Antibiotics in Neonatal Sepsis

Dr Mussab Ahmad

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MBBS, FCPS (Paeds), FCPS (Neonatology)

LEARNING OUTCOME

At the end of todays sessions learner will be able to:

1. Classify antibiotics used for neonatal sepsis
2. Select appropriate antibiotics
3. Identify the role of oral antibiotics in neonatal sepsis
4. Decide the duration of therapy
5. Know the important drug interactions and side effects

Defining Neonatal Sepsis

Early-Onset Sepsis (EOS)

Occurs within the first 72 hours of life. 1

Late-Onset Sepsis (LOS)

Occurs after 72 hours of age. 1

Common Pathogens

• Group B Streptococcus (GBS)

• E. coli

• Staphylococcus aureus

The overall pooled incidence of neonatal sepsis worldwide was 22 per 1000 live births, with an associated mortality rate of 11 to 19 percent. 2

Classification by Spectrum of Activity

1

Narrow-spectrum

2

Extended-spectrum

3

Broad-spectrum

Antibiotic Selection for EOS

1

Empiric Therapy

Ampicillin + Gentamicin (common first-line).

2

GBS Coverage

Ampicillin or Penicillin G.

3

E. coli Coverage

Gentamicin / Cephalosporins.

Adjust antibiotic selection based on culture and sensitivity results. Tailor therapy to the specific infection.

Antibiotic Selection for LOS

Empiric Therapy

Vancomycin + Nafcillin/oxacillin/ Gentamicin/Cefotaxime.

1

Coagulase-Negative Staph

Vancomycin.

2

Gram-Negative Coverage

Gentamicin or Cefotaxime.

3

Consider fungal coverage in high-risk neonates. Broaden coverage based on risk factors.

LATEST ANTIBIOTICS..WAY FORWARD?

• Ceftazidime–Avibactam (Zavicefta®)
• Use: Effective against carbapenem-resistant Enterobacteriaceae (CRE).
• Meropenem–Vaborbactam
• Use: Targets ESBL(Extended- spectrum B-Lctamase) and carbapenemase-producing Gram-negative bacteria.
• Cefiderocol
• Mechanism: Siderophore cephalosporin that utilizes bacterial iron transport mechanisms.
• Use: Effective against XDR Gram-negative infections, including Acinetobacter baumannii and Pseudomonas.​
• Fosfomycin (IV)
• Use: Broad-spectrum activity against Gram-negative and some Gram-positive bacteria; often used in combination therapy.

ANTIBIOTICS IN DEVELOPMENT FOR NEONATAL SEPSIS

• NeoSep1 Trial

Objective: Evaluating new combinations of existing antibiotics for neonatal sepsis treatment.

Details: An international clinical trial assessing the efficacy of various antibiotic regimens in newborns with suspected sepsis.

• Global Antibiotic Research and Development Partnership (GARDP) Initiatives

Focus: Identifying and developing new treatments for neonatal sepsis, particularly in low- and middle-income countries.

Approach: Repurposing older antibiotics and developing new regimens tailored for neonates. ​

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ORAL ANTIBIOTICS- ROLE AND CONSIDERATION�

PROBLEM STATEMENT

1. More than 90% of neonates in NICUs receive empirical antibiotics
2. Blood culture positivity rates - <15%
3. Oral antibiotics in neonates are underutilized.
4. Limited pharmacokinetic and dosing data
5. In LMICs like Pakistan, inappropriate antibiotic prescriptions are very high due to fear, lack of diagnostics, and poor guidelines.
6. Pakistan lacks national guidelines or enforcement on neonatal antimicrobial stewardship.

RECOMMENDATIONS

World Health Organization (WHO) Guidelines

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• Managing Serious Bacterial Infections in Young Infants When Referral is Not Possible

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• Oral antibiotics - amoxicillin

RECOMMENDATIONS

Integrated Management of Neonatal and Childhood Illness (IMNCI)

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• Oral amoxicillin is recommended for the treatment of pneumonia in neonates

RECOMMENDATIONS

American Academy of Pediatrics (AAP) Guidelines

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• Red Book provides dosages for oral antibiotics, including amoxicillin, for use in neonates.

RECOMMENDATIONS

Centers for Disease Control and Prevention (CDC)

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• Oral Antibiotics in Outpatient Settings
• With less severe infections, oral amoxicillin

RECOMMENDATIONS

• Management of Neonates With Suspected or Proven Early-Onset Bacterial Sepsis
• This guideline discusses managing early-onset sepsis and highlights when oral antibiotics may be appropriate following intravenous therapy, once the neonate is stable and improving.

DURATION OF ANTIBIOTICS USE

• American Academy of Pediatrics (AAP)
• Culture-negative, asymptomatic infants: Discontinue antibiotics at 36–48 hours if blood cultures are negative and the infant remains well.​
• Culture-positive sepsis: Treat for 10 days; extend to 14 days for meningitis.

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• World Health Organization (WHO)
• Simplified treatment for serious neonatal infections in low-resource settings (when referral not possible):
• Uncomplicated sepsis: Use oral amoxicillin + injectable gentamicin for 7 days.
• If meningitis is suspected or confirmed: Treat for 14–21 days.

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• IMNCI (Integrated Management of Neonatal and Childhood Illness):
• For clinical signs of infection, initiate antibiotics and refer; oral treatment may be used if referral not feasible. Duration typically 7–10 days.

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• National Institute for Health and Care Excellence (NICE), UK (NHS-endorsed)
• Suspected neonatal infection (early- or late-onset):

Start antibiotics promptly.

• Review at 36 hours: Stop if cultures are negative, clinical condition is reassuring, and CRP is not elevated.
• Culture-confirmed sepsis: Treat for at least 10 days.
• Meningitis: Treat for 14–21 days or longer depending on organism.

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COMMON SIDE EFFECTS AND DRUG INTERACTIONS

Ampicillin

Side Effects

• Rash

• Diarrhea

• Transaminitis

• Hypersensitivity

Interactions

• May reduce aminoglycoside efficacy if given together IV

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• Increases rash risk with allopurinol

Gentamicin

Side Effects

• Nephrotoxicity

• Ototoxicity

• Neuromuscular blockade

Interactions

• Increased ototoxicity with loop diuretics (e.g., furosemide)
• Additive nephrotoxicity with vancomycin

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Cefotaxime

1

Side Effects

• Diarrhea

• Rash

• Elevated liver enzymes

• Superinfection

2

Interactions

• Incompatible with calcium-containing solutions

• Additive nephrotoxicity with aminoglycosides

.

Meropenem

Side Effects

• Seizures (especially in preterms)

• Diarrhea

• Rash

• Transaminitis

Interactions

• Reduces valproic acid levels

• Risk of neurotoxicity with phenobarbital/phenytoin

• Caution with caffeine

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Vancomycin

Side Effects

• Nephrotoxicity

• Ototoxicity

• Red man syndrome

Interactions

• Additive nephrotoxicity with aminoglycosides, furosemide, amphotericin B

Ceftazidime

Side Effects

• Diarrhea

• Rash

• Eosinophilia

• Elevated transaminases

• Potential risk of seizures at high doses

Interactions

• Nephrotoxicity when combined with aminoglycosides

• Reduces effect of oral contraceptives

Cefepime

1

Side Effects

Neurotoxicity (encephalopathy, seizures), rash, elevated liver enzymes.

2

Interactions

Additive neurotoxicity with other CNS-active drugs.

Piperacillin/Tazobactam

1

Side Effects

• Thrombocytopenia

• Hypokalemia

• Rash

• Diarrhea

• Hepatic enzyme elevation

2

Interactions

• Increased nephrotoxicity when combined with aminoglycosides

• May prolong bleeding time if used with anticoagulants

Fluconazole: Adverse Effects

Hepatotoxicity

Monitor liver function, especially with long-term use.

Gastrointestinal Upset

Nausea and vomiting are common.

Skin Rash

Discontinue if severe.

QT Prolongation

Rare, but use caution in susceptible patients.

Teicoplanin (Targocid): Side Effects

Nephrotoxicity

Monitor kidney function regularly.

Ototoxicity

Less common than with vancomycin.

Rash & Eosinophilia

Hypersensitivity reactions may occur.

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Acyclovir: Adverse Effects

Nephrotoxicity

Especially with rapid IV infusion.

Neutropenia

Monitor blood counts.

Phlebitis

At injection site.

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Cefoperazone: Considerations

Hypoprothrombinemia

Vitamin K interference can lead to bleeding.

Diarrhea & Elevated Enzymes

May indicate liver involvement.

Alcohol Interaction

Avoid alcohol due to disulfiram-like reaction.

Cefoperazone can cause bleeding issues. Diarrhea and liver enzyme elevation are possible side effects. Avoid alcohol consumption to prevent adverse reactions.

Colistin (Polymyxin E)

Side Effects

• Nephrotoxicity

• Neurotoxicity (paresthesia, ataxia)

• Apnea in neonates

1

Interactions

• Increased nephrotoxicity with vancomycin, aminoglycosides, or NSAIDs

• Caution with muscle relaxants

2

REFERENCES

1. Le Doare K, Bielicki J, Heath PT, Sharland M. Systematic review of antibiotic resistance rates among Gram-negative bacteria in children with sepsis in resource-limited countries. J Antimicrob Chemother. 2015;70(2):615-23.
2. Jackson C, Hsia Y, Basmaci R, et al. Global divergence from WHO treatment guidelines for neonates and children with severe infections: a systematic review and evidence synthesis. Lancet Infect Dis. 2019;19(5):409-417.
3. Khalid M, Rasheed J, Nawaz I. Pattern of hospital antibiotic use in term neonates using WHO Access, Watch and Reserve Classification (AWaRe). Pak J Med Sci. 2022;38(8):2212-2217.
4. van den Anker JN, Allegaert K. Oral antibiotics for neonatal infections: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2019;104(3):F274-F280.
5. Cohen-Wolkowiez M, Poindexter B, Bidegain M, et al. Dosing antibiotics in neonates: review of the pharmacokinetic data. J Perinatol. 2017;37(4):409-421.
6. Arif F, Malik F, Khan A, et al. Antimicrobial utilization among neonates and children: A multicenter point prevalence study from leading children’s hospitals in Punjab, Pakistan. Antibiotics (Basel). 2022;11(8):1056.
7. Saleem Z, Hassali MA, Godman B, et al. Pattern of inappropriate antibiotic use among hospitalized patients in Pakistan: A longitudinal surveillance and implications. Antimicrob Resist Infect Control. 2019;8:188.
8. WHO. Managing Possible Serious Bacterial Infection in Young Infants When Referral is Not Feasible. 2015. Available from: who.int
9. WHO. Integrated Management of Neonatal and Childhood Illness (IMNCI) Chart Booklet. 2016. Available from: platform.who.int
10. AAP. Red Book: 2021–2024 Report of the Committee on Infectious Diseases. Available from: publications.aap.org
11. AAP. Management of Neonates With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics. 2012;129(5):1006-1013. Available from: publications.aap.org
12. CDC. Outpatient Antibiotic Use for Pediatrics. Available from: cdc.gov
13. Puopolo KM, Benitz WE, Zaoutis TE. Management of neonates born at ≥35 0/7 weeks’ gestation with suspected or proven early-onset bacterial sepsis. Pediatrics. 2018;142(6):e20182894. doi:10.1542/peds.2018-2894.
14. World Health Organization. Managing possible serious bacterial infection in young infants when referral is not feasible. Geneva: WHO; 2015. Available from: https://www.who.int/publications/i/item/9789241509268
15. World Health Organization. Integrated Management of Childhood Illness: Chart Booklet. Geneva: WHO; 2014. Available from: https://www.who.int/publications/i/item/9789241506823
16. National Institute for Health and Care Excellence (NICE). Neonatal infection: antibiotics for prevention and treatment (NG195). London: NICE; 2021. Available from: https://www.nice.org.uk/guidance/ng195

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