Can a β‑lactamase‑negative, ampicillin‑resistant (BLNAR) Haemophilus influenzae infection persist after treatment?

BLNAR Infection Persistence After Treatment

Yes, BLNAR H. influenzae infections can persist after treatment, particularly when inappropriate antibiotics are selected or when low-level resistance strains are not properly identified, leading to treatment failure and bacterial persistence.

Understanding BLNAR Resistance Mechanisms

BLNAR strains develop resistance through alterations in penicillin-binding proteins (PBPs 3a and 3b) rather than β-lactamase production, making them resistant to aminopenicillins and some cephalosporins despite negative β-lactamase testing 1. This chromosomally-mediated resistance mechanism is particularly problematic because:

• Most BLNAR strains in Europe and the United States have low-level ampicillin MICs (0.5-4 μg/mL), making them appear susceptible by standard testing but clinically resistant 2
• Standard disk diffusion and even some Etest methods fail to reliably identify these low-BLNAR strains, with 76.5% appearing falsely susceptible to ampicillin by microdilution using CLSI breakpoints 2
• 79.4% of BLNAR strains show nonsusceptibility to amoxicillin when properly tested by broth microdilution, the most accurate detection method 2

Why Treatment Failures Occur

Inappropriate Antibiotic Selection

Plain amoxicillin or ampicillin will fail against BLNAR strains, as these organisms have intrinsic resistance to aminopenicillins regardless of β-lactamase status 1. The European Respiratory Society guidelines explicitly note that β-lactamase production is a well-known predictor of treatment failure in community-acquired respiratory tract infections 1.

Macrolide Ineffectiveness

Macrolides and azalides are essentially ineffective against H. influenzae despite appearing active in vitro 3. Over 98% of H. influenzae strains possess chromosomally-mediated efflux pumps (acrAB genes) that actively remove macrolides from the bacterial cell 1. This means azithromycin, clarithromycin, and erythromycin are unreliable choices that can lead to persistent infection 3.

Inadequate Tissue Penetration

Even with appropriate antibiotics, low sputum concentrations can lead to treatment failure. A clinical study found sputum amoxicillin levels of only 0.05-0.54 μg/mL, below the MICs needed for H. influenzae, which may explain the 22% relapse rate observed 4.

Preventing Persistent Infection

First-Line Treatment Selection

Use amoxicillin-clavulanate (90 mg/kg/day of amoxicillin with 6.4 mg/kg/day of clavulanate in 2 divided doses for pediatrics; 500-1000 mg every 8 hours for adults) as first-line therapy 3. This combination:

• Covers both β-lactamase-producing strains (16.9-23% prevalence) and BLNAR strains (19.2% prevalence) 5, 6
• Achieves essentially 100% susceptibility against H. influenzae, including BLNAR strains 7, 3
• Demonstrated excellent eradication rates with 18 of 19 β-lactamase-producing strains cleared in clinical trials 4

Alternative Options for Severe Cases

For severe infections or treatment failures, use ceftriaxone (1 g IV every 24 hours or 50 mg IM/IV for 3 days) 3. This third-generation cephalosporin:

• Maintains 95-100% activity against H. influenzae including BLNAR strains 3
• Remains bactericidal against BLNAR isolates, achieving bacterial killing after 4 hours of incubation 5
• Provides superior tissue penetration compared to oral agents 3

Cefotaxime and imipenem maintain greater than 98% susceptibility rates against invasive BLNAR isolates 5, making them reliable alternatives for hospitalized patients.

Treatment Duration

Treat respiratory tract infections for at least 7 days and reassess clinical response at days 5-7 3. For hospitalized pneumonia cases, reassess at days 2-3 for fever resolution and lack of radiographic progression 3.

Critical Pitfalls to Avoid

• Never use plain amoxicillin or ampicillin in areas where β-lactamase production exceeds 10% 3, as these achieve only 70-85% activity using pharmacokinetic/pharmacodynamic breakpoints 3
• Avoid macrolides as monotherapy for confirmed or suspected H. influenzae infections due to intrinsic efflux-mediated resistance 1, 3
• Do not rely on disk diffusion or low-strength ampicillin disks for BLNAR detection, as they poorly identify low-BLNAR isolates 2
• First-generation cephalosporins should be avoided in areas with high β-lactamase production 3

Geographic Considerations

BLNAR prevalence varies geographically, with mean European prevalence of 7.6% (range 0.7-17.6%) 1. In Spain, 12% of β-lactamase-negative strains showed diminished ampicillin susceptibility (BLNAR phenotype) 6. The American Academy of Otolaryngology-Head and Neck Surgery notes that while rare, BLNAR strains are of significant concern where they exist 1.