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Maternal-Neonatal Reports

Bloodstream Infections at Two Neonatal Intensive Care Units in Ghana

Multidrug Resistant Enterobacterales Undermine the Usefulness of Standard Antibiotic Regimes

Labi, Appiah-Korang MBChB, PhD*,†,‡; Enweronu-Laryea, Christabel C. MBBS, MSc§; Nartey, Edmund T. PhD; Bjerrum, Stephanie MD, MPH, PhD; Ayibor, Prosper K. MBChB**; Andersen, Leif P. MD; Newman, Mercy J. MBChB, MSc††; Kurtzhals, Jorgen A. L. MD, PhD†,‡

Author Information
The Pediatric Infectious Disease Journal: December 2021 - Volume 40 - Issue 12 - p 1115-1121
doi: 10.1097/INF.0000000000003284

Abstract

Approximately three million cases of neonatal sepsis occur annually1 with the greatest burden in low- and middle-income countries (LMICs). In 2014, 178,000–303,000 neonatal sepsis-related deaths occurred in sub-Saharan Africa with an estimated financial cost of $10–469 billion.2

Various studies from LMICs have shown a high prevalence of resistance to recommended empirical antibiotic therapies among invasive bacterial isolates, especially Gram-negative organisms from sub-Saharan Africa.3–6 This has led to recommendations for an urgent review of guidelines for treating neonatal infections.5

Etiology of neonatal infections and antibiotic resistance varies depending on geography and localized risk factors such as antibiotic prescribing patterns.6,7 In sub-Saharan Africa, inadequate diagnostic microbiology testing has resulted in limited information on the spectrum of organisms causing neonatal sepsis.6,8 Due to this limited access to microbiologic services, studies on neonatal sepsis become a resource that can inform empiric treatment protocols and guidelines.

Ghana, like most sub-Saharan African countries, has limited data on the etiology of neonatal sepsis.3,9–11 We report findings from a prospective study of bloodstream infections (BSIs) among neonates admitted to 2 tertiary hospitals in Ghana.

MATERIALS AND METHODS

Study Design and Setting

We conducted a prospective cohort study of BSIs among neonates admitted from October 2017 to September 2019 at the neonatal intensive care units (NICUs) of Korle-Bu Teaching Hospital (KBTH) and 37 Military Hospital (37MH). The study was part of a hand hygiene intervention trial (NCT03755635, clinicaltrials.gov).12 The trial currently completed, evaluated the impact of hand hygiene intervention on hand hygiene compliance and the incidence of bloodstream infections. Patients were recruited during the entire length of the intervention trial, baseline, intervention and postintervention phase.

The NICU at KBTH is a 55-bed facility, with 3 cubicles for intensive and high-dependency care and a 5-bed kangaroo mother care ward. Approximately 2600 neonates are admitted per year.13 The annual number of deliveries at KBTH is approximately 10,400 with a cesarean section rate of 37%–43% and 4%–6% preterm births.13,14 Approximately 14% of neonates born in the hospital are admitted to the NICU and 91% arrive within 24 hours of birth.14 The mean annual neonatal mortality rate in the unit is 19.2%.14 The nurse–patient ratio varies between 1:10 and 1:18 depending on the time of day.14 The standard empirical antibiotic combination therapy for neonatal sepsis is amikacin and cloxacillin.

The 37MH NICU has 20 beds, it is divided into 3 cubicles and admits approximately 800 neonates annually. In 2019, 3053 deliveries occurred in the hospital, with a 50% cesarean section rate and 8.5% preterm births. Fifteen percent were admitted to the NICU. The average nurse–patient ratio in the unit is 1:4. Empirical sepsis treatment varied and included penicillin/gentamicin and cloxacillin/amikacin combinations. Central venous catheterization and ventilator support were not in used in any of the NICUs at the time of the study, but there was access to continuous positive airway pressure treatment.

Study Participants

All admitted neonates were eligible, but those detained for short-term observation <24 hours were excluded. Medical records were reviewed daily and, if blood culture was performed, the date and clinical indications were recorded. Blood culture was performed at no cost for neonates suspected of sepsis or at risk of sepsis as part of clinical care by the attending clinician. Diagnosis was based on clinical judgment according to institutional guidelines of the NICUs.

Microbiologic Sampling and Antibiotic Susceptibility of Pathogens

Venous blood samples were collected into Bactec Peds plus (Becton Dickinson, MD) culture bottles with a sampling volume of 1–3 mL of blood. Culture bottles were incubated using the Bactec Fx (Becton Dickinson) culture system. Skin preparation was performed using povidone iodine applied for a period of 2 minutes. Primary identification and susceptibility testing was conducted locally and all isolates later transported to the University of Copenhagen Hospital, Rigshospitalet, Department of clinical microbiology for confirmation of identity using MALDI TOF Biotyper (Bruker Daltonics, Bremen, Germany) and antibiotic susceptibility testing repeated based on the 2019 EUCAST guidelines.15 Susceptible isolates reported here include isolates with intermediate susceptibility (susceptible and increased exposure). Enterobacterales resistant to third-generation cephalosporins and those with reduced susceptibility to carbapenems were screened for extended-spectrum beta-lactamase (ESBL) and carbapenemase production respectively according to EUCAST guidelines.16

Definitions and Statistical Analysis

Isolation of the same species with similar susceptibility pattern from the same neonate within two weeks were considered as one infection.17 The following organisms were considered clinically nonsignificant contaminants according to in house laboratory guidelines; Corynebacterium spp., Micrococcus spp. and Bacillus spp.18 The pathogenic role of Coagulase negative Staphylococci (CoNS) could not be determined. In the primary analysis, we conducted all analyses, counting cultures with CoNS as BSI negative.19 To assess the possible role of CoNS, we performed secondary analysis with CoNS included as culture positive.

Birth weight was classified into <1000, 1000–1499, 1500–2499 and >2500 g. Categorical variables were presented using frequencies and proportions, and compared using the Chi-squared test. Quantitative variables were presented as means and standard deviations for normally distributed variables and medians and interquartile ranges (IQR) for nonnormally distributed variables. Medians were compared between groups using Wilcoxon rank-sum score. Person-years for BSI was calculated using duration between the date of admission and date of first clinically significant positive blood culture. To evaluate predictors of mortality in neonates who developed BSI, we used cox regression model and reported the hazard ratios (HRs) for univariate and multivariate analysis with 95% confidence intervals (CIs). We adjusted for birth weight and mode of delivery which are known risk factors for neonatal mortality.20,21 Data analysis was performed using Stata (STATCORP version 14, TX). P values <0.05 were considered significant.

Ethical Considerations

The study forms part of a larger project given ethical approval by the Institutional Review Boards of KBTH (IRB/0025/2017) and 37MH (37MH-IRB IPN 144/2017).

RESULTS

Patient Characteristics

Overall, 5433 neonates were included at the 2 NICUs, 76.6% (4161/5433) from KBTH. Of 5413 neonates with data available on mode of delivery, 54.4% (2944/5413) were delivered by cesarean section. The median birth weight was 2400 g (IQR: 1600–3100). The median duration of admission was 6 days (IQR: 3–11) (Table 1). Figure 1 describes the study population and mortality.

TABLE 1. - Demographic and Clinical Characteristics of Enrolled Neonates
Characteristic All Neonates (N = 5433) Neonates Enrolled From KBTH (N = 4161) Neonates Enrolled From 37MH (N = 1272)
Sex 5416 4144 1272
 Male 2946 (54.4) 2266 (54.7) 680 (53.5)
 Female 2470 (45.6) 1878 (45.3) 592 (46.5)
Mode of delivery 5365 4117 1248
 C/S 2944 (54.9) 2123 (51.6) 821 (65.8)
 SVD 2421 (45.1) 1994 (48.4) 427 (34.2)
Birth weight 5399 4161 1238
 <1000 g 300 (5.6) 253 (6.1) 47 (3.8)
 ≥1000–<1500 g 695 (12.9) 576 (13.8) 119 (9.6)
 ≥1500–<2500 g 1767 (32.7) 1391 (33.4) 376 (30.4)
 ≥2500 g 2673 (49.5) 1941 (46.6) 696 (55.8)
Duration of admission 6 (3–11) 7 (4–13) 4 (2–7)
Outcome of admission 5416 4156 1260
 Dead 1066 (19.7) 764 (18.4) 302 (24.0)
 Alive 4301 (79.4) 3354 (80.7) 947 (75.2)
 Referred 49 (0.9) 38 (0.9) 11 (0.9)
Blood culture done 3514 (64.7) 2579 (62.0) 935 (73.5)
Blood cultures N = 3514 N = 2579 N = 935
Culture positive* 849 (24.2) 583 (22.6) 266 (28.4)
Data are presented as N (%) and medians and interquartile ranges where appropriate.
NB-total numbers for individual parameters may not add up to total number of included neonates (5433) due to missing data.
*Includes contaminants.

FIGURE 1.
FIGURE 1.:
Flowchart showing study cohort and mortality.

Characteristics of BSIs

A total of 4725 blood cultures were performed for 3514 neonates. Overall, 24.2% (849/3514) neonates had at least one positive culture, and 1025 organisms were isolated. Forty-two (4.9%) neonates had multiple episodes of BSI. We excluded 28 of these that were due to the same organism within a 2-week period. Twenty-one positive blood cultures had multiple organisms. Eighteen of these 21 included at least one pathogen. This resulted in a total of 997 isolated organisms. Of these, 90 (9.0%) were contaminants and considered BSI negative in the further analyses.

Overall, 22.6% (583/2,579) and 28.4% (266/935) neonates at KBTH and 37MH, respectively, had at least one blood culture with at least one organism (Table 1). This reduced to 7.6% (195/2579) and 17.1% (160/935), respectively, when contaminants and CoNS were considered BSI negative. The incidence rate of BSI with a known pathogen was 1.0 (95% CI 0.9–1.1) per 100 person days. Incidence rate of BSI stratified according to birth weight are shown in Table, Supplemental Digital Content 1 and 2, https://links.lww.com/INF/E499.

Gram-negative pathogens accounted for 73.1% (269/368) of the isolated pathogens. Klebsiella pneumoniae was the predominant pathogen at both study sites (see Figures, Supplemental Digital Content 3 and 4, https://links.lww.com/INF/E499) accounting for 68.0% (183/269) of all Gram-negative organisms. K. pneumoniae was found in a significantly higher proportion at 37MH compared with KBTH (78.3 % vs. 26.2%, P < 0.001). S. agalactiae accounted for 3.5% (13/368) and other Streptococcus spp. accounted for 7.1% (26/368) of pathogens. Enterococcus spp. accounted for 9.0% (33/368). Detailed analysis of isolated organisms by the study site can be found in Table, Supplemental Digital Content 5, https://links.lww.com/INF/E499.

Temporal Variation of Organisms Causing BSIs

Date of blood collection was available for 97.0% (880/907) of the cultured organisms (see Figures, Supplemental Digital Content 6 and 7, https://links.lww.com/INF/E499). Of these, 512 (58%) were CoNS and were considered culture-negative in primary analysis. Of the 368 remaining isolates, from 355 patients, 160 (43.5%) were obtained within 72 hours after birth. The majority of Gram-positive organisms 61.1% (58/95) were isolated within the first 48 hours of life, while the majority of Gram-negative organisms 74.7% (204/273) were isolated after 48 hours of admission (Fig. 2A). The proportion of cultures with CoNS was stable over time (Fig. 2B).

FIGURE 2.
FIGURE 2.:
Number of isolates from positive blood cultures by day of life isolated. A: Pathogen profile (without CoNS) by day of life isolated. B: Pathogen profile (including CoNS) by day of life isolated. Others: Burkholderia spp., Candida sp., Stenotrophomonas maltophilia, Aeromonas spp. and Salmonella spp. A total of 880 of total 907 isolates were used.

Antibiotic Susceptibility

High levels of antibiotic resistance were observed to commonly used agents at both sites, including second-line agents such as extended-spectrum cephalosporins (Tables 2 and 3). ESBL production was observed in 97% (177/183) and 50% (8/16) of K. pneumoniae and Escherichia coli, respectively. All but one of the 130 K. pneumoniae isolates from 37MH were ESBL producing, and whole-genome sequencing of 10 randomly selected isolates over the study period indicated that 90% (9/10, 95% CI 55.5%–99.8%) belonged to an outbreak clone (data not shown). Among K. pneumoniae, 91.8% (168/183) were resistant to gentamicin and 16.4% (30/183) were resistant to amikacin (Table 2). Carbapenem resistance was observed in Acinetobacter spp. (36.0%, 9/25), Pseudomonas spp. (21.1%, 4/19) and K. pneumoniae (4.4%, 8/183). All carbapenem-resistant K. pneumoniae isolates were related to an outbreak.22 Thirteen percent (3/23) of Staphylococcus aureus were methicillin resistant and one Enterococcus faecium was resistant to vancomycin of 33 Enterococcus spp. (Table 3), whereas no resistance to linezolid was detected among Gram-positive bacteria. Resistance patterns varied between sites, for example amikacin and carbapenem resistance among Enterobacterales and Acinetobacter spp. were solely observed at KBTH. Analysis of antibiotic resistance profile by site can be found in Tables, Supplemental Digital Content 8 and 9, https://links.lww.com/INF/E499.

TABLE 2. - Antibiotic Resistance Pattern of Gram-negative Bloodstream Isolates
Organism Penicillins Cephalosporins Aminoglycosides Others
AMP AMC TZP CTX CAZ CXM CN AN MEM CIP SXT ESBL CP
Klebsiella pneumoniae (183) 183 (100.0) 181 (98.9) 47 (25.7) 178 (97.3) 178 (97.3) 183 (0.0) 168 (91.8) 30 (16.4) 8 (4.4) 148 (80.9) 177 (96.7) 177 (96.7) 8 (4.4)
Acinetobacter spp. (25) 13 (52.0) 12 (48.0) 9 (36.0) 12 (48.0) 13 (52.0)
Pseudomonas spp (19) 3 (15.8) 3 (15.8) 2 (10.5) 4 (21.1) 4 (21.1)
Escherichia coli (16) 15 (93.8) 11 (68.8) 5 (31.2) 9 (56.3) 9 (56.3) 10 (62.5) 7 (46.7) 0 (0.0) 0 (0.0) 6 (37.5) 13 (81.3) 9 (56.3)
Serratia marcescens (8) 8 (100.0) 8 (100.0) 1 (12.5) 4 (50.0) 2 (25.0) 6 (75.0) 1 (12.5) 1 (12.5) 1 (12.5) 0 (0.0) 1 (12.5)
Enterobacter spp. (6) 6 (100.0) 6 (100.00 1 (16.7) 4 (66.7) 4 (66.7) 6 (100.0) 2 (33.3) 1 (16.70 0 (0.0) 3 (50.0) 5 (83.3)
Burkholderia spp. (4)
Stenotrophomonas maltophilia (4) 0 (0.0)
Salmonella sp. (1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Proteus mirabilis (1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Aeromonas spp. (2) 0 (0.0) 0 (0.0) 0 (0.0)
Data are presented as N (%).
AMC, amoxicillin-clavulanic acid; AMP, Ampicillin; AN, amikacin; CAZ, ceftazidime; CIP, ciprofloxacin; CN, gentamicin; CP, carbapenemase producing; CTX, cefotaxime; CXM, cefuroxime; MEM, meropenem; SXT, sulfamethoxazole/trimethoprim; TZP, tazobactam-piperacillin.

TABLE 3. - Antibiotic Resistance Pattern of Gram-positive Bloodstream Isolates
Organism Antibiotics
AMP CIP CN FOX CC ERY TET LZD SXT VA P
Coagulase-negative Staphylococci (512) 300 (58.6) 301 (58.8) 386 (75.4) 270 (52.7) 326 (63.7) 268 (52.3) 0 (0.0) 301 (58.8)
Staphylococcus aureus (23) 4 (17.4) 2 (8.7) 3 (13.0) 3 (13.0) 7 (30.4) 6 (26.1) 0 (0.0) 7 (30.4)
Streptococcus spp. (39) 0 (0) 13 (33.3) 28 (71.8) 0 (0.0) 0 (0.0) 0 (0)
Enterococcus spp. (33) 9 (27.2) 0 (0.0) 1 (3.0)
Other Gram-positive organisms isolated but susceptibility not reported (13), Athrobacter spp. 3, Brevibacterium luteolum 2, Clostridium tertium 2, Gemella mobillorum 1, Lactobacillus spp. 2, Lysibacillus fusiformes 2, Microbacterium paraoxydans 1, Pseudoclavibacter spp. 2, Pseudoglutamicrobacter cummnsii 2 and Weisella confusa 1. Data are presented as N (%).
AMC, amoxicillin-clavulanic acid; AMP, Ampicillin; AN, amikacin; CAZ, ceftazidime; CC, clindamycin; CIP, ciprofloxacin; CN, gentamicin; CP, carbapenemase producing; CTX, cefotaxime; CXM, cefuroxime; ERY, erythromycin; FOX, cefoxitin; LZD, linezolid; MEM, meropenem; P, penicillin; SXT, sulfamethoxazole/trimethoprim; TET, tetracycline; TZP, tazobactam-piperacillin; VA, vancomycin.

Impact of BSIs on Length of Stay and Case Fatality

For 5416 neonates with outcome data available, the case fatality rate was 19.7% (1066/5416), with 37MH recording significantly higher case fatality rate of 24.0% (302/1260) compared with 18.4% (764/4156) at KBTH (P < 0.0001). Case fatality rates among neonates with no culture done was 23.4% (447/1913) (Fig. 1). The majority 83.2% (372/447) of these deaths occurred within 72 hours of life and most were considered clinically to be due to peripartum complications. The median length of hospital stay for neonates with BSI was 14 days compared with 8 days for individuals who were culture-negative. Neonates who survived BSI spent a median of 18 days in hospital compared with 8.5 days in culture-negative individuals who survived. Neonates with BSI had higher case fatality rate than culture-negative neonates (27.9%, n = 99/355 vs. 16.5%, n = 520/3,148; HR 1.4, 95% CI 1.07–1.70). However, in multivariate analysis, this difference was not significant (Table 4).

TABLE 4. - Impact of BSI on In-hospital Case Fatality Rates for Neonates Who Had at least One Blood Culture Performed
Characteristic Total Dead, n, % Alive, n, % Crude HR [95% CI] P Adjusted HR [95% CI] P
Sex
 Male 1,906 327 (17.2) 1579 (82.8) 0.99 (0.84–1.16) 0.869 1.13 (0.96–1.34) 0.150
 Female 1,584 288 (18.2) 1296 (81.8) 1.00
Birth weight (g)
 <1000 163 117 (71.8) 46 (28.2) 7.3 (5.7–9.3) 0.000 7.3 (5.7–9.4) 0.000
 ≥1000–1499 497 155 (31.2) 342 (68.8) 2.3 (1.8–2.9) 0.000 2.3 (1.8–2.9) 0.000
 ≥1500–≤2499 1,125 168 (14.9) 957 (85.1) 1.3 (1.0–1.6) 0.025 1.3 (1.0–1.6) 0.020
 ≥2500 1,695 171 (10.1) 1,523 (89.9) 1.00
Mode of delivery
 C/S 1,862 302 (16.2) 1560 (83.8) 1.00 0.036 1.0 (0.89–1.25) 0.513
 SVD 1,596 307 (19.2) 1289 (80.8) 1.2 (1.01–1.40)
BSI
 Positive 355 99 (27.9) 256 (72.1) 1.4 (1.07–1.70) 0.010 1.1 (0.91–1.45) 0.252
 Negative 3148 520 (16.5) 2628 (83.5) 1.00
BSI, bloodstream infection (cultures with coagulase negative Staphylococci were considered BSI negative), level of significance set at P < 0.05, crude HR adjusted using sex, birth weight and mode of delivery; C/S, cesarean section; SVD, spontaneous vaginal delivery.

Effect of Aminoglycoside-resistance on Case Fatality

At KBTH, 78 neonates developed BSI with Enterobacterales, with 42% (33/78) being resistant to the standard treatment with amikacin. Of these, 45.5% (15/33) died compared with 33.3% (15/45) neonates with amikacin susceptible enterobacterales. The difference was not significant (HR 1.4 [95% CI 0.7–2.9], P = 0.4).

At 37MH, 96.2% (126/131) of neonates had BSI with Enterobacterales resistant to gentamicin, which was the most commonly used aminoglycocide in this hospital. Of these, 31.7% (40/126) died compared with none (0/5) with gentamicin-susceptible enterobacterales. This difference was not significant P = 0.3.

Secondary Analysis Including CoNS

In a secondary analysis, we included CoNS among the positive BSIs. Using this definition, neonates with BSI spent a median of 13 days in hospital compared with 8 days for culture-negative individuals. Neonates who survived BSI spent 14 days in hospital compared with 8 days for culture-negative neonates who survived. Although mortality was higher in neonates with BSI compared with culture-negative neonates (20.3%, n = 154/759 vs. 17%, n = 465/2744; HR 0.92, 95% CI 0.8–1.1), this was not significant in univariate and multivariate analyses (see table, Supplemental Digital Content 10, https://links.lww.com/INF/E499). The mortality rate in patients with a blood culture with only CoNS was slightly lower than that of culture-negative neonates (13.6% [55/404] vs. 16.7% [444/2654], Fig. 1) but the difference was not significant (P = 0.1).

DISCUSSION

We documented a high incidence of BSI caused by Gram-negative bacteria, especially K. pneumoniae in 2 NICUs in Ghana. There were high levels of resistance to ampicillin, gentamicin and cefotaxime, and lower levels of resistance to amikacin and meropenem among Enterobacterales.

The profile of pathogens isolated from BSIs was similar to other low-resource settings including sub-Saharan Africa.6,23,24S. agalactiae was not commonly detected in blood cultures which is similar to previous findings from Ghana.3,9,11 Despite the low detection rates, previous studies have documented 19%–26% carriage rates among pregnant women in Ghana.25,26 The low proportion (3.6%) of S. agalactiae in our study is, however, similar to the low proportions of 1% and 0.06% in India and sub-Saharan Africa.6,23 In our study, laboratory methodologic challenges are less likely to have caused the low detection rates since the BACTEC system used is known to be sensitive.27 Also, free universal access to blood culture bottles ensured that cultures were taken before the start of antibiotics. We cannot rule out the possibility that some of the early deaths for which no culture was performed could have been caused by missed S. agalactiae infections. Further studies are needed to clarify the role of S. agalactiae-carriage in women for early onset neonatal BSI in our setting.

Gram-negative infections were predominant causes of BSI after 48 hours of birth. This is in agreement with the literature.6,23,24 The high number of K. pneumoniae infections is not unusual, as it is the commonest organism isolated in studies of neonatal colonization studies and also a common cause of outbreaks in neonatal units.28–32 It is also the commonest cause of neonatal BSI in LMIC settings, accounting for approximately half of all neonatal Gram-negative infections in sub-Saharan Africa.5,6,23

Despite the reported importance of S. aureus in neonatal sepsis, especially in West Africa,6 few were isolated in this study. We, however, observed high numbers of CoNS similar to previous studies from Ghana.3,11 Clinically relevant BSIs with CoNS are usually of late-onset and associated with device use (eg, central venous catheters) in neonates with very low birth weight.33 At our study sites, there was no use of central venous catheters, suggesting that the majority of the observed CoNS were likely contaminants, possibly due to insufficient skin preparation or difficult phlebotomy.19 The doubtful pathogenic role of CoNS was further indicated by the comparable case fatality rates between neonates with CoNS and culture-negative neonates, in agreement with other studies.33,34 This suggests that treatment protocols for neonatal BSIs need not consider resistance patterns among CoNS.34

Among Enterobacterales, we observed higher levels of resistance to third-generation cephalosporins and gentamicin than in other West African countries. For example, K. pneumoniae showed 97% and 91% resistance to third-generation cephalosporins and gentamicin, respectively, compared with 54% and 47% West African averages.6 Relatively, low amikacin resistance (16%) was recorded, similar to 14% reported from the rest of sub-Saharan Africa.6 Amikacin resistance was only observed at KBTH, where amikacin is part of the recommended empirical therapy. However, at this site, gentamicin resistance remained high despite its replacement with amikacin for the past 10 years. This is contrary to studies showing that substitution of gentamicin with amikacin leads to a decrease in gentamicin resistance among Gram-negative organisms.35,36

The variation in etiology of BSIs and the increasing antibiotic resistance reported in our study highlight the difficulty likely to be faced when suggesting a single empiric therapy that adequately covers common organisms responsible for neonatal BSIs in our setting. It will be critical for NICUs in LMICs to have prompt access to diagnostic microbiology services to aid appropriate selection of antibiotics. Although our study was not powered to show an effect on mortality, BSI was associated with increased mortality in univariable but not multivariable analysis. This loss of effect observed may be attributed to potential confounders of mortaltiy such as gestational age, level of antibiotic resistance of the pathogen and the type of antibiotics used for treatment. Our data, however, did suggest an increase in case fatality associated with gentamicin- and amikacin-resistant Enterobacterales infections.

The study is limited by our inability to define the pathogenic role of CoNS. In defining the risk factors for mortality and duration of admission, we did not control for severity of illness, such as peripartum complications and treatment following infection, which could influence clinical outcomes. The incidence of BSI in this study may be affected negatively as only single aerobic cultures were conducted in most cases. Although BSI with strict anaerobic organisms is uncommon, the use of several culture bottles is known to increase the sensitivity of the test.37 Hand hygiene intervention at KBTH may have lowered the incidence of BSI. Conversely, it is possible that the outbreaks of MDR K. pneumoniae observed during the study may have increased the prevalence of BSI, skewed the distribution toward a predominance of Gram negatives and affected antibiotic resistance and mortality rates. Participating hospitals were tertiary facilities and findings may not be extrapolated to other healthcare settings especially those managing infections from the community.

ACKNOWLEDGMENTS

We acknowledge Mary Magdalene Osei Department of Medical Microbiology, University of Ghana Medical School, Captain Morgan Tetteh and Lieutenant Daniel Siaw of 37MH microbiology laboratory and technical staff at the Department of Clinical Microbiology, Rigshospitalet, Copenhagen for the assistance with laboratory work. We also thank the staff and patients from the participating hospitals for their cooperation during the conduct of the study.

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Keywords:

neonate; neonatal intensive care unit; bloodstream infection; antibiotic resistance; Ghana

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