Respiratory tract infections (RTIs) are a dominant driver of pediatric healthcare visits and antibiotic exposure. While most acute RTIs in children are viral or self-limiting, antibiotics are frequently prescribed—particularly for syndromes such as acute otitis media (AOM), suspected bacterial pneumonia, bacterial sinusitis, and complicated presentations—creating strong ecological pressure for antimicrobial resistance (AMR). [3–5] At a population level, AMR is now recognized as a major cause of morbidity and mortality worldwide, with the heaviest burdens falling on low-resource settings. [1,2] In pediatrics, AMR is particularly consequential because children experience high RTI incidence, have frequent contact networks (e.g., daycare), and represent key reservoirs for respiratory bacterial carriage and transmission. [4,5]

Among bacterial pathogens, Streptococcus pneumoniae remains central to pediatric RTIs, contributing to community-acquired pneumonia (CAP), AOM, and invasive pneumococcal disease (IPD). Contemporary data demonstrate that pneumococcal resistance persists despite vaccine-driven shifts in serotype distribution, with ongoing concern about multidrug resistance and macrolide non-susceptibility in multiple regions. [5,9,10] The clinical implication is practical: when resistance prevalence is high, standard empiric therapy may underperform, and escalation to broader-spectrum agents may occur—potentially reinforcing AMR if not targeted appropriately. [3,5]

Non-typeable Haemophilus influenzae (NTHi) has become increasingly prominent in pediatric respiratory disease after widespread Hib vaccination, particularly for AOM and bronchopulmonary infections. [12,13] β-lactam resistance mechanisms (e.g., β-lactamase production and BLNAR phenotypes) complicate β-lactam selection, particularly in recurrent or treatment-failure AOM and in settings with high ampicillin/amoxicillin resistance. [12,13]

Atypical bacterial pathogens also contribute to pediatric RTIs, most notably Mycoplasma pneumoniae, which is implicated in school-age CAP and outbreaks. [3,6] Macrolides are often first-line therapy in children for suspected atypical pneumonia. However, macrolide-resistant M. pneumoniae (MRMP) has expanded substantially in some regions, raising questions about empiric macrolide utility and the role of alternative agents and supportive diagnostics. [6]

Given the clinical and public health relevance, the present systematic review synthesizes peer-reviewed evidence on resistance prevalence across core pediatric RTI pathogens, emphasizing pneumococcus and M. pneumoniae, and integrates evidence-based mitigation approaches—including stewardship and diagnostic strategies—to reduce unnecessary antibiotic exposure and thereby reduce selective pressure. [8,14–20]

Design and reporting This systematic review was designed and reported according to PRISMA 2020 guidance. [8] Data sources and search strategy We conducted structured searches in PubMed/MEDLINE, Embase, and Scopus to identify peer-reviewed studies reporting antibiotic resistance in pediatric RTI pathogens. Search concepts included: (1) pediatrics/children; (2) respiratory tract infection/pneumonia/otitis/sinusitis/pharyngitis; (3) antimicrobial resistance/antibiotic susceptibility; and (4) key pathogens (S. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae). We additionally screened reference lists of eligible systematic reviews and high-impact primary studies. Eligibility criteria Inclusion criteria: 1. Peer-reviewed observational studies, surveillance studies, and systematic reviews/meta-analyses; 2. Pediatric populations (0–18 years) with RTIs or relevant respiratory carriage studies informing RTI pathogen resistance; 3. Reported resistance proportions or non-susceptibility to common antibiotic classes (β-lactams, macrolides, tetracyclines, TMP-SMX, etc.); 4. Clear microbiologic methods (culture and susceptibility testing and/or genotypic resistance markers, as appropriate). Exclusion criteria: 1. Case reports without susceptibility denominators; 2. Exclusively adult populations; 3. Non-peer-reviewed sources (editorials without original data); 4. Studies lacking extractable resistance prevalence. Outcomes The primary outcome was prevalence (proportion) of antibiotic resistance/non-susceptibility in pediatric RTI pathogens to commonly used agents. Secondary outcomes included regional variation, multidrug resistance prevalence, and evidence describing interventions that reduce inappropriate antibiotic exposure (stewardship, decision support, and point-of-care diagnostics). Data extraction and synthesis We extracted study design, setting, age group, syndrome/pathogen, sample size, and key resistance outcomes. Because included studies were heterogeneous by syndrome, laboratory breakpoints, and sampling frame (invasive vs non-invasive vs carriage), we used a structured narrative synthesis and presented key quantitative findings from high-sample and multi-region evidence. Where meta-analytic estimates were available from eligible systematic reviews, we reported pooled or regional summary measures.

Study selection and overview

The included evidence base comprised large multicenter surveillance studies, regional carriage/clinical cohorts, and systematic reviews/meta-analyses addressing pneumococcal AMR and MRMP. Major outcome domains were: (1) pneumococcal resistance to β-lactams and macrolides, (2) MRMP prevalence and regional patterns, (3) β-lactam resistance in H. influenzae linked to pediatric AOM/carriage, and (4) AMR mitigation strategies that reduce antibiotic exposure (a proximal driver of resistance selection).

Table 1. Key included studies and evidence sources informing resistance prevalence

The evidence base combined large denominator surveillance (US pneumococcal isolates), multi-country systematic reviews (Latin American IPD and global MRMP), and pediatric carriage/clinical cohorts from Africa, Europe, and North Africa. [5,6,9–13] This mix is relevant because pediatric RTI pathogens circulate between carriage and clinical disease, and resistance patterns differ by invasiveness and sampling site. [3,5,10,11] Across studies, macrolide resistance emerged as a recurrent concern (pneumococcus and M. pneumoniae), with β-lactam resistance patterns varying by pathogen and region. [5,6,11–13]

Table 2. Streptococcus pneumoniae resistance prevalence (selected high-yield estimates)

Across distinct sampling frames, pneumococcal resistance was substantial and clinically meaningful. In US children, Mohanty et al. reported high resistance burdens including macrolide resistance near 40% and penicillin resistance near 40%, with significant annual increases in key resistance metrics. [5] In Latin American invasive disease, Sandoval et al. summarized penicillin resistance at approximately one-quarter of isolates. [9] Carriage-based data (Morocco) showed high penicillin resistance and measurable multidrug resistance, supporting the role of colonization reservoirs. [11]

Table 3. Macrolide-resistant Mycoplasma pneumoniae (MRMP): global and regional prevalence (meta-analysis)

MRMP prevalence showed pronounced geographic heterogeneity. Kim et al. synthesized 153 studies and demonstrated the highest MRMP prevalence in the Western Pacific region (>50%), with substantially lower prevalence in Europe and the Americas (<10% in pooled estimates). [6] Importantly for pediatric RTIs, studies restricted to children showed a higher pooled MRMP proportion (37%) than adult-only datasets, suggesting heightened pediatric vulnerability or exposure dynamics. [6] These findings imply that empiric macrolide effectiveness for suspected atypical pneumonia may vary sharply by region. [3,6]

Table 4. Evidence-informed levers that reduce antibiotic exposure for RTIs (relevant to resistance containment)

Although not direct resistance prevalence measures, these intervention studies address the upstream driver of resistance selection: unnecessary antibiotic exposure. CRP point-of-care testing reduced immediate antibiotic prescribing in a systematic review/meta-analysis, with acceptable safety signals. [14] Pediatric RTI stewardship interventions in emergency settings generally reduced prescribing and improved spectrum selection. [15] Clinical decision support tools reduced inappropriate prescribing overall, though effects depended on implementation features. [16] Not all strategies succeed: a major pediatric primary-care trial showed no overall dispensing reduction, highlighting contextual barriers. [20]

This systematic review demonstrates that antibiotic resistance among key pediatric RTI pathogens is common, clinically significant, and geographically variable. The most consistent and actionable signals were: (1) high and rising pneumococcal resistance to macrolides and penicillins in large pediatric datasets; (2) substantial MRMP prevalence in some regions, particularly the Western Pacific; and (3) persistent β-lactam resistance complexity in H. influenzae within AOM-linked populations and infant surveillance. [5,6,9,11–13]

Pneumococcal resistance: sustained burden with implications for empiric therapy

Pneumococcus remains central to pediatric bacterial RTIs, especially CAP and AOM, and thus resistance directly impacts first-line treatment performance. [3,5] The multicenter US analysis by Mohanty et al. is especially informative due to its large denominator and decade-scale view: over half of pediatric isolates showed resistance to ≥1 drug class, nearly one-third to ≥2 classes, and macrolide and penicillin resistance were both around 40%. [5] These values are large enough to affect empiric treatment choices and to increase the likelihood of failure with macrolide monotherapy where pneumococcus is a plausible pathogen. The finding of significant annual increases in resistance outcomes further suggests that static guideline assumptions may become progressively misaligned with real-world susceptibility. [5]

Regional summaries reinforce this concern. In Latin American IPD, Sandoval et al. reported that approximately one-quarter of invasive isolates displayed penicillin resistance. [9] Although invasive disease isolates may not mirror outpatient AOM or non-invasive RTI isolates, IPD resistance patterns often track broader pneumococcal ecology and can reflect vaccine- and antibiotic-driven serotype shifts. [9,10] Carriage cohorts add complementary insight: Amari et al. found high penicillin resistance in nasopharyngeal isolates and ~17% multidrug resistance, supporting the concept that pediatric colonization is a reservoir through which resistant clones circulate and seed disease. [11] Post-vaccine-era settings such as Botswana demonstrate why ongoing monitoring matters: serotype replacement can change the resistance landscape even when overall pneumococcal disease burden declines. [10]

MRMP: the clearest example of geographic heterogeneity

MRMP exemplifies the practical need for regionally tailored guidance. Kim et al. documented MRMP prevalence exceeding 50% in the Western Pacific region while remaining under 10% in pooled estimates for Europe and the Americas. [6] For child-only studies, the pooled MRMP prevalence was 37%, which is clinically consequential because macrolides are the most common first-line therapy for atypical pneumonia in children. [6] In high-MRMP settings, clinicians may face a higher probability of delayed effective therapy if macrolide resistance is not considered. The implication is not that macrolides should be abandoned universally, but that empiric algorithms should account for local MRMP prevalence and use diagnostics—where feasible—to target therapy, particularly during outbreaks.

1. influenzae and the “β-lactam problem” in otitis-linked cohorts

The H. influenzae evidence illustrates a different challenge: resistance mechanisms that complicate common β-lactam selection and dosing. The large French ambulatory cohort in children with AOM provides robust epidemiologic context: H. influenzae was isolated in about half of sampled children, indicating its major role in AOM-related respiratory microbiology. [12] Belgian surveillance combining daycare infants and AOM cases underscores the importance of ongoing resistance profiling (including reduced β-lactam susceptibility workups). [13] Taken together, these studies support continued attention to β-lactam resistance phenotypes, especially in recurrent AOM, treatment failure, and high antibiotic exposure contexts. [12,13]

Reducing selection pressure: stewardship and diagnostics as resistance containment tools

Because resistance prevalence is largely shaped by antibiotic selection pressure, interventions that reduce inappropriate prescribing are indirectly resistance-preventive. CRP point-of-care testing reduced immediate antibiotic prescribing in a meta-analysis, with a clinically interpretable effect size (RR 0.79). [14] Pediatric emergency stewardship interventions generally reduced prescribing and improved spectrum targeting. [15] Decision support tools also reduced inappropriate antibiotic use, though implementation matters and long-duration interventions were not uniformly effective. [16] Importantly, not all strategies translate into population-level reductions: a major pediatric primary-care trial found no overall reduction in dispensing, emphasizing that sociobehavioral and workflow factors can overwhelm technical solutions. [20]

Overall interpretation

The convergence of high pneumococcal resistance, regionally high MRMP prevalence, and persistent H. influenzae resistance complexity suggests that pediatric RTI management requires: (1) local antibiograms and surveillance; (2) syndrome-based, guideline-concordant empiric therapy with reassessment; and (3) scaled stewardship and diagnostic strategies to reduce unnecessary antibiotic exposure. [5,6,9,10,14–16,20] The public health objective is not simply broader antibiotics, but smarter antibiotics.

Antibiotic resistance among pediatric RTI pathogens is prevalent and clinically consequential. Large multicenter data show substantial pneumococcal resistance to macrolides and penicillins, with multidrug resistance present in meaningful proportions. Macrolide-resistant Mycoplasma pneumoniae demonstrates marked regional heterogeneity, exceeding 50% in some settings and reaching high pooled prevalence in pediatric studies. Haemophilus influenzae remains a major pediatric pathogen in otitis-linked populations, and resistance surveillance remains essential for informing β-lactam choices. Because antibiotic exposure is the primary ecological driver of resistance selection, interventions such as CRP point-of-care testing, pediatric stewardship programs, and appropriately designed clinical decision support can reduce inappropriate antibiotic use—though effectiveness varies by context. Future pediatric RTI policy should prioritize continuous surveillance, diagnostic strengthening, and pragmatic stewardship integrated into routine care.

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