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

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By Kaitlyn Kenyon, PharmD

Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE) aren’t just hospital buzzwords anymore — they’re among the leading drug-resistant pathogens gaining ground since the COVID-19 pandemic, turning once-routine infections into increasingly difficult treatment challenges and raising the stakes for antibiotic selection decisions in children.1

The Controversy of Vancomycin

Vancomycin was discovered and has commonly been used since the 1950s, however, in early 2026, the Journal of the Pediatric Infectious Diseases Society published what may be one of the most entertaining antimicrobial stewardship debates in recent history.2-4 After decades of service treating resistant Gram-positive infections, debate arose that it may finally be time to let the old workhorse retire. The authors emphasized vancomycin’s associated nephrotoxicity, the burden of therapeutic drug monitoring, vancomycin’s “Mississippi Mud”, vancomycin infusion reaction, increasing resistance with VRE, and the increasing availability of potentially less toxic alternatives such as ceftaroline, doxycycline, trimethoprim-sulfamethoxazole, and dalbavancin as evidence that the field should begin moving on.3

Vancomycin responded in a defense against the accusations and that its demise was greatly exaggerated. Modern AUC-guided monitoring has and continues to address many historical concerns surrounding this nephrotoxicity. Additionally in vancomycin’s defense, resistance remains extraordinarily rare despite decades of use. This agent also plays an important role in neonatal infections, invasive MRSA disease, and patients requiring management of resistant Gram-positive infections.4

For pharmacists caring for pediatric patients, the debate raises an important question: Is vancomycin truly becoming obsolete, or are we finally learning when it should (and should not) be used? I find this answer may be that neither side is completely right, however hold the view that vancomycin’s utility maintains utmost relevancy. Historical nephrotoxic concerns with the impurities and brown color of the infamous vancomycin “Mississippi Mud” formulation in the mid-1950’s has been phased out.5 Despite this, vancomycin’s reputation nephrotoxicity has stuck around. While vancomycin remains a cornerstone of therapy for many invasive MRSA infections, the modern pharmacist caring for pediatric patients has more treatment options than ever before. The challenge is no longer knowing whether an antibiotic covers MRSA. The challenge is knowing which anti-MRSA agent is best for a particular child.

Challenges in Care: Staphylococcus aureus and Enterococcus Resistance

If B-lactam antibiotics are the key, MRSA changes the lock. The mecA gene produces PBP2a, allowing S. aureus to evade an entire class of antibiotics while continuing to build its cell wall uninterrupted.6 In a national analysis of antibiograms from 2023, that included data from 46 U.S. children’s hospitals, Markham et al. found that 35.4% of roughly 35,000 S. aureus isolates were methicillin-resistant, highlighting the continued importance of MRSA as a pediatric pathogen. Nearly 80% of isolates remained susceptible to clindamycin, although regional variability was observed.7 VRE takes resistance to the next level by replacing the vancomycin target D-Ala-D-Ala with D-Ala-D-Lac (most commonly mediated by the vanA or vanB genes), preventing the vancomycin from binding and leaving clinicians with fewer treatment options.8 Among isolates of E. faecalis and E. faecium in children 0-18 years of age, vancomycin retains susceptible MICs for 99.8% and 73.8% of isolates respectively according to CLSI, EUCAST, and US FDA breakpoints.9 Despite the potential lapses in coverage with vancomycin occasionally covering E. faecium, if susceptible, ampicillin/amoxicillin should be used and remain the preferred choices for Enterococcus.10  In cases where ampicillin/amoxicillin not viable choices multiple options remain and are further discussed below.

Calling in the Experts: What should Pharmacists Recommend in Gram-Positive Resistance?

Clindamycin

Despite concerns regarding Clostridioides difficile infection (CDI), clindamycin continues to play an important role in pediatric infectious diseases practice. While clindamycin is well recognized as a high-risk antibiotic for CDI in adults, the epidemiology of CDI differs substantially in children.11,12 Pediatric patients generally experience lower rates of antibiotic-associated CDI than adults, particularly outside of children with significant healthcare exposure or underlying medical conditions. Furthermore, asymptomatic colonization with C. difficile is common in infants and young children, making the relationship between antibiotic exposure and clinically significant disease less common and straightforward than is seen in adult populations. As a result, many clinicians remain comfortable utilizing clindamycin for susceptible MRSA infections in children, when clinically appropriate.11,12 It has excellent oral bioavailability, reliable tissue penetration, activity against both MRSA and Streptococcus species, and extensive pediatric experience continue to make it an attractive option for treatment of many disease states.13 Rather than avoiding clindamycin altogether because of concerns derived primarily from adult literature, pharmacists caring for children, should balance clinical advantages it provides in individual patients with low risks of CDI.

Doxycycline

Doxycycline is the “don’t forget about me” oral option for pediatric Gram-positive resistance, especially for MRSA infections when the isolate is susceptible and an oral step-down agent is needed. Although tetracyclines were historically avoided in children less than 8 years due to tooth-staining concerns, doxycycline is now recognized as different from other tetracyclines, with short courses less than 21 days having not shown to cause permanent tooth discoloration or enamel weakening.11,14,15 Its role remains best for stable patients with mild-to-moderate MRSA infections, not invasive MRSA bacteremia, endocarditis, or severe disease where it has not been shown to be effective.11,16

Ceftaroline

Ceftaroline is a valuable option, when MRSA coverage is needed but vancomycin may be suboptimal or undesirable. Although FDA-approved in children ≥ 2 months of age for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, its unique ability among B-lactams to bind PBP2a and retain activity against MRSA has led to frequent off-label use for invasive MRSA infections, including bacteremia, osteomyelitis, septic arthritis, complicated pneumonia, and occasionally CNS infections.11,17,18 Ceftaroline is particularly attractive when clinicians desire the bactericidal activity and tissue penetration of a B-lactam, when vancomycin therapeutic targets are difficult to achieve, or when nephrotoxicity is a concern. Recent pediatric real-world data demonstrate high rates of clinical success across respiratory, bloodstream, and skin/soft tissue infections, supporting its growing role as a salvage or alternative anti-MRSA agent.17,18 However, prolonged courses (>2 weeks), which are common for osteomyelitis and bacteremia, warrant monitoring for hematologic toxicity, particularly neutropenia.19 Interestingly, ceftaroline is approved for administration over 5-60 minute infusions, however the evidence for target attainment by different infusion durations has been evaluated.20,21 In a study assessing the PK/PD target attainment of ceftaroline, the PK/PD target of 100% fT>4xMIC for Staphylococcus spp. was achieved in 75% of patients on prolonged infusions (including those receiving continuous, 3- or 6-hour infusions), while none of the intermittent-infusion patients met this target.21 This data presents benefit for prolonged ceftaroline infusions over package insert recommended infusion times. Overall, ceftaroline occupies an important niche in pediatric practice as the “MRSA cephalosporin” that bridges the gap between traditional anti-staphylococcal B-lactams and agents such as vancomycin, daptomycin, and linezolid.

Daptomycin

Daptomycin has some key differences in dosing in pediatrics compared to adults. Younger children clear daptomycin more rapidly than adults, requiring higher weight-based doses and age-specific dosing regimens to achieve comparable drug exposures. Daptomycin dosed once daily by patient age: 12-17 years, 7 mg/kg; 7-11 years, 9 mg/kg and 1-6 years, 12 mg/kg, resulted in plasma levels across age groups were only comparable with those in adults receiving daptomycin at 6 mg/kg.22 Important to note, for many of these resistant infections (e.g., MRSA and VRE) adults would require higher doses/exposures than what 6 mg/kg provides and these higher equivalents have not yet been well studied in pediatric patients.23  The daptomycin package insert notes that is not recommended in infants <1 year old because of concerns for neuromuscular and nervous system toxicity observed in animal studies.24  The Key Potentially Inappropriate Drugs in Pediatrics (KID) List initially listed daptomycin as a medication that had demonstrated toxicity in infants and should be avoided, but noted in the 2025 revision it was removed as the data was vague information in the package insert and case reports in infants without toxicity has been found without issues.25,26  Additionally, Ye and colleagues published their pharmacovigilance data last year showing no positive signals related to the nervous system observed in infants under 1 year old receiving daptomycin.27 It was found that hepatobiliary disorders from daptomycin use in this age group was the strongest associated adverse effect, with hepatic cytolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) being the most significant risk signals.27

Trimethoprim-sulfamethoxazole

The Pediatric Infectious Diseases Society and Infectious Diseases Society of America 2021 osteomyelitis and 2023 septic arthritis guidelines acknowledge trimethoprim-sulfamethoxazole as an option for oral step-down therapy of CA-MRSA musculoskeletal infections, but note that no controlled comparative data exist.28,29 The only published pediatric series (20 children with osteomyelitis, median trimethoprim dose ~16 mg/kg/day) reported a 100% cure rate with trimethoprim-sulfamethoxazole-containing regimens, though 40% experienced mild adverse events.28,29 A theoretical concern exists that thymidine released from damaged tissues may overcome the folate antagonism of trimethoprim-sulfamethoxazole in deep-seated infections.30

Dalbavancin

is FDA-approved for the treatment of acute bacterial skin and skin structure infections in pediatric patients from birth to <18 years, including infections caused by MRSA.31 The approved pediatric dosing is a single-dose IV (22.5 mg/kg for ago 0 to <6 years and 18mg/kg for age 6 to <18 years old with maximum doses of 1500 mg) regimen administered over 30 minutes.31 Despite the limited on-label indications for dalbavancin in the pediatric population, a growing body of case-series data supports dalbavancin as consolidation therapy for deeper gram-positive infections in children. In a multicenter case series of 15 patients with a median age 7.1 years, dalbavancin was used for endocarditis (26%), endovascular infections (20%), osteoarticular infections, and deep surgical site infections of which, S. aureus was the most common pathogen (60%).32 This study revealed 93% were cured at day 90, with one discontinuation due to rash/ diarrhea.32 A 3-compartment, linear PK model showed that dalbavancin exposure in children was similar to that in adults administered a 2-dose regimen for children 6 to <18 years of age receiving 12 mg/kg (1000 mg maximum) on day 1 and 6 mg/kg (500 mg maximum) on day 8 and children aged 3 months to <6 years receiving 15 mg/kg (1000 mg maximum) on day 1 and 7.5 mg/kg (500 mg maximum) on day 8. Similarly, adult exposure after a single-dose of 1500 mg were comparable to children 6 to <18 years of age receiving 18 mg/kg (1500 mg maximum) on day 1 and those 3 months to <6 years of age receiving 22.5 mg/kg (1500 mg maximum) on day 1.33 Where dalbavancin has potential with MRSA infections, dalbavancin is not recommended for the treatment of VRE infections in children (or adults). Its activity is critically dependent on the vancomycin resistance genotype as it retains activity against VanB phenotype VRE but lacks activity against VanA phenotype VRE, which accounts for the majority of VRE infections in the US.34

Key Takeaways

Vancomycin is far from obsolete, but it is no longer the only answer for pediatric Gram-positive resistance. Understanding when to reach for alternatives such as clindamycin, doxycycline, ceftaroline, or daptomycin is becoming just as important as knowing when vancomycin remains the right choice.

About the author: Kaitlyn Kenyon is a PGY-2 Infectious Diseases Pharmacy resident at Hartford Hospital. This post was written as part of her Pediatric Infectious Diseases Learning Experience under the guidance of her preceptor, Jennifer Girotto, PharmD, BCPPS, BCIDP, who also reviewed and edited this piece. 

References

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