Treatment of Multidrug-Resistant Organisms in Children: Challenges and Current Strategies

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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 staining8.

 

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

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  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
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  9. Clinical and Laboratory Standards Institute. M100-ED35:2025 Performance Standards for Antimicrobial Susceptibility Testing. 35th ed. ; 2025
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