β‐Lactamase‐Producing Haemophilus influenzae Pneumonia in a 1‐Month‐Old Infant With Respiratory Syncytial Virus Bronchiolitis

1. Presentation of Case

A 1‐month‐old male infant presented to our emergency department with a 1‐week history of nasal discharge and cough, followed by fever onset on day 8 of illness. He was born at 37 weeks and 3 days of gestation, weighing 2700 g, with Apgar scores of 9/9 at 1 and 5 min. He was exclusively formula‐fed.

At the referring hospital, the infant tested positive for respiratory syncytial virus (RSV) antigen. Laboratory findings showed a WBC count of 8000/μL (Lymphocytes 57.6%, Granulocytes 18.6%, Monocytes 20.9%) and a CRP level of 6.0 mg/dL. The referring physician was concerned about clinical deterioration and the possibility of bacterial superinfection.

Upon arrival at our institution, the vital signs were as follows: temperature, 37.2°C; respiratory rate, 52 breaths/min; heart rate, 130 beats/min; SpO₂ 92% on room air. Physical examination revealed tachypnea without obvious retractions, wet crackles in the bilateral lower lung fields, but no meningeal signs. Additionally, there were no signs and symptoms of heart failure, such as general edema or heart murmurs. Formula intake had decreased from the usual 120 mL per feeding to 30–50 mL per feeding.

Chest X‐ray demonstrated bilateral hilar prominence with generalized increased bronchovascular markings and some peribronchial thickening, consistent with viral bronchiolitis (Figure 1). Notably, no focal infiltrates or consolidation were observed. Upon closer inspection, there was involvement of the horizontal fissure in the right lung and slightly asymmetric hyperinflation of the lower lobes, with the right lower lobe appearing more radiotransparent than the left (Figure 1, yellow arrow). While these findings were predominantly consistent with viral bronchiolitis, the asymmetric hyperinflation and fissure involvement raised consideration for superimposed bacterial infection. Blood cultures, urine analysis, and urine cultures showed no abnormalities.

FIGURE 1.

Chest radiograph on admission. Anteroposterior chest radiograph showing bilateral hilar prominence with increased bronchovascular markings and peribronchial thickening. Horizontal fissure involvement is visible in the 5th intercostal space on the right (yellow arrow), and the right lower lobe demonstrates greater radiotransparency compared to the left, suggesting asymmetric hyperinflation. While predominantly consistent with viral bronchiolitis, these findings also raise consideration for bacterial superinfection.

2. Clinical Reasoning Point 1

2.1. What Factors Should Guide the Decision to Initiate Antibiotic Therapy in This RSV‐Positive Infant?

The clinical scenario presents several concerning features that warrant careful consideration:

1. Age vulnerability: At 1 month of age, this infant falls into the high‐risk category for serious bacterial infections (SBI). The immature immune system and limited clinical signs in neonates make bacterial infections potentially life‐threatening. Additionally, dual pathogen infections in infants with bronchiolitis have been associated with more severe disease, with coinfected patients having a 2.7‐fold increased risk of pediatric intensive care unit admission compared to those with single infections [1].

2. Atypical RSV bronchiolitis progression: RSV bronchiolitis typically demonstrates a predictable clinical course, with the symptom peak occurring between days 5 and 7 of illness [2]. According to the American Academy of Pediatrics' clinical practice guidelines, bronchiolitis is defined as a constellation of clinical symptoms and signs, including viral upper respiratory prodrome followed by increased respiratory effort and wheezing, in children younger than 24 months [2]. In the United States, RSV accounts for approximately 800,000 outpatient visits annually in children under 12 months, with 2%–3% requiring hospitalization. RSV infects ciliated epithelial cells of the bronchiolar mucosa and alveolar pneumocytes, causing cellular infiltration, edema, increased mucus secretion, and impaired ciliary beating. Most hospitalized children recover within 2–3 days, with bronchiolar epithelium regeneration typically beginning 3–4 days after symptom resolution. The infant's presentation on day 8, with clinical deterioration rather than expected improvement, suggests a deviation from the typical viral bronchiolitis progression, raising suspicion of bacterial superinfection.

3. Elevated inflammatory markers: The CRP of 6.0 mg/dL (normal < 0.3 mg/dL in neonates) suggests a significant inflammatory response that could indicate bacterial co‐infection, though viral infections can also cause elevated inflammatory markers.

4. Clinical deterioration: The combination of poor feeding (reduced by two‐thirds from baseline) and persistent wet cough suggests possible bacterial pneumonia superimposed on viral bronchiolitis.

However, we acknowledge that elevated CRP and poor feeding are nonspecific findings that can occur in severe viral bronchiolitis alone.

Given the infant's age, elevated CRP, and clinical signs suggestive of bacterial superinfection, empirical antibiotic therapy was initiated with sulbactam/ampicillin (SBT/ABPC) at 150 mg/kg/day divided into three doses intravenously, selected to cover common neonatal pathogens including Group B Streptococcus, Escherichia coli , and Haemophilus influenzae [3].

3. Intermediate Course and Microbiological Findings

After 48 h of SBT/ABPC therapy, the infant achieved fever resolution but continued to exhibit persistent clinical concerns. Formula intake remained poor at 30–50 mL per feeding, and wet cough continued.

On hospital day 3, posterior nasopharyngeal culture results revealed the growth of Haemophilus influenzae with β‐lactamase production. The isolate was presumed to be non‐typeable H. influenzae (NTHi) based on non‐mucoid colony morphology on chocolate agar, as mucoid colonies suggestive of encapsulated strains were absent. The organism demonstrated resistance to sulbactam/ampicillin (SBT/ABPC) (minimum inhibitory concentration [MIC] 8 μg/mL), which was unexpected given that beta‐lactamase inhibitor combinations typically remain effective against β‐lactamase‐producing strains (Table 1).

TABLE 1.

Antimicrobial susceptibility results.

Antibiotic	MIC (μg/mL)	Interpretation
ABPC (ampicillin)	8	Resistant
PIPC (piperacillin)	64	Resistant
CTM (cefotiam)	8	Resistant
CTX (cefotaxime)	1	Susceptible
CAZ(ceftazidime)	1	Susceptible
CDTR (cefditoren)	0.25	Susceptible
IPM (imipenem)	1	Susceptible
MEPM (meropenem)	0.5	Susceptible
SBT/ABPC (sulbactam/ampicillin)	8	Resistant
GM (gentamicin)	2	Susceptible
EM (erythromycin)	2	Resistant
CLDM (clindamycin)	4	Resistant
MINO (minocycline)	1	Susceptible
LVFX (levofloxacin)	≤ 0.5	Susceptible
β‐lactamase	Positive	—

Abbreviation: MIC, minimum inhibitory concentration.

4. Clinical Reasoning Point 2

4.1. How Should Posterior Nasopharyngeal Culture Results Be Interpreted in the Context of RSV Bronchiolitis, and What Resistance Mechanism Explains SBT/ABPC Failure?

The detection of H. influenzae in nasopharyngeal specimens presents significant interpretive challenges, as the nasopharynx naturally harbors various bacterial species [4]. Polymicrobial colonization patterns vary significantly during health, viral upper respiratory infections, and bacterial infections, with infection‐prone children demonstrating higher baseline colonization rates [4]. While we cannot definitively establish causation of pneumonia from nasopharyngeal cultures alone, several factors support a pathogenic role rather than mere colonization:

1. Temporal correlation: The persistent clinical symptoms despite fever resolution

2. Resistance pattern: The organism's resistance to the current therapy

3. Clinical context: The deviation from the expected RSV recovery pattern

The combination of β‐lactamase production and sulbactam/ampicillin (SBT/ABPC) resistance (MIC 8 μg/mL) suggests a BLPACR (β‐lactamase‐producing amoxicillin/clavulanic acid‐resistant) mechanism. This indicates that β‐lactamase inhibitors cannot overcome the resistance due to altered penicillin‐binding proteins (PBPs), particularly PBP3 [5]. The ftsI gene encoding PBP3 contains critical amino acid substitutions that confer β‐lactam resistance in β‐lactamase‐negative ampicillin‐resistant (BLNAR) strains [5]. Recent genomic analyses have revealed that mutational resistance mechanisms in H. influenzae are becoming increasingly complex, with multiple amino acid substitutions contributing to β‐lactam resistance [6]. Particularly concerning are substitutions near the conserved Lys‐Thr‐Gly (KTG) and Ser‐Ser‐Asn (SSN) motifs, which significantly reduce PBP3 affinity for β‐lactams [5]. Our institutional surveillance data (Table 2) demonstrate concerning trends in antimicrobial resistance patterns.

TABLE 2.

Institutional resistance surveillance data (2023–2025).

Year	Isolates	BLNAS (%)	BLPAR (%)	BLNAR (%)	BLPACR (%)	ABPC‐I (%)	ABPC susceptibility (%)
2023	110	43 (39)	12 (11)	23 (21)	4 (4)	28 (25)	41
2024	76	16 (21)	10 (13)	34 (45)	4 (5)	12 (16)	21
2025 a	45	12 (27)	10 (22)	18 (40)	2 (4)	3 (7)	27

Abbreviations: ABPC‐I, ampicillin‐intermediate; BLNAR, β‐lactamase‐negative ampicillin‐resistant; BLNAS, β‐lactamase‐negative ampicillin‐susceptible; BLPACR, β‐lactamase‐positive amoxicillin‐clavulanic acid‐resistant; BLPAR, β‐lactamase‐positive ampicillin‐resistant; MIC, minimum inhibitory concentration.

^a 2025 data represents April–July provisional results. All isolates were from pediatric patients (age < 15 years) and included respiratory specimens (nasopharyngeal swabs). ABPC‐I: ampicillin intermediate susceptibility (MIC = 2 μg/mL) according to Clinical and Laboratory Standards Institute (CLSI) criteria.

Statistical analysis revealed a significant increase in BLNAR rates from 2023 to 2024 (21% vs. 45%) compared to other drug‐susceptibility patterns (p = 0.001, χ² test; odds ratio = 3.04, 95% confidence interval: 1.53–6.15), highlighting the clinical relevance of our case. The ABPC susceptibility rate declined from 41% in 2023 to 21% in 2024, with a slight recovery to 27% in the 2025 provisional data. These findings align with global antimicrobial resistance (AMR) trends, where bacterial AMR was associated with 4.95 million deaths worldwide in 2019, with lower respiratory infections accounting for over 1.5 million AMR‐associated deaths [7]. In pediatric populations, H. influenzae demonstrates particularly concerning resistance patterns, with Chinese surveillance data showing 58.1% ampicillin resistance, primarily due to β‐lactamase production (50.3%), and 9.3% β‐lactamase‐negative ampicillin‐resistant strains [3]. These findings reflect the broader challenge of increasing antibiotic resistance in H. influenzae isolates from pediatric populations worldwide.

5. Clinical Reasoning Point 3

5.1. How Should Antibiotic Therapy Be Modified Based on Susceptibility Results and Clinical Assessment?

Given the BLPACR pattern, third‐generation cephalosporins (cefotaxime [CTX], ceftazidime [CAZ], cefditoren [CDTR]) or carbapenems (imipenem [IPM], meropenem [MEPM]) represent appropriate alternatives, showing excellent in vitro activity (MIC 0.25–1 μg/mL) [8]. The persistent poor feeding and wet cough, despite fever resolution, suggested inadequate antimicrobial coverage.

We changed antibiotic therapy to cefotaxime (CTX) 100 mg/kg/day, divided into two doses intravenously.

6. Clinical Outcome

Following the switch to cefotaxime, a remarkable clinical improvement was observed within 24 h. Formula intake returned to the usual 120 mL per feeding, the wet cough significantly decreased, and overall clinical condition improved markedly. This rapid response pattern, occurring within one bacterial doubling time and preceding the expected RSV resolution by several days, provided suggestive evidence supporting the presence of bacterial superinfection contributing to the clinical syndrome.

Cefotaxime was continued for 5 days, after which we transitioned to oral cefdinir (avoiding pivoxil ester‐containing antibiotics due to the risk of carnitine deficiency in neonates) and discharged home. Outpatient follow‐up confirmed complete clinical recovery.

7. Discussion

This case illustrates the complexity of managing respiratory infections in neonates, where viral and bacterial pathogens may coexist. The key clinical challenge was distinguishing between expected RSV bronchiolitis progression and bacterial superinfection, given the limited availability of definitive diagnostic methods.

1. Diagnostic approach: Our decision‐making centered on temporal discordance analysis. According to the American Academy of Pediatrics guidelines, the diagnosis of bronchiolitis relies primarily on history and physical examination findings [2]. RSV bronchiolitis exhibits a well‐characterized illness progression, with symptom peaks occurring at days 5–7, followed by gradual improvement. However, the guidelines acknowledge that bacterial superinfection can complicate the clinical course, particularly in high‐risk populations, including infants younger than 3 months [2]. This patient's deterioration on day 8, manifested by significant feeding reduction and persistent respiratory symptoms, deviated from this expected trajectory.

The chest radiograph showed horizontal fissure involvement and asymmetric hyperinflation, which, combined with focal crackles rather than diffuse wheezing, suggested possible bacterial pneumonia superimposed on viral bronchiolitis [2]. Point‐of‐care lung ultrasound, which demonstrates superior sensitivity to chest radiography for pneumonia detection [9, 10], might have provided earlier diagnostic clarification had it been available. We acknowledge that the unavailability of procalcitonin or lower airway sampling represents a limitation of our diagnostic workup.

• 2Resistance implications: The emergence of H. influenzae with BLPACR mechanisms poses a challenge to conventional therapeutic approaches. Our surveillance data demonstrate an alarming increase in BLNAR prevalence (114% relative increase from 2023 to 2024), suggesting that traditional ampicillin‐sulbactam empirical therapy now fails against nearly half of H. influenzae isolates at our institution.

Interpretive limitations: While we acknowledge that nasopharyngeal culture cannot definitively establish lower respiratory tract pathogenicity, the combination of resistant organism detection, clinical deterioration timing, therapeutic response pattern, and temporal correlation suggests a pathogenic role rather than simple colonization. The rapid clinical improvement following targeted antimicrobial therapy provided retrospective validation of our diagnostic hypothesis [1]. Clinical implications: This case suggests that RSV‐positive infants who show deterioration after day 7, particularly with elevated CRP and feeding reduction, warrant consideration for bacterial superinfection and empirical therapy guided by local resistance patterns. NTHi, which resides exclusively in human pharynges and is increasingly recognized as pathogens causing both localized respiratory tract infections and systemic infections such as bacteremia and pneumonia [11], warrants particular attention in pediatric respiratory infections. This case highlights the challenges of discovering NTHi vaccine antigens and the limited efficacy of current preventive measures.

Future perspectives on RSV prevention: Long‐acting monoclonal antibody nirsevimab has demonstrated a 74.5% reduction in medically attended RSV lower respiratory tract infections and a 62.1% reduction in hospitalization [12]. Maternal RSV prefusion F protein vaccination shows 81.8% efficacy against severe RSV lower respiratory tract infection through 90 days of life and 69.4% through 180 days [13]. Real‐world data from the United Kingdom confirm effectiveness ranging from 72% to 82.2%, with particularly high protection in preterm infants (89.9%), and large‐scale surveillance has found no increase in adverse maternal outcomes [14, 15, 16]. As these preventive strategies become widespread, atypical presentations with late deterioration—as in our case—may suggest bacterial superinfection, underscoring ongoing vigilance for antimicrobial resistance.

8. Conclusion

This case highlights the importance of systematic clinical reasoning when managing complex respiratory infections in high‐risk neonates. The emergence of multiply‐resistant H. influenzae strains with BLPACR mechanisms emphasizes the critical need for microbiological surveillance, culture‐directed therapy, and careful clinical correlation. While diagnostic uncertainty regarding the definitive role of nasopharyngeal bacterial isolates persists, the patient's clinical response to targeted antimicrobial therapy based on susceptibility results supported our therapeutic decision in this specific context.

Author Contributions

Kazumasa Zensho: conceptualization, investigation, writing – original draft, writing – review and editing, methodology. Naoki Nojima: writing – review and editing, investigation, validation. Ryoma Hino: investigation, writing – review and editing. Naohi Isse: supervision, writing – original draft, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

This case report was conducted in accordance with the principles of the Declaration of Helsinki and did not require institutional review board approval as it involved retrospective analysis of a single clinical case without patient identification.

Consent

Oral informed consent was obtained from the patient's guardian for publication of this case report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.