Clinical Features of B. Cereus Sepsis in Premature Neonates

Abstract

Background: To analyze the clinical characteristics and prognosis of bacillus cereus sepsis in premature neonates.

Method: Retrospectively analyze the data of 8 premature neonates of bacillus cereus sepsis in Shanghai Children’s Hospital from January 2015 to December 2019, where clinical information is collected from patients’ medical records and charts, information of neurodevelopment is collected for patients from follow-up visits at corrected age of 6 months and 12 months.

Results: 8 premature neonates of bacillus cereus sepsis were identified, among which 5 cases developed meningitis, abnormal Cerebral MRI images were seen in 5 cases. After empirical antibiotic treatment with Meropenem and Vancomycin, 1 patient died, 7 patients survived to discharge. Follow-up visits discovered that 1 patient developed hydrocephalus and showed severely delayed neurodevelopment, 2 patients had mild neurodevelopmental delay, and neurodevelopment was basically normal in other 4 patients.

Conclusions: Bacillus cereus infection can cause severe nervous system complications, and affect neurodevelopmental outcome. Empirical antibiotic treatment with Meropenem and Vancomycin is proven effective.

Background

Neonatal sepsis is a serious disease which threatens life of neonates. Its incidence among survived neonates is 4.5‰~9.7‰^[1]. It is a major risk factor in late-onset sepsis among term and/or premature neonates. Incidence rate increases as gestational age and body weight decreases^[2]. Common pathogens for late-onset sepsis in China are Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, etc. The Bacillus cereus group is comprised of eight closely related species: B. cereus, B. cytotoxicus, B. mycoides, B. pseudomycoides, B. thuringiensis, B. weihenstephanensis, B. toyonensis, and B. anthracis^[3–5].

Bacillus Cereus is a type of gram positive, aerobic facultative bacillus which is widely distributed in the environment^[6]. Besides food poisoning^[7], Bacillus Cereus can cause focal or systemic infection, including sepsis, endophthalmitis, pneumonia, meningitis and encephalitis, especially among immunosuppressed patients. Mortality of neonatal Bacillus Cereus infection is approximately 10%. However, as B. cereus is mainly considered as an environmental contaminant, delays in treatment may compromise the clinical outcome.

Method

Eight premature neonates of bacillus cereus sepsis were identified in Department of Neonatology, Shanghai Children’s Hospital from January 2015 to December 2019, and the clinical features and treatments were analyzed.

Result

2.1 General data: Among the 8 cases, 6 were male, 2 were female. 4 cases were delivered by Cesarean section, other 4 were spontaneous vaginal delivered; gestational age at birth: 29–35^+ 4weeks; birth weight: 1,060 − 2,330 g; Apgar score at 5 minutes: 8’-10’; Age at onset: 4–31 days; 5 cases had history of PPROM(premature prolonged rupture of membrane, PPROM); 1 case was recorded with maternal cervical incompetence; 2 cases were SGA (smaller than gestational age, SGA)

2.2 Cinical manifestations: 6 cases had fever, highest temperature was 38.2–38.8℃; none of the cases developed hypothermia; 1 case presented with convulsions; 4 cases developed apnea; 2 cases had abdominal distension and feeding intolerance; 1 case refuse feeding; 1 case was on NPO due to suspicion of necrotizing enterocolitis (NEC); 2 cases were fed with expressed breast milk; 4 cases were fed with formula; 4 cases had PICC line; 3 cases had peripheral venous catheter; 1 case had no peripheral venous catheter.

2.3 Treatment: Upon change in condition, 5 cases needed respiratory support; 2 cases were intubated and put on mechanical ventilation, 3 cases were on non-invasive ventilation; 2 cases developed septic shock, and received fluid resuscitation and inotropes; 5 cases received immune support with IVIG. Based on blood culture results, we changed antibiotics to Vancomycin, 6 cases saw their condition improve after being administered with Vancomycin; 1 case was administered with Meropenem and Ampicilin to fight infection before its condition improved; 1 case was initially administered with Benzylpenicilin and Ceftazidime before the therapy was changed into Meropenem which showed no effect and neonate died. Among those whose condition improved, anti-infection treatment lasted 14–49 days. See Table 1.

2.4 Laboratory examination. Increased WBC and increased neutrophil ratio were seen in 2 cases; Leukocytopenia was seen in 5 cases; 2 cases developed thrombocytopenia; all the 8 cases had various degrees of increased CRP and increased PCT. All Bacillus cereus strains were resistant to penicillin and compound trimethoprim, sensitive to erythromycin, Clindamycin, Gentamicin, Vancomycin and Levofloxacin; All 8 cases received lumbar puncture; 5 cases had combined meningitis (Table 2).

2.5 Cerebral MRI: Cerebral MRI was performed on 6 patients. 1 patient had normal result; 5 patients had presentations of intracranial hemorrhage or leukomalacia; 1 patient had meningeal enhancement; 1 case developed hydrocephalus during follow-ups, ventricular-peritoneal shunt (VP shunt) was performed. See Fig. 1

2.6 Outcome:1 patient died, 7 patients survived to discharge. All the survived patients have regular outpatient follow-ups to evaluate the development of nervous system and to have early intervention; 4 of the patients completed Gesell Developmental Schedules at six months of corrected age; 7 of the patients completed ASQ-3(Ages & Stages Questionnaires, Third Edition)at 12 months of corrected age. 1 patient had severe neurodevelopmental delay and underwent rehabilitation treatment, 2 patients had mild neurodevelopmental delay, and neurodevelopment was basically normal in other 4 patients.

discussion

Bacillus cereus is a spore forming and ubiquitous bacterium presents in soil, foods, insect larvae, almost all surfaces and human skin^[8–9]. B. cereus has been found in environmental reservoirs such as ventilator equipment, intravascular catheters, and linen. In addition to food poisoning, B. cereus causes a number of systemic and focal infections in both immunologically compromised and immunocompetent individuals. Among those most commonly infected are neonates, especially with indwelling catheters. The spectrum of infections includes fulminant bacteremia, central nervous system(CNS) involvement(meningitis and brain abscesses), to name a few^[6]. Research found that a majority of strains(41%) were isolated in newborns, among which 3/4 were premature infants with low birth weight^[10]. And, with virulence test of bacterial strain, it is found that the average production of bacterial strain toxin from newborns is low, this suggests that newborn may be particularly sensitive to B. cereus strains, even those with low toxin production, or that other unknown factors may be responsible for newborn infection. The pathogenicity of bacillus cereus is closely related to the production of tissue damaging/reactive exoenzymes. The secretin includes four kinds of hemolysins, three distinct phospholipases, an emesis-in-ducing toxin, and three pore-forming enterotoxin: hemolysin BL (HBL), nonhemolytic enterotoxins (NHE) and cytotoxin K.

Besides, B. cereus can cause severe late-onset hemorrhagic meningoencephalitis in preterm infants. In this study, 7/8 infants had signs and symptoms of meningitis (CSF showed leukocytosis, low glucose, and increased protein), among which 6 patients have shown abnormal expressions in cerebral MRIs. Early and continuous brain sonography is very important for neonates,especially for premature infants༌who are suspected of septicemia or having convulsions. Some research states^[11], Serial brain sonography showed that the hemorrhagic meningoencephalitis affects first the white matter and later the basal ganglia and cortex.

According to past research, most bacillus cereus are resistant to penicillin and cephalosporin, but sensitive to aminoglycoside, carbapenem, vancomycin and chloramphenicol^[12]. The cases in this research are all responsive to meropenem and vancomycin treatments.

In short, the clinical symptoms of bacillus cereus sepsis in preterm neonates are non-specific, with increased CRP in lab tests, meningitis expressions in CSF examinations, and hemorrhagic meningoencephalitis in cerebral MRI. Meropenem and vancomycin are proven effective in treatment. The limit of the study is the small sample size, therefore more clinical and lab test features cannot be summarized.

Conclusion

Positive blood culture of bacillus cereus in premature neonates should not be deemed as contamination. Bacillus cereus infection can cause severe nervous system complications. Lumbar puncture should be completed and anti-infection treatment should be given. Meropenem and vancomycin are effective in treatment.

Declarations

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Na Li and Yunlin Shen concevived and designed the study, analysed the data, and drafted the manuscript. Xiaohui Gong helped design the study, Juan Li and Hongzhuan Zhang helped analysed the data. All authors read and approved the final manuscript.

References

1. Kissoon, Niranjan, Reinhart, Konrad, Fleischmann-Struzek, Carolin, et al. The global burden of paediatric and neonatal sepsis: a systematic review[J]. The lancet. Respiratory medicine.,2018,6(3):223-230.
2. Tsai MH, Hsu JF, Chu SM, Lien R, Huang HR, Chiang MC, Fu RH, Lee CW, Huang YC. Incidence, clinical characteristics and risk factors for adverse outcome in neonates with late-onset sepsis. Pediatr Infect Dis J. 2014 Jan;33(1):e7-e13.
3. Jimenez G, Urdiain M, Cifuentes A, et al. Description of Bacillus toyonensis sp. nov., a novel species of the Bacillus cereus group, and pairwise genome comparisons of the species of the group by means of ANI calculations. Syst Appl Microbiol 2013; 36:383.
4. Guinebretiere MH, Auger S, Galleron N, et al. Bacillus cytotoxicus sp. nov. is a novel thermotolerant species of the Bacillus cereus Group occasionally associated with food poisoning. Int J Syst Evol Microbiol 2013; 63:31.
5. Ehling-Schulz M, Lereclus D, Koehler TM. The Bacillus cereus Group: Bacillus Species with Pathogenic Potential. Microbiol Spectr 2019; 7.
6. Bottone EJ. Bacillus cereus, a volatile human pathogen.[J].Clinical microbiology reviews,2010,23(2):382-398.
7. Glasset B, Herbin S, Guillier L, Cadel-Six S, Vignaud ML, Grout J, Pairaud S, Michel V, Hennekinne JA, Ramarao N, Brisabois A. Bacillus cereus-induced food-borne outbreaks in France, 2007 to 2014: epidemiology and genetic characterisation. Euro Surveill. 2016 Dec 1;21(48):30413.
8. Tran SL, Guillemet E, Gohar M, Lereclus D, Ramarao N. CwpFM(EntFM)is a Bacillus cereus potential cell wall peptidase implicated in adhesion, biofilm formation and virulence. J Bacteriol. 2010;192:2638-42.
9. Auger S, Ramarao C, Fouet A, Aymerich S, Gohar M. Biofilm formation and cell surface properties amorc and non pathogenic strains of the Bacillus cereus group. App Environ Microbiol. 2009; 75:6616-8.
10. Glasset B, Herbin S, Granier SA, et al. Bacillus cereus, a serious cause of nosocomial infections: Epidemiologic and genetic survey. PLoS One. 2018;13(5):e0194346. Published 2018 May 23.
11. Lequin MH, Vermeulen JR, van Elburg RM, et al. Bacillus cereus meningoencephalitis in preterm infants: neuroimaging characteristics. AJNR Am J Neuroradiol. 2005;26(8):2137‐2143.
12. Gaur AH, Shenep JL. The expanding spectrum of disease caused by Bacillus cereus. Pediatr Infect Dis J. 2001;20(5):533‐534.

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