Influenza Disease and Vaccination

Influenza activity has been increasing for the past few weeks. Centers for Disease Control and Prevention (CDC) influenza surveillance week 50 shows increasing influenza with children especially impacted.  Influenza-like illness last week, was highest in those 0-4 years (11.2%) followed by 5–24-year-olds (7.5%).¹ Emergency department visits for influenza were also significant youth accounting for 9.2% of 5-17 year-old visits and 7% of visits for those 0-4 years-old.¹

Among typed influenza viruses, about 90% are influenza A (H3N2), predominantly the drifted clade 2a.3a.1 subclade K.¹  As you have likely heard, the subclade K is a drifted variant and thus not optimally matched to the H3N2 strain included in the 2025-2026 influenza vaccine.¹ Despite the mismatch, vaccine effectiveness against severe disease and outcomes in pediatrics appears strong. Preliminary data from the United Kingdom suggest that the vaccine has 74.7% (95% CI 52.3 – 87.9) effectiveness against emergency department visits and 72.8% (95% CI 48.3-87.1) effectiveness against hospital admission in children 2-17 years, respectively.²  These findings reinforce the role of influenza vaccination in preventing severe disease in children.

Unfortunately, pediatric influenza vaccination rates are concerningly low with only 40.8% of US children currently vaccinated against influenza.³  Pharmacists play a critical role in educating parents, addressing vaccine hesitance, and reinforcing that vaccination remains important throughout the influenza season.

Key influenza vaccine points to remember^4-6:

• The only way to protect children < 6 months of age is via maternal immunization at least 2 weeks prior to delivery.
• Children 6 months to ≤ 9 years who have not previously received 2 doses of influenza vaccine, require 2 doses this season, separated by ≥ 28 days.
• Other patients should receive 1 dose of influenza vaccine this year.
• Protective immunity takes about 2 weeks (for those needing 2 doses, the 2-week count begins after the second dose).

Influenza Treatment Recommendations

If children become sick with influenza, it is important to ensure they receive guideline recommended treatments.  Data from 2023-2024 US influenza season indicate substantial underutilization of anti-influenza therapy in pediatric patients. Only 31% pediatric outpatients and 52-59% hospitalized pediatric patients with influenza received recommended treatment.⁷ Clinician surveys using pediatric case scenarios highlight gaps in guideline adherence.  In March – June 2024, two surveys (1 outpatient and 1 inpatient) with clinical pediatric influenza cases was sent to prescribers in 7 children’s hospitals and their affiliated community hospitals.^8,9  In the outpatient analysis, clinicians generally only recommended treatment for one of the three recommended cases.⁹ Approximately 50% of inpatient providers recommended therapy for the hospitalized pediatric influenza cases (32% – 59%, depending on the case).⁸  In both studies, pediatric infectious diseases physicians were most likely to choose oseltamivir treatment, with the generalists (e.g., pediatric primary care or hospitalists) least likely.^8,9

Importantly, the CDC reports that anti-influenza treatments (e.g.,  neuraminidase inhibitors, PA Cap-Dependent Endonuclease Inhibitor) continue to be effective against the circulating strains, including H3N2 subclade K.¹  The Infectious Diseases Society of America, American Academy of Pediatrics, and Centers for Disease Control and Prevention all recommend prompt treatment with oseltamivir, regardless of duration of symptoms for all patients with high risk conditions.

Pediatric Patients that are at high risk and should receive treatment with oseltamivir, regardless of duration of symptoms: ^10-12

• All < 2 years of age per CDC ¹¹ or < 5 years of age AAP ¹²;
• All with underlying conditions that increase risk for complications,
• All with severe, complicated, or progressing disease,
• All who are hospitalized with influenza disease.

Consider those with uncomplicated disease who present within 48 hours of symptoms may receive antiviral treatment with any of the neuraminidase inhibitors (i.e., oseltamivir, zanamivir, peramivir) or baloxavir, that are age appropriate (see Table 1).^11,12

Pediatric Specific Outcome Data

Outcome data for anti-influenza treatment in pediatric patients are limited.  Available evidence suggests benefits in prompt treatment of pediatric patients in the outpatient and hospital settings.   Walsh and colleagues evaluated the impact of prompt anti-influenza treatment in pediatric patients hospitalized with influenza.¹³  They included almost 56,000 pediatric patients from multiple centers from 2007 – 2020 in a retrospective analysis.  Those who received prompt oseltamivir within day 0-1 of hospitalization had reduced length of stay, decreased 7-day hospital readmission, and lower risk of ECMO use/death compared to those who received delayed or no oseltamivir treatment.¹³ In the outpatient setting, an individual patient meta-analysis was performed including 5 trials and 2,561 pediatric patients who were randomized to receive oseltamivir or placebo within 48 hours of symptom onset.¹⁴  Oseltamivir reduced symptom duration by 17.6 hours (0.7 – 34.5 hours) and had a 34% risk reduction in acute otitis media infections. An increase in vomiting was found in those that received oseltamivir (RR 1.63 (95% CI 1.3-2.04).¹⁴

Pharmacists Role

With the increasing influenza disease activity, pharmacists have an essential role to ensure parents understand the importance and effectiveness of the influenza vaccination.  In addition, cases of clinical influenza disease provides an antimicrobial stewardship opportunity to recommend appropriate anti-influenza therapy in high-risk pediatric patients.

 

Table 1.  Anti-Influenza Medications for Treatment of Influenza Disease^11,15

Medication	FDA approval ages for treatment	Notes
Oseltamivir (Tamiflu®)	≥ 14 days-old (any age)	Intermittent shortage reported for some manufacturers as of Dec 2025
Zanamivir (Relenza®)	≥ 7 years-old	Do not use in those with respiratory disease or lactose/milk protein allergy
Peramivir (Rapivab™)	≥ 6 months-old
Baloxavir (Xofluza®)	≥ 5 years	Do not crush tablets, instead use suspension packets in those < 20 kg or who cannot take tablets. Not recommended as monotherapy for immunocompromised

References

1. Centers for Disease Control and Prevention. FluView:Weekly US Influenza Surveillance Report. Accessed December 23, 2025https://www.cdc.gov/fluview/surveillance
2. Kirsebom FC, Thompson C, Talts T, et al. Early influenza virus characterisation and vaccine effectiveness in England in autumn 2025, a period dominated by influenza A(H3N2) subclade K. Euro Surveill. 2025;30(46):2500854. doi: 10.2807/1560
3. Centers for Disease Control and Prevention. FluVaxView. Accessed Deccember 23, 2025. Available at: https://www.cdc.gov/fluvaxview/dashboard/vaccine-doses-distributed.html
4. American Academy of Pediatrics, Committee on Infectious Diseases. Red Book : Report of the Committee on Infectious Diseases 2024 – 2027. AAP Immunization Schedule. Accessed December 12, 2025. Available at: https://publications.aap.org/redbook/resources/15585/AAP-Immunization-Schedule
5. American Academy of Family Physicians. Immunization Schedules. Accessed December 12, 2025. Available at: https://www.aafp.org/family-physician/patient-care/prevention-wellness/immunizations-vaccines/immunization-schedules.html
6. Centers for Disease Control and Prevention. Child and Adolescent Immunization Schedule by Age (Addendum updated August 7, 2025). Accessed September 20, 2025. Available at: https://www.cdc.gov/vaccines/hcp/imz-schedules/child-adolescent-age.html
7. Frutos AM, Ahmad HM, Ujamaa D, et al. Underutilization of Influenza Antiviral Treatment Among Children and Adolescents at Higher Risk for Influenza-Associated Complications – United States, 2023-2024. MMWR Morb Mortal Wkly Rep. 2024;73(45):1022–1029
8. Bassett HK, Rao S, Beck J, et al. Variability of Clinician Recommendations for Oseltamivir in Children Hospitalized with Influenza. Pediatrics. 2025;155(5):e2024069111. doi: 10.1542/peds.2024–069111
9. Bassett HK, Rao S, Beck J, et al. Clinician Preferences for Oseltamivir Use in Children With Influenza in the Outpatient Setting. Pediatrics. 2025;156(3):e2025071193. doi: 10.1542/peds.2025–071193
10. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. Clin Infect Dis. 2019;68(6):895–902
11. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians. Accessed December 23, 2025. Available at: https://www.cdc.gov/flu/hcp/antivirals/summary-clinicians.html
12. Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2025-2026: Policy Statement. Pediatrics. 2025;156(6):e2025073620. doi: 10.1542/peds.2025–073620
13. Walsh PS, Schnadower D, Zhang Y, et al. Association of Early Oseltamivir with Improved Outcomes in Hospitalized Children with Influenza, 2007-2020. JAMA Pediatr. 2022;176(11):e223261
14. Malosh RE, Martin ET, Heikkinen T, et al. Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials. Clin Infect Dis. 2018;66(10):1492–1500
15. Michelle Wheeler. ASHP Drug Shortages – Current Shortages. Accessed December 23, 2025. Available at: https://www.ashp.org/drug-shortages/current-shortages/drug-shortage-detail.aspx?id=881&loginreturnUrl=SSOCheckOnly

 

By Marissa Galicia, PharmD candidate

Multidrug-resistant organisms (MDROs) represent a threat to global health, causing infections that are difficult to treat due to resistance to multiple antimicrobial classes. Some preventable ways that MDROs develop are when antibiotics are used longer than necessary or taken inappropriately.¹ Initially, only a few bacteria may survive antibiotic treatment, but frequent or inappropriate use increases the likelihood of resistant bacteria surviving and causing infections. Rising resistance rates, emphasizing the urgency of optimizing treatment strategies for pediatric populations.¹

Antibiotic Susceptibility in Children’s Hospitals Across the United States

In a 2025, Markham and colleagues published a multicenter analysis of antibiograms from 46 U.S. children’s hospitals.²   Most isolates in these hospitals remained susceptible with about 65% of Staphylococcus aureus was methicillin susceptible and 80% susceptible to clindamycin. Among Gram-negative bacteria, there was high susceptibility to cefazolin.²  For Gram-negatives greater than 85% E. coli and 78% Klebsiella sp. were susceptible to cefazolin.  Although many of these isolates were susceptible, resistance does sometimes occur.  Thirty-five percent of Staphylococcus aureus isolates and 57% of coagulase negative staphylococcus were resistant to oxacillin.   Almost 6% of E. coli, 9% of Klebsiella sp., and 17% of Serratia sp. resistant to ceftriaxone [possibly a signal for a possible extended spectrum beta-lactamase (ESBL) producer or other multidrug resistance (MDR) mechanism].  Enterobacter is generally thought to be resistant to ceftriaxone, regardless of the reporting, but in this study almost 6% were also resistant to ertapenem.  Cefepime, meropenem, and piperacillin-tazobactam, common anti-pseudomonas therapies each were reported to have about 10% pseudomonal resistance.  Lastly, and a bit concerningly 17% of Acinetobacter sp. were listed with meropenem resistance.²

In recent years, the Infectious Diseases Society of America has published recommendations for treatment of MDR infections.³  This includes the treatment of some important Gram-negative resistances such as Carbapenem-resistant Enterobacterales (CRE), Carbapenem-resistant Acinetobacter, Extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E), and multidrug-resistant (MDR) Pseudomonas aeruginosa.  As a pharmacist, it is essential to consider the significant differences that often exist in pediatric and adult pharmacokinetics (e.g., increased distribution, increased clearance) these can impact on likelihood of attaining pharmacodynamic targets.⁴,  Thus the dose becomes as important as the choice of agents. A group that included pediatric infectious diseases physician and pharmacist experts published consensus recommendations for the dosing of select beta-lactam agents used to treat these antimicrobial-resistant Gram-negative infections in children.⁵ This review focuses on the treatment of these MDROs, which may be uncommon, but important infections in pediatrics (with dosing considerations for older children and adults).

Types of Resistance Impacting Enterobacterales

ESBLs enzymes inactivate most penicillins, cephalosporins, and aztreonam. When present, they are most frequently seen in Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis.³  AmpC enzymes are primarily involved in cell wall recycling they can hydrolyze many beta-lactam agents. Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii are most at risk for inducing AmpC production. IDSA Guidance document suggests that resistance to common beta-lactams (e.g., ceftriaxone, piperacillin-tazobactam) develops in 20% of infections caused by these agents.³ Carbapenem Resistant Enterobacterales (CRE) are another significant MDRO which can be caused by carabapenemases (CP-CRE; e.g., KPC, NDM, OXA-48, VIM, and IMP) or can be caused by non-enzyme mechanisms such as altered membrane porins and overproduction of AmpC or ESBL enzymes (CRE).^3,6

The IDSA recommends the following treatments when an ESBL, AmpC, CRE, and CP-CRE are identified below. Note dosing will be provided with the first instance and can be assumed to be the same throughout unless otherwise stated.

Uncomplicated cystitis caused by ESBL, AmpC, CRE, CP-CRE: ^3,7,8

First line recommendations:

• Oral nitrofurantoin (< 12 years: 1.25 – 1.75 mg/kg/dose 4 times a day; max 100mg/dose; ≥12 years: Macrobid 100 mg twice daily) or
• Oral sulfamethoxazole/trimethoprim (3 to 6 mg/kg/dose (trimethoprim component) PO twice daily; max 320 mg/dose).

Alternatives: all oral: ciprofloxacin (15mg/kg/dose twice daily; max 500mg/dose), levofloxacin (< 50 kg: 8 mg/kg/dose twice daily; max 500 mg/day, ≥ 50 kg: 500 mg once daily), or carbapenems.

Complicated urinary tract infections (e.g., pyelonephritis) caused by ESBL, AmpC, CRE, CP-CRE: ^3,5,9-12

First-line recommendations:

• For AmpC, ESBL, or CRE/CP-CRE: Sulfamethoxazole/trimethoprim or fluroquinolones are considered first line if susceptible.
• For CRE/CP-CRE: ceftazidime-avibactam (50 mg/kg/dose Q8h over 3 hours; max 2g/dose), meropenem-vaborbactam (40 mg/kg/dose Q8h over 3 hours; max 2 g/dose), imipenem-cilastain-relebactam (25 mg/kg/dose Q6h; max 1 g/dose), or cefiderocol (60 mg/kg/dose Q8h over 3 hours; max 2g/dose) are other first-line options.

Alternatives:

• For AmpC, ESBL, or CRE/CP-CRE: aminoglycoside (e.g., gentamicin – dosing depending on patient age)
• For ESBLs: carbapenems [e.g., meropenem (20mg/kg/dose q8h; max 2,000 mg/dose) or ertapenem (<13 years: 15mg/kg/dose q12h, max 1000 mg/day; ≥13 years: 1000 mg/day once daily)]

 For all other systemic infections caused by AmpC, ESBL, or CRE/CP-CRE:³

First-line recommendations: ^3,9,11

• AmpC: Cefepime dosing dependent on MIC, fully susceptible (i.e., MICs < 2 mg/L) 50 mg/kg/dose Q12h as 3-hour infusion or 50 mg/kg/dose Q8h as traditional 0.5 hour infusion can be used. For those with susceptible dose dependent organisms (e.g., MIC 4-8 mg/L) the 50 mg/kg/dose Q8h as a 3-hour infusion may be needed.
• ESBL and some CRE: Carbapenems, are recommended first-line for ESBL until the patient is well enough to transition to oral therapy (ertapenem is cautioned in critically ill or malnourished). In cases of CRE when only ertapenem is resistant, meropenem is susceptible (i.e., MIC < 1 mg/L) meropenem can be used at high dose-prolonged infusion (e.g., 40 mg/kg/dose Q8h over 3 hours).
• AmpC and ESBL(improving): Guidance suggests considering either sulfamethoxazole/ trimethoprim or fluoroquinolone, when the patient is well enough to transition to oral therapy and it is susceptible to the agent.
• CRE/CP-CRE: Patients with organisms that demonstrate resistance to carbapenems beyond ertapenem are recommended to receive ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-cilastain-relebactam.

Carbapenem-resistant Acinetobacter baumannii (CRAB)

Acinetobacter baumannii (A. Baumannii) is a major pathogen of significance that has demonstrated mortality rates in adults between 26-56%. ¹³  Firstline treatment recommendations include sulbactam-durlobactam with either imipenem-cilastin or meropenem. Limited data exists on sulbactam-durlobactam in pediatrics.  Based upon extrapolation and a population-pharmacokinetic model study, estimates suggest dose of 50 mg/kg/dose sulbactam Q6h (max 1g of each component/dose) and infused over 3-4 hours may be reasonable in cases of life-threatening A. baumannii infection.^3,14.

Difficult-to-Treat Resistant (DTR) Pseudomonas aeruginosa

Difficult to treat P. aeruginosa is defined by non-susceptibility to at least one antibiotic in three classes commonly active against P. aeruginosa. Preferred treatments include high-dose extended infusion of non-carbapenem beta-lactams for susceptible strains. For resistant strains, ceftolozane-tazobactam (30mg/kg q8h; max 1.5g/dose), ceftazidime-avibactam, or imipenem-cilastin-relebactam may be necessary.³

Stenotrophomonas maltophilia

Stenotrophomonas maltophilia (S. maltophilia) is a glucose non-fermenting gram-negative bacillus that produces metallo-beta-lactamases leading to resistance of many antibiotics. Decisions to provide targeted therapy for S. maltophilia are difficult as it is can sometimes be a colonizer and frequently identified within polymicrobial infections. Further, data comparing the effectiveness of commonly used agents for S. maltophilia are lacking. IDSA guidance recommended treatment includes any two of the following options: cefiderocol, sulfamethoxazole/ trimethoprim, levofloxacin, ceftazidime-avibactam in combination with aztreonam (30 mg/kg/dose 4 times daily; max 2000 mg/day) another one of the options would be minocycline (2 mg/kg/dose twice daily; max 100mg/dose – see pediatric considerations below).

Pediatric Specific Considerations:

In addition to dosing, there are other important considerations that should be considered when using antibiotics for pediatric patients with MDROs.

• Sulfamethoxazole/ trimethoprim is not generally recommended in children < 2 months; however it has been used in neonates in rare cases when the benefits outweigh the risks.^15-18
• Fluoroquinolones should only be used in pediatric patients when there is no other alternative or the only other option is parenteral therapy, this is because of significant adverse effects including tendinitis and tendon rupture, peripheral neuropathy, and central nervous system effects (e.g., dizziness, restlessness, confusion, and insomnia to toxic psychosis).^{19-21 .}
• Minocycline as a traditional tetracycline, is generally not recommended in pediatric patients less than 8 years of age due to teeth staining^8.

 

Table 1.  Summary of Treatment Recommendations

Resistant Organism	Preferred Therapy
Systemic Infection Caused by ESBL-producing Enterobacterales	Carbapenem
Systemic Infection Caused by AmpC-producing Enterobacterales	Cefepime, when able to transition to oral: sulfamethoxazole/trimethoprim or fluoroquinolone
CRE	If non CP-CRE, and only resistant to ertapenem: high dose extended infusion meropenem. CP-CRE: ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-cilastain-relebactam
DTR Pseudomonas aeruginosa	Ceftolozane-tazobactam, ceftazidime-avibactam, or imipenem-cilastin-relebactam
CRAB (Acinetobacter baumannii)	Sulbactam-durlobactam + carbapenem (imipenem-cilastin or meropenem)
Stenotrophomonas maltophilia	Any 2 of the Following: cefiderocol, sulfamethoxazole/ trimethoprim, levofloxacin, minocycline, or ceftazidime-avibactam plus aztreonam

 

About the author: Marissa Galicia is a Doctor of Pharmacy candidate at the University of Connecticut. This post was written as part of her Advanced Pharmacy Practice Experience under the guidance of her professor, Jennifer Girotto PharmD, BCPPS, BCIDP, who also reviewed and edited the piece.

 

 

References

1. Centers for Disease Control and Prevention. Antimicrobial Resistant Threats in the United States 2021-2022. Accessed July 9, 2025https://www.cdc.gov/antimicrobial-resistance/data-research/threats/update-2022.html#:~:text=Findings,-resistant%20(MDR)%20Pseudomonas%20aeruginosa
2. Markham JL, Hall M, Burns A, et al. Antibiotic susceptibility patterns in US children’s hospitals. J Hosp Med. 2025
3. Tamma PD, Heil EL, Justo JA, et al. Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin Infect Dis. 2024
4. Batchelor HK, Marriott JF. Paediatric pharmacokinetics: key considerations. Br J Clin Pharmacol. 2015;79(3):395–404
5. Lockowitz CR, Hsu AJ, Chiotos K, et al. Suggested Dosing of Select Beta-lactam Agents for the Treatment of Antimicrobial-Resistant Gram-Negative Infections in Children. J Pediatric Infect Dis Soc. 2025;14(2):piaf004
6. Suay-García B, Pérez-Gracia MT. Present and Future of Carbapenem-resistant Enterobacteriaceae (CRE) Infections. Antibiotics (Basel). 2019;8(3):122. doi: 10.3390/antibiotics8030122
7. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128(3):595–610
8. Kimberlin DW, Banerjee R, Barnett E, Lynfield R, Sawyer MH. Red book: 2024-2027 Report of the Committee on Infectious Diseases American Academy of Pediatrics. Thirty-third edition. ed. American Academy of Pediatrics. Committee on Infectious Diseases, author.; American Academy of Pediatrics; 2024
9. Clinical and Laboratory Standards Institute. M100-ED35:2025 Performance Standards for Antimicrobial Susceptibility Testing. 35th ed. ; 2025
10. Ertapenem Product Information. Accessed Dec 3, 2025 https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021337s051lbl.pdf
11. Courter JD, Kuti JL, Girotto JE, Nicolau DP. Optimizing bactericidal exposure for beta-lactams using prolonged and continuous infusions in the pediatric population. Pediatr Blood Cancer. 2009;53(3):379–385
12. Bradley JS, Orchiston E, Portsmouth S, et al. Pharmacokinetics, Safety and Tolerability of Single-dose or Multiple-dose Cefiderocol in Hospitalized Pediatric Patients Three Months to Less Than Eighteen Years Old With Infections Treated With Standard-of-care Antibiotics in the PEDI-CEFI Phase 2 Study. Pediatr Infect Dis J. 2025;44(2). https://journals.lww.com/pidj/fulltext/2025/02000/pharmacokinetics,_safety_and_tolerability_of.9.aspx
13. Appaneal HJ, Lopes VV, LaPlante KL, Caffrey AR. Treatment, Clinical Outcomes, and Predictors of Mortality among a National Cohort of Admitted Patients with Acinetobacter baumannii Infection. 2022;66(3):1975
14. Onita T, Sano Y, Ikawa K, et al. Population Pharmacokinetic Analysis and Pharmacodynamic Evaluation of Sulbactam in Pediatric Patients: Dosing Suggestions for Acinetobacter baumannii Infections. J Pediatric Infect Dis Soc. 2025;14(5):piaf043. doi: 10.1093/jpids/piaf043
15. Ryan KL, Dersch-Mills D, Clark D. Trimethoprim-Sulfamethoxazole for Treatment of Stenotrophomonas maltophilia Pneumonia in a Neonate. Can J Hosp Pharm. 2013;66(6):384–387
16. Bang AT, Reddy HM, Deshmukh MD, et al. Neonatal and infant mortality in the ten years (1993 to 2003) of the Gadchiroli field trial: effect of home-based neonatal care. J Perinatol. 2005;25 Suppl 1:92
17. Bang AT, Bang RA, Baitule SB, et al. Effect of home-based neonatal care and management of sepsis on neonatal mortality: field trial in rural India. Lancet. 1999;354(9194):1955–1961
18. Bhutta ZA, Zaidi AKM, Thaver D, et al. Management of newborn infections in primary care settings: a review of the evidence and implications for policy? Pediatr Infect Dis J. 2009;28(1 Suppl):22
19. Jackson MA, Schutze GE, COMMITTEE ON INFECTIOUS DISEASES. The Use of Systemic and Topical Fluoroquinolones. Pediatrics. 2016;138(5):e20162706
20. Muradian M, Khan S. Levofloxacin-induced Psychosis in a Young Healthy Patient. Cureus. 2019;11(11):e6217
21. Tandan M, Cormican M, Vellinga A. Adverse events of fluoroquinolones vs. other antimicrobials prescribed in primary care: A systematic review and meta-analysis of randomized controlled trials. Int J Antimicrob Agents. 2018;52(5):529–540

 

By Sydney E. Kolosky, PharmD candidate

Neonatal late-onset sepsis is a systemic infection that is acquired from the hospital environment after 72 hours of life.¹ It represents a major cause of morbidity and mortality among neonates, particularly those born very preterm, with an incidence of 9% which results in approximately 11% lower risk of survival.² Unfortunately, despite improved infection prevention efforts, this decreased survival rate across all gestational ages remains.² The increase in mortality among the most preterm infants is, at least in part, one driver of antimicrobial usage in this population. Currently, there is an absence of specific recommendations guiding empirical antibiotic selection for treatment of late-onset sepsis in neonates due to variability in pathogens and local susceptibility.

The study Late Antibiotic Use Among Preterm Infants Admitted to the Neonatal Intensive Care Unit, published in 2025 by Coggins and colleagues, touches upon the impact of the variability for antibiotic selection in neonates with late-onset sepsis. It investigated antibiotic use among 420,000 infants from 2009-2023 to describe contemporary antibiotic patterns in preterm infants with late-onset neonatal sepsis.³ The study found that the use of antibiotics for late-onset sepsis was inversely proportional to the gestational age group with antibiotics being administered to 75% of infants born 22 to 24 week’s gestational age compared to about 4% of infants born 33 to 34 week’s gestational age.³ The Coggins study inspired this review, which will summarize the current United States epidemiology, causative pathogens, and antibiotic use trends to improve understanding and treatment of late-onset sepsis in neonates.

Causative Pathogens

Two articles from 2022 offer updated evidence regarding current pathogens driving neonatal late-onset sepsis in the United States. In 2022, the study Late-Onset Sepsis Among Very Preterm Infants, by Flannery and colleagues using the Vermont Oxford Network data, identified Gram-positive bacteria as the predominant pathogens accounting for 63% of isolates (29% coagulase-negative staphylococci, 23% Staphylococcus aureus, 5% Enterococcus spp., 5% Group B Streptococcus)²  The two most common Gram-negative bacteria identified included Escherichia coli (12%) and Klebsiella spp. (8%).² The review article Updates in Late-Onset Sepsis: Risk Assessment, Therapy, and Outcomes also reported that neonatal late-onset sepsis is primarily driven by Gram-positive bacteria, with coagulase-negative staphylococci isolated in more than half of gram-positive bacteremia among preterm infants.⁴ Although these data capture a broader picture of common causative pathogens in NICUs throughout the United States. Variation in pathogen patterns and susceptibility data across different geographic regions still exists and should be considered when selecting appropriate empiric treatment.

New Insights on Antibiotic Utilization in Late-Onset Neonatal Sepsis

To identify possible opportunities for antimicrobial stewardship, the 2025 study by Coggins and colleagues described recent trends in antibiotic utilization for late onset sepsis in the United States. The study found vancomycin and gentamicin was the most common regimen, representing 19% of all courses of antibiotics given after the first 72 hours of life, followed by ampicillin plus gentamicin (12%) and cefazolin (8%).³ Alternative regimens that contained gram-negative agents beyond gentamicin include cefotaxime and vancomycin (4%), tobramycin and vancomycin (4%), cefepime and vancomycin (3%), piperacillin/tazobactam (2%), ceftazidime and vancomycin (2%), amikacin and vancomycin (2%), cefepime (1%), meropenem and vancomycin (1%).³ Susceptibility data varies across geographic regions leading to certain antibiotics being resistant in specific areas of the country while others are susceptible in other areas. Ultimately, this susceptibility plays a major role in the choice of antibiotics and leads to variations in antibiotic regimens for this disease state.

In addition to studying the trends across combination antibiotic regimens, the study also looked at the individual components of the regimens. Vancomycin was the most common individual component (45%) in the antibiotic regimens, however, the use of vancomycin-containing regimens remarkably declined from 58.8% of all courses in 2009 to 36.0% in 2023 (P < .001).³ The decline of vancomycin occurred at the same time there were increases of prescriptions for antistaphylococcal penicillins (i.e., nafcillin, oxacillin [7% to 18%, P < .001]), piperacillin/tazobactam (3% to 9%, P < .001), and cefepime (2% to 12%, P < .001).³ Additionally, antibiotic choice notably changed over the course of NICU care with cefazolin becoming the main antibiotic exposed to the neonate after 90 days of age.³ The increased utilization of cefazolin suggests its use for surgical site infection prophylaxis in these older infants.

This study contributes new insights to late-onset neonatal sepsis in two important ways. First, it quantifies how antibiotic use in late-onset sepsis has shifted across the United States, illustrating changing stewardship priorities to reduce the use of broad-spectrum antibiotics in the neonatal population, particularly those with methicillin-resistant S. aureus (MRSA) coverage. Secondly, it demonstrates how significant variability exists in practice despite the availability of national guidance, underscoring the need for standardized empiric treatment frameworks that align with current microbiology, local resistance data, and American Academy of Pediatrics (AAP) recommendations.

Antibiotic Treatment Patterns in the United States

MRSA infections have been found to be less common in comparison to methicillin-susceptible S. aureus (MSSA) infections in late-onset sepsis.² In the neonatal population, S. aureus infections (either MRSA or MSSA) develop after the neonate is colonized with the bacteria. Colonization of MRSA in the NICU has been a focus of infection prevention and control initiatives, particularly those aimed at developing strategies and recommendations to de-colonize infants to prevent infection. The Centers for Disease Control and Prevention (CDC) and Society for Healthcare Epidemiology of America (SHEA) advocate for routine active surveillance of S. aureus, including MSSA and MRSA, especially in neonates with low birth weight who are at higher risk for infection.⁵ This strategy allows NICUs to determine the baseline S. aureus colonization status of a neonate. If a neonate is determined to be colonized with either MSSA or MRSA, SHEA suggests that intranasal mupirocin twice daily for 5-7 days for decolonization in the NICU population.⁵

The empiric treatment for late-onset sepsis can be tailored to the neonate based on their baseline S. aureus colonization status. The 2022 study Safety and Efficacy of Nafcillin for Empiric Therapy of Late-Onset Sepsis in the NICU by Nationwide Children’s Hospital concluded nafcillin is a safe alternative to vancomycin for empiric therapy in neonates with late-onset sepsis not colonized by MRSA as there was no difference in mortality.⁶ This is despite many infections being caused by coagulase-negative staphylococcus. It is also consistent with the AAP Red Book recommendation for MSSA infections, where nafcillin or oxacillin are recommended as preferred agents, especially when there is a risk for meningitis as cefazolin may not have optimal cerebrospinal fluid concentrations.⁷ For sepsis caused by MRSA, vancomycin remains the preferred agent.⁷

Gram-negative infections are less common than Gram-positive infections, accounting for roughly a quarter of neonatal late-onset sepsis infections.² The prevalence of these infections underscores the need for effective antimicrobial therapy targeting key Gram-negative pathogens, such as Escherichia coli and Klebsiella spp. For neonatal sepsis with suspected or confirmed infection by Enterobacterales or Group B Streptococci, the AAP Red Book recommends that ampicillin and an aminoglycoside be considered as first-line therapy.^8-10 Typically, gentamicin is the aminoglycoside of choice for neonates who have infections without central nervous system involvement.¹⁰

The 2023 study Antibiotic Use Among Infants Admitted to Neonatal Intensive Care Units, by Flannery and colleagues, concluded that gentamicin follows vancomycin as the second most prevalent empiric antimicrobial agent at 48% compared to 51%, respectively.¹¹ However, new data suggests that resistance to gentamicin is increasing with 7% of E. coli neonatal late-onset sepsis cases being gentamicin resistant.¹² If resistance precludes use of gentamicin, the AAP Red Book recommends replacement with ceftazidime, cefepime, amikacin, or a carbapenem.^9,10 The role of pharmacists is critical in this context to ensure individual institutions choose empiric therapy options that both cover isolates seen in their units and penetrate effectively to the source of infection, while also utilizing traditional stewardship efforts to guide clinicians towards the narrowest agents expected to cover the organisms of concern.

The duration of treatment is of equal importance to the selection of the empiric therapy itself and is another area of opportunity for antimicrobial stewardship. Although there are not any consensus guidelines in the United States, the National Institute for Health and Care Excellence (NICE) in the United Kingdom recommends an antibiotic treatment duration of 7 days in neonates with late-onset sepsis who have a positive blood culture, keeping in mind that causative organisms and source may also influence the duration.¹³ Additionally, NICE recommends that antibiotics be discontinued before 48 hours if the neonate has a negative blood culture and thought to no longer have an infectious cause.¹³ Recent data from Speier and colleagues found that the median antibiotic treatment durations for late-onset sepsis was 4 days for a culture-negative evaluation and 12 days for a culture-positive episode.¹⁴ The longer duration of treatment in both groups emphasizes the need for Antimicrobial Stewardship Program (ASP) targets to help ensure prompt discontinuation of antibiotics when treatment is no longer required to minimize antibiotic exposure and resistance development.

Conclusion

Neonatal late-onset sepsis remains a strong area of focus for ASP focus given the increased morbidity, mortality, and antibiotic exposure among neonates. While there is commonality in the antibiotics used to treat this condition based on predominant pathogens, treatment patterns still vary widely across the country. Recent shifts in antibiotic utilization reflect progress towards more targeted therapy informed by causative pathogens, local susceptibility data, and resistance trends, making this an important area for continued stewardship intervention. These findings also highlight the critical role pharmacists can play in guiding empiric antibiotic selection that incorporates local susceptibility data and assists in discussions regarding duration to limit excessive antibiotic exposure. Overall, continued efforts to standardize treatment practices and minimize unnecessary antibiotic exposure in the neonatal population are essential to improving ASP in this disease state.

 

Empiric Treatment Considerations*
No History of MRSA Colonization or Infection	nafcillin or oxacillin PLUS gentamicin, an extended-spectrum cephalosporin (e.g., ceftazidime, cefepime), amikacin, or a carbapenem
MRSA Colonization and/or History of MRSA Infection	vancomycin PLUS gentamicin, an extended-spectrum cephalosporin (e.g., ceftazidime, cefepime), amikacin, or a carbapenem

*Consider local susceptibility data when developing initial empiric antibiotic therapy plans.

 

About the author: Sydney E. Kolosky is a Doctor of Pharmacy candidate at the University of Connecticut. This post was written as part of her Advanced Pharmacy Practice Experience under the guidance of her professor, Jennifer Girotto PharmD, BCPPS, BCIDP, who also reviewed and edited the piece.

References

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