no conflicts of interest to disclose.

Address for correspondence: Krishnee Moodley, MBChB, FCPath, MMed, 74 Ismail C Meer Street, Durban, South Africa, 4000. E-mail: krishnee.moodley@lancet.co.za; moodleykrishnee@gmail.com.

Invasive pneumococcal disease (IPD) is a significant cause of mortality and morbidity in children ≤ 5 years of age, with the highest incidence (an estimated 75% of reported cases) in children ≤ 2 years of age.1 , 2 An estimated 6–8% of globally reported IPD in children < 5 years of age occurred in under 2 month old infants.3

The estimated global incidence of neonatal IPD in 2010 was 36 per 100 000 live births, when many low-income countries were still not using the pneumococcal conjugate vaccine (PCV).4 This incidence, however, varies markedly from low- and middle-income countries such as Chile, with an incidence of 59 per 100,000 population,5 and high-income countries such as the United States and England and Wales, with an incidence of 11–13 per 100,000 live births.6 , 7 The incidence of neonatal IPD in South Africa, a middle-income country with a high maternal HIV infection rate, is not known.8

Neonates are at risk for IPD via exposure to Streptococcus pneumoniae either during passage through the birth canal, by hematogenous spread in utero, or by horizontal spread from caregivers and siblings.9 , 10 The presenting clinical features are nonspecific.11 Neonatal IPD isolates are reported to be more susceptible to antimicrobials than those found in older children.12 The case fatality ratio (CFR) in neonatal IPD may be high, up to 50%.11

The 7-valent PCV (PCV 7) was introduced into the routine immunization schedule in South Africa in 2009 and replaced by the 13-valent PCV (PCV13) in 2011. Globally, most of the serotypes in neonatal IPD, serotypes 1, 3, 5, 12, 7F, are included in the PCV13.12 , 13 Herd protection with the use of PCV occurs through vaccinated individuals who are less likely to carry vaccine-type pneumococci, thus reducing transmission and conferring protection to those who are unimmunized.14 Neonates may be protected by maternal antibodies or by the indirect effects of PCV. There is currently no recommendation for routine immunization of pregnant mothers against pneumococcus.15 , 16 The serotype distribution of neonatal IPD in South Africa and other developing countries before the introduction of PCV is largely unknown.4

This study describes neonatal IPD, in the pre-PCV era, in South Africa, with the aim of providing baseline data to assist the interpretation of changes, with respect to incidence, serotype distribution, clinical presentation and antimicrobial susceptibility that may have occurred since the introduction of PCV. In view of the lack of prevaccine data on neonatal IPD in low- and middle-income countries, the findings in this study are also of value to other countries who are still in the introductory phases of PCV implementation.4

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METHODS

Ethics

Ethical clearance was obtained from the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (BE 012/010). In addition, ethical clearance and permission to conduct laboratory-based and enhanced surveillance (ES) in South Africa for this study was obtained from the Health Research Ethics Committee (Human), University of Witwatersrand (Clearance number M02-10–42); the University of Stellenbosch Health Research Ethics Committee (Reference number N04/01/0021), the National Institute for Communicable Diseases (NICD) Research Committee (Clearance number M060449); and the South African Department of Health (Reference H2/12/8).

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Surveillance

Surveillance data were extracted from an ongoing, active, laboratory-based surveillance system, performed through GERMS-SA (Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa), commencing in 1999 and enhanced in 2003.17 The ES stabilized in 2005 and continued through 2008. Reports and pneumococcal isolates from individuals with laboratory-confirmed IPD were submitted from > 130 laboratories (public and private sector) nation-wide to the NICD in Johannesburg, South Africa. Each report contained patient demographic data including age, sex, date of specimen collection and specimen type. Additional information including admission date, HIV status, clinical diagnosis and outcome were collected only at the ES sites, 25 hospital-based laboratories in the 9 provinces. Audits were performed using a laboratory information system for the public sector laboratories (80% of health care in South Africa), where all cases satisfying the case definition not already reported to the surveillance system were added to the database.

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Definitions

IPD cases were defined as all children with a known age of ≤ 2 years with S. pneumoniae isolated from a normally sterile body site specimen, such as cerebrospinal fluid (CSF), blood, pleural and joint fluids, from January 2003 through December 2008, in South Africa. Individuals who presented within 21 days with a second episode of IPD were excluded.

Neonates were defined as infants 0–27 days of age. We compared the characteristics of IPD in neonates with non-neonates (28 days to ≤ 2 years of age), the age group associated with the highest incidence of IPD.

Early-onset disease (EOD) was defined where the specimen collection date was at age < 7 days old, while late onset-disease (LOD) included all neonates with a specimen collection date at ≥ 7–27 days of age.18

Specimen source was defined according to the specimen type positive for pneumococcus as follows: CSF specimen, irrespective of any other specimen; blood specimen irrespective of other specimen type (excluding CSF); and “other” including all other normally sterile specimen types (excluding blood and CSF).

Clinical syndromes, available from ES sites only, were defined as: meningitis, as documented in clinical notes or if the IPD specimen was CSF; lower respiratory tract infection, as documented in clinical notes, together with culture of an isolate from a sterile site (including blood, pleural fluid); bacteremia without focus, where a focus was not documented and the specimen was blood; “other” included all cases not included in the definitions above.

“Pediatric” serotypes were defined as serotypes 6B, 9V, 14, 19F and 23F. These have been defined as a group of serotypes associated with increased antimicrobial resistance and frequently isolated from children.19

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Incidence Rates

Incidence rates were calculated using the number of reported cases of IPD with known ages for each group as the numerator. The denominator for neonates was live births for each year, while that for the non-neonates was the number of 1-month-old children subtracted from the mid-year population estimates for ≤ 2-year-old children, for each year. The population estimates were extracted from Statistics South Africa.20 Incidence was reported per 100,000 population.

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Microbiology and Serotyping

Identification of the submitted pneumococcal isolates was confirmed at the NICD using standard microbiologic techniques, that is, colony morphology, hemolysis and optochin susceptibility. Serotyping was performed with the Quellung reaction, using specific pneumococcal antisera (Statens Serum Institut, Copenhagen, Denmark). The serotypes included in 7-valent pneumococcal conjugate vaccine (PCV7) are 4, 6B, 9V, 14, 18C, 19F and 23F. PCV10 includes 3 additional serotypes: 1, 5, 7F and PCV13 an additional 3: 3, 6A, 19A.2

All isolates were screened for penicillin resistance by disk diffusion testing using a 1 µg oxacillin disk (Mast diagnostics, Merseyside, United Kingdom). Isolates testing nonsusceptible on screening had minimum inhibitory concentrations (MICs) determined by agar dilution or Etest® (AB-Biodisk, Solna, Sweden) for penicillin and ceftriaxone. Isolates were also tested against the following agents using the disk diffusion method: erythromycin, clindamycin, chloramphenicol, tetracycline, rifampicin, cotrimoxazole and ofloxacin—if nonsusceptible, MICs were determined by Etest®. Results were interpreted using Clinical and Laboratory Standards Institute 2013 guidelines.21 Isolates were considered nonsusceptible to penicillin at MICs ≥ 0.12 mg/L using the parenteral penicillin meningitis breakpoints. For other antimicrobial agents, isolates were defined as nonsusceptible if they were intermediately or fully resistant to the agent tested. Multidrug-resistance (MDR) was defined as nonsusceptibility to at least 1 agent in 3 or more different classes.22

The recommendation for HIV testing at the time of the study was to perform a qualitative DNA polymerase chain reaction for children < 18 months of age and an enzyme-linked immunosorbent assay for children ≥ 18 months of age,23 as requested by the attending clinician.

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Statistical Analysis

Medians and interquartile ranges (IQRs) are presented for continuous variables, and frequencies are presented for categorical variables. χ2 Tests are used to compare groups. A P value (2-tailed) of ≤ 0.05 was considered significant. Epi Info™ version 7.2.1.0 (available at http://www.cdc.gov/epiinfo/; accessed March 2017) was used to analyze the data.

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RESULTS

Demographics

There were 27,630 reported IPD cases from January 2003 through December 2008, 26,277 (95%) with known ages, of whom 25% (6 583) were ≤ 2 years of age, and 4.5% (294/6583) of these were neonates. Forty-two percentage (2747/6583) of IPD cases were from ES sites, 31% (92/294) were neonates and 42% (2655/6289) non-neonates (P < 0.01; Table 1). In 2008, the national incidence of neonatal IPD was 5 per 100,000 live births (54 cases), 22-fold lower than the non-neonatal incidence of 110 per 100,000 population (1123 cases). The change in incidence was relatively stable from 2003 to 2008 among both neonates (3.9–5.0 per 100,000 live births) and non-neonates (79–110 per 100,000 population; P = 0.05), except for a peak in neonatal incidence in 2007 (from 44 cases in 2006 to 70 cases in 2007; incidence 4–6.5 per 100,000 live births; data not shown). There was no spatial or serotype clustering among these cases.

Although there was some variation in IPD incidence in the 9 provinces, there was no statistically significant difference in provincial incidence when neonates were compared with non-neonates (data not shown).

The median age among neonates was 6 days (IQR, 1.5–14) and among non-neonates was 231 days (IQR, 127–386). There were more females among the neonates (151/286, 53%) than non-neonates (2788/6113, 46%; P = 0.02; Table 1). Of the 43 (43/92, 47%) neonates tested for HIV, 44% (19/43) were HIV infected, while 67% (1218/1831) of tested non-neonates (1831/2655, 69%) were HIV infected (P < 0.01; Table 1). This difference was mainly because of a smaller proportion of EOD cases being HIV positive (4/16, 25%) than LOD cases (15/27, 56%; P = 0.1; Table 2).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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Clinical Features and CFR

Clinical syndromes were available from 91/92 neonates and 2647/2655 non-neonates from ES sites only. Neonates presented most frequently with meningitis (36/91; 40%) compared with non-neonates (898/2647; 34%, P = 0.3; Table 1). Non-neonates presented most frequently with lower respiratory tract infections (1318/2647; 50%; neonates 28/91; 31%; P < 0.01; Table 1).

The outcomes were available for 90/92 neonates and 2627/2655 non-neonates from the ES sites. Overall, CFR was similar for both neonates and non-neonates (Table 1). CFR was highest for meningitis for both age groups (14/36 (39 %) versus 13/53 (25 %), P = 0.2 for neonates and 327/882 (37%) versus 285/1501 (19%), P < 0.01 for non-neonates.

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Serotype Distribution

Viable isolates were available for 76% (5021/6583) of reported cases, 195 neonatal and 4826 non-neonatal isolates. There were 16 isolates that were nontypeable, 1 neonatal and 15 non-neonatal. PCV7 serotypes were responsible for 31% (61/194) neonatal IPD and 59% (2853/4811) non-neonatal IPD (P = 0.05; Table 1). The PCV13 serotypes were responsible for 69% (134/194) of IPD in neonates and 84% in non-neonates (4 042/4 811; Table 1). The proportion of PCV7 and PCV13 serotypes responsible for IPD in neonates was significantly lower than in non-neonates (P < 0.01; Table 1). Forty-six percent (90/194) of neonatal IPD were accounted for by serotypes 5 (n = 18), 1 (n = 17), 19F (n = 15), 3 (n = 14), 8 (n = 13) and 14 (n = 13). These serotypes were responsible for 33% (1572/4811) of non-neonatal IPD serotypes (P < 0.01; Fig. 1). Serotypes 1, 3 and 5 were more frequently isolated among neonates, 25% (49/194), than among non-neonates, 5% (247/4 811; P < 0.01; Fig. 1). The most common non-neonatal serotypes were 14 (n = 805), 6B (n = 618), 6A (n = 580), 23F (n = 542), 19F (n = 520) (Fig. 1). The non-PCV13 serotypes 8, 12F and 13 accounted for 13% (25/194) of neonatal and 4% (183/4811) of non-neonatal isolates (Fig. 1).

FIGURE 1

FIGURE 1

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Antimicrobial Susceptibility

Antimicrobial susceptibility testing was performed on all 5021 viable isolates. Among neonates, 76% (148/195) of isolates were susceptible to penicillin, compared with 50% (2424/4826) non-neonatal IPD isolates (P < 0.01; Table 1). Most isolates in this study were susceptible to ceftriaxone, 99% (194/195) and 98% (4757/4826) among neonates and non-neonates, respectively (Table 1). Cotrimoxazole nonsusceptibility was lower among neonates (77/195, 39%) than non-neonates (3542/4826, 73%; P < 0.01; Table 1). Among all tested isolates, 27% (1361/5021) were MDR, of which 15% (30/195) were neonatal and 28% (1331/4826) non-neonatal isolates (P < 0.01; Table 1).

Six serotypes most commonly associated with nonsusceptibility to penicillin were serotypes 14, 19F, 6B, 23F, 6A and 19A. These accounted for 89% (42/47) and 91% (2124/2402) of penicillin nonsusceptible isolates among neonates and non-neonates, respectively (Fig. 2). These 6 serotypes were also the most frequent among the MDR isolates. Serotype 14 was the predominant MDR serotype: 40% (12/30) and 51% (684/1 331) in neonates and non-neonates, respectively (Fig. 2).

FIGURE 2

FIGURE 2

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Early-onset Versus Late-onset Disease

Fifty-one percentage (149/294) of neonates presented with EOD (Table 2). The median age for EOD was 0 days (IQR, 0–2), with 66% (99/149) presenting within 48 hours of birth. The median age for LOD was 14 days (IQR, 10–22). The EOD patients were more likely to have blood specimen sources than LOD patients (110/149, 74% vs. 76/145, 52%, P < 0.01, Table 2). LOD cases presented with meningitis more frequently than EOD cases (LOD, 25/48; 52% vs. EOD: 11/43; 26%, P = 0.01; Table 2). The high neonatal CFR did not differ by age of onset (EOD, 14/42, 33% and LOD 14/48, 29%, P = 0.7). Cases with meningitis contributed substantially to the CFR in both EOD and LOD (4/11 [36%] in EOD; 10/25 [40%] in LOD), P = 0.7. In addition, pneumonia CFR did differ by age: in EOD (6/14 [43%] versus 1/14 [7%] in LOD), P < 0.03.

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DISCUSSION

In this study, conducted before introduction of PCV7 vaccination in South Africa, neonatal IPD accounted for an estimated 4.5% of IPD cases in children ≤ 2 years of age. Fifty-one percentage of these neonates presented within the first week of life. Meningitis was the most common clinical diagnosis among neonates, particularly among those with LOD. PCV13 serotypes accounted for a substantial portion, 69%, of neonatal cases. The most frequent neonatal serotypes 1, 3 and 5 accounted for 25% of neonatal and only 5% of non-neonatal IPD cases. The high neonatal CFR (31%) varied by site of infection, but not by age of onset.

The national incidence of neonatal IPD, 5 per 100,000 live births in South Africa in 2008, was lower than the estimated global incidence of 36 per 100,000 live births in 2010.4 Billings et al reported an incidence of 16 per 100,000 live births, before the introduction of PCV, in less-developed UN strata countries.4 Our incidence is also much lower than the incidence reported in Chile, of 59 per 100,000 population, and closer to that reported in the United States in 2006 (11 per 100,000 live births), and in England and Wales in 2013 (13 per 100,000 live births) before PCV, among < 90 day old infants.5–7 The incidence in this study is similar to that reported by Cutland,24 from a South African city, Soweto, where the incidence of neonatal sepsis due to the pneumococcus was reported as 8 per 100,000 live births among neonates. In the Sowetan study, S. pneumoniae was noted to occur less frequently than other common causes of neonatal sepsis, such as Streptococcus agalactiae, Staphylococcus aureus, Streptococcus viridans and Escherichia coli.24 Differences in incidence may be attributed to the higher threshold for taking blood culture specimens in neonatal units in South Africa, variation in surveillance methodologies and completeness in reporting.4 , 7 The incidence we report may be an underestimate of true neonatal incidence as infants with clinically evident, but microbiologically negative, sepsis would not have been included in this study. Vaccine probe studies such as that by Palmu et al25 demonstrated that inclusion of these clinically evident, microbiologically negative cases significantly increased the incidence estimates of IPD among children. In addition, the sensitivity of cultures among neonates is low, attributable to inadequate sample volumes being submitted, as well as empiric antimicrobials being commenced before cultures were taken.26 , 27

Among South African neonates, a large proportion of IPD cases, 51%, presented with EOD, similar to high-income countries like the United States and United Kingdom where 70% (19/27) and 77% (101/131), respectively, of neonatal IPD cases had EOD.6 , 7 This contrasts with studies from Utah and Mexico, where only 11% (2/9) and 20% (25/126) of neonatal cases, respectively, were EOD.28 , 29 The higher rates of EOD in South African neonates and those of the United States and England and Wales may be due to similar at risk populations, access to care and specimen-taking practices.4 The variation between and within countries may be attributed to differences in small hospital-based studies, socioeconomic status, access to antenatal care and maternal and infant risk factors.28 , 29

In this study, 66% (99/149) of the EOD neonates presented within the first 48 hours of life, similar to that reported by Ladhani et al7 in the United Kingdom, 67% (84/101), who indicated that these infants were more likely to be premature. Early-onset sepsis has been found to be associated with prematurity, maternal chorioamnionitis, or social factors influencing prenatal care.30 We were unable to analyze for prematurity or other maternal factors as these data were not collected during the study period.

Although the association of IPD and HIV infection in children has been well documented in South African children,31 this was not clear among neonates in this study. The high rates among neonates with IPD, 48%, may be because children who were most ill or had signs of HIV were preferentially tested, or would have presented to a health care setting. In addition, HIV status data were only available for 15% (44/294) of neonates as there was no policy for universal HIV testing at birth at the time of this study.

We observed a female sex preponderance in this study. Two studies, in Mexico and Denmark, reported a male sex preponderance,29 , 32 while others do not report a sex preponderance6 , 7 among neonates with IPD. A male sex predisposition to neonatal sepsis, particularly Gram-negative sepsis, has been attributed to x-linked immunoregulatory genes.33 , 34 This predisposition may be specific to Gram-negative sepsis in neonates and therefore not consistently observed in neonatal IPD.

The predominant clinical presentation among the neonatal group overall (40%) and the LOD group was meningitis (52%). However, the predominant clinical presentation among EOD cases was bacteremia (42%). This was consistent with findings from Ladhani et al7 in England and Wales, and Soto-Noguerón et al29 in Mexico who reported bacteremia as the predominant presentation in the EOD cases and meningitis in the LOD cases. The more frequent diagnosis of bacteremia among EOD cases may relate to an inability of the immature immune system in these very young babies to localize the infection.30 , 35

Although the CFR among neonates (31%) was higher than that among non-neonates (26%), this did not reach statistical significance. The neonatal CFR was also lower than those in other studies in England and Wales and the United States.7 , 11 This may be attributed to an underestimation of the neonatal CFR, as infants who demised at home would not have been included in this database. In addition, only 32% (90/294) of neonates with IPD had outcomes available for analysis. Meningitis, an established risk factor for death in patients with IPD,7 , 36 was associated with the highest CFR among both neonates and non-neonates in this setting. The CFR in neonates with IPD in this study was higher than that of neonates with sepsis due to more frequently encountered pathogens, such as Group B Streptococcus, 16.9%24 or Escherichia coli, 6%,37 in South Africa.

The neonatal isolates were generally more susceptible to antimicrobials tested (penicillin and ceftriaxone) than the non-neonatal isolates, as in the United States and Mexico, before PCV7.11 , 30 This is not unexpected as the neonatal serotypes, unlike the pediatric serotypes, are usually not associated with antimicrobial resistance.13 , 38 , 39

Our findings of 31% PCV7 serotypes in neonatal IPD are consistent with pneumococcal vaccine studies from Mexico (34%), and England and Wales (44%), before PCV7.7 , 29 The PCV13 serotype coverage among neonatal IPD isolates (69%) was also comparable with those in Mexico (64%), and England and Wales (67%).7 , 29 While a substantial proportion of neonatal IPD (69%) were due to PCV13 serotypes, this was significantly less than that observed in the non-neonatal IPD group (84%). The common neonatal IPD serotypes 1, 3 and 5 among South African neonates is consistent with other studies from the United States and Denmark.11 , 32 These serotypes have been reported to occur more frequently among adults than children in the United Kingdom, Denmark and South Africa.7 , 31 , 32 This supports the widely accepted premise of neonatal IPD being acquired via horizontal spread from mother or adult caregiver.9

This study has several limitations. First, the data were collected using a laboratory-based surveillance system, where isolate submission is dependent on diligent local laboratory and surveillance staff. Case ascertainment also suffers from differential access to care and specimen-taking practices throughout the country. Only cases with known ages were included. In addition, audits performed on the surveillance database did not include private sector cases. Therefore, our estimates are an underestimation of actual disease burden in children ≤ 2 years old in South Africa. Second, as the study was performed retrospectively, we were unable to check for maternal factors, such as premature labor, preterm rupture of membranes, maternal HIV infection, vaginal colonization or maternal IPD. Neonatal data, especially relating to HIV infection and outcomes, were also incomplete in our database. Third, susceptibility test results were interpreted using meningitis breakpoints irrespective of the clinical syndrome; therefore, the resistance rates appear higher in this study. This was appropriate as our study looked at trends over time, and not treatment outcomes. Fourth, susceptibility testing for ceftriaxone was revised from an agar dilution method to a Clinical and Laboratory Standards Institute-recommended broth microdilution method, using TREK panels, in 2009,21 as the agar dilution method was found to underestimate beta-lactam resistance.40

Our findings suggest that the pneumococcus, while not as common a cause of neonatal sepsis as other agents like Group B Streptococcus or E.coli, is associated with a higher CFR. Neonatal IPD in this country is found to be similar to neonatal IPD in other countries in terms of clinical presentation, serotype distribution, antimicrobial susceptibility, and CFRs. The findings in this study establish a baseline against which to interpret changes due to herd protection that may occur in neonatal IPD since the implementation of PCV in South Africa.

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REFERENCES

1. Watt JP, Wolfson LJ, O’Brien KL, et al; Hib and Pneumococcal Global Burden of Disease Study Team. Burden of disease caused by Haemophilus influenzae type b in children younger than 5 years: global estimates. Lancet. 2009;374:903–911.
2. Pneumococcal vaccines WHO position paper 2012. Weekly epidemiological record/Health Section of the Secretariat of the League of Nations. 2012;87:Geneva: World Health Organization. 129–144.
3. Russell F, Sanderson C, Temple B, et al. Global review of the distribution of pneumococcal disease by age and region. 2011. Available from: http://www,who.int/immunization/sage/6_Russel_review_age_specific_epidemiology_PCV_schedules_session_novl1.pdf. Accessed March 2017.
4. Billings ME, Deloria-Knoll M, O’Brien KL. Global burden of neonatal invasive pneumococcal disease: a systematic review and meta-analysis. Pediatr Infect Dis J. 2016;35:172–179.
5. Lagos R, Muñoz A, San Martin O, et al. Age- and serotype-specific pediatric invasive pneumococcal disease: insights from systematic surveillance in Santiago, Chile, 1994–2007. J Infect Dis. 2008;198:1809–1817. doi: 10.1086/593334.
6. Poehling KA, Talbot TR, Griffin MR, et al. Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine. JAMA. 2006;295:1668–1674.
7. Ladhani SN, Andrews NJ, Waight P, et al. Impact of the 7-Valent pneumococcal conjugate vaccine on invasive pneumococcal disease in infants younger than 90 days in England and Wale. Clinical Infectious Diseases. 2013;56:633–640.
8. Barron P, Pillay Y, Doherty T, et al. Eliminating mother-to-child HIV transmission in South Africa. Bull World Health Organ. 2013;91:70–74.
9. Malhotra A, Hunt RW, Doherty RR. Streptococcus pneumoniae sepsis in the newborn. J Paediatr Child Health. 2012;48:E79–E83.
10. Rodriguez BF, Mascaraque LR, Fraile LR, et al. Streptococcus pneumoniae: the forgotten microorganism in neonatal sepsis. Fetal Pediatr Pathol. 2015;34:202–205.
11. Gomez M, Alter S, Kumar ML, et al. Neonatal Streptococcus pneumoniae infection: case reports and review of the literature. Pediatr Infect Dis J. 1999;18:1014–1018.
12. Hoffman JA, Mason EO, Schutze GE, et al. Streptococcus pneumoniae infections in the neonate. Pediatrics. 2003;112:1095–1102.
13. Hausdorff WP, Feikin DR, Klugman KP. Epidemiological differences among pneumococcal serotypes. Lancet Infect Dis. 2005;5:83–93.
14. Kim TH, Johnstone J, Loeb M. Vaccine herd effect. Scand J Infect Dis. 2011;43:683–689.
15. Holmlund E, Nohynek H, Quiambao B, et al. Mother-infant vaccination with pneumococcal polysaccharide vaccine: persistence of maternal antibodies and responses of infants to vaccination. Vaccine. 2011;29:4565–4575.
16. Chaithongwongwatthana S, Yamasmit W, Limpongsanurak S, et al. Pneumococcal vaccination during pregnancy for preventing infant infection. Cochrane Database Syst Rev. 2015;1:CD004903.
17. Huebner RE, Klugman KP, Matai U, et al. Laboratory surveillance for Haemophilus influenzae type B meningococcal, and pneumococcal disease. Haemophilus Surveillance Working Group. S Afr Med J. 1999;89:924–925.
18. Pathirana J, Muñoz FM, Abbing-Karahagopian V, et al; Brighton Collaboration Neonatal Death Working Group. Neonatal death: case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34:6027–6037.
19. Crewe-Brown HH, Karstaedt AS, Saunders GL, et al. Streptococcus pneumoniae blood culture isolates from patients with and without human immunodeficiency virus infection: alterations in penicillin susceptibilities and in serogroups or serotypes. Clin Infect Dis. 1997;25:1165–1172.
20. Mid-year population estimates, South Africa. 2010. Available from: http://www.statssa.gov.za/publications/P0302/P03033010.pdf. Accessed July 2016.
21. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Twenty-third informational supplement. 2013; M100–S23.
22. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18:268–281.
23. Singh E, Cohen C, Govender N, et al. A description of HIV testing strategies at 21 laboratories in South Africa. Commun Dis Surveill Bull. 2008; 6:16–17.
24. Cutland CL. Epidemiology and Prevention of Sepsis in Young Infants and the Potential Impact of Maternal HIV Infection on Neonatal Sepsis. 2016. Wits Institutional Repository on DSpace, Electronic Theses and Dissertations; Available from: http://wiredspace.wits.ac.za/bitstream/handle/10539/22516/Cutland_PhD_final_28Oct16.pdf. Accessed October 2017.
25. Palmu AA, Kilpi TM, Rinta-Kokko H, et al. Pneumococcal conjugate vaccine and clinically suspected invasive pneumococcal disease. Pediatrics. 2015;136:e22–e27.
26. Lebea MM, Davies V. Evaluation of culture-proven neonatal sepsis at a tertiary care hospital in South Africa. South African J Child Health. 2017;11:170–173. Available from: http://www.sajch.org.za/index.php/SAJCH/article/view/1395. Accessed October 2017.
27. Schelonka RL, Chai MK, Yoder BA, et al. Volume of blood required to detect common neonatal pathogens. J Pediatr. 1996;129:275–278.
28. Olarte L, Ampofo K, Stockmann C, et al. Invasive pneumococcal disease in infants younger than 90 days before and after introduction of PCV7. Pediatrics. 2013;132:e17–e24.
29. Soto-Noguerón A, Carnalla-Barajas MN, Solórzano-Santos F, et al. Streptococcus pneumoniae as cause of infection in infants less than 60 days of age: serotypes and antimicrobial susceptibility. Int J Infect Dis. 2016;42:69–73.
30. Simonsen KA, Anderson-Berry AL, Delair SF, et al. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014;27:21–47.
31. von Gottberg A, Cohen C, de Gouveia L, et al. Epidemiology of invasive pneumococcal disease in the pre-conjugate vaccine era: South Africa, 2003–2008. Vaccine. 2013;31:4200–4208.
32. Kaltoft Zeuthen N, Konradsen HB. Epidemiology of invasive pneumococcal infections in children aged 0-6 years in Denmark: a 19-year nationwide surveillance study. Acta Paediatr Suppl. 2000;89:3–10.
33. Nagwa GM, Begum S, El-Batanony MH, et al. Clinical and bacteriological profile of neonatal sepsis in King Khaleed Civilian Hospital, Tabuk, Kingdom of Saudi Arabia. Eur J Prev Med. 2016;4:1–6.
34. Karambin M, Zarkesh M. Entrobacter, the most common pathogen of neonatal septicemia in Rasht, Iran. Iran J Pediatr. 2011;21:83–87.
35. Bulkowstein S, Ben-Shimol S, Givon-Lavi N, et al. Comparison of early onset sepsis and community-acquired late onset sepsis in infants less than 3 months of age. BMC Pediatrics. 2016;16:82.
36. Nyasulu P, Cohen C, De Gouveia L, et al. Increased risk of death in human immunodeficiency virus-infected children with Pneumococcal meningitis in South Africa, 2003–2005. PIDJ. 2011;30:1075–1080.
37. Motara F, Ballot DE, Perovic O. Epidemiology of neonatal sepsis at Johannesburg Hospital. Southern African J Epidemiol Infect. 2005;20:90–93.
38. Hausdorff WP. The roles of pneumococcal serotypes 1 and 5 in paediatric invasive disease. Vaccine. 2007;25:2406–2412.
39. Von Mollendorf C, Cohen C, Tempia S, et al. Epidemiology of serotype 1 invasive Pneumococcal disease, South Africa, 2003–2013. Emerg Infect Dis. 2016;22:261–270.
40. von Mollendorf C, Cohen C, de Gouveia L, et al. Factors associated with ceftriaxone non-susceptibility of Streptococcus pneumoniae: analysis of South African national surveillance data, 2003 to 2010. Antimicrob Agents Chemother. 2014;58:3293–3305.
Keywords:

neonates; invasive pneumococcal disease; South Africa

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