Haemophilus influenzae global epidemiology and antimicrobial susceptibility patterns including ampicillin and amoxicillin-clavulanate resistance based on β-lactamase production, 2013–2022 – BMC Infectious Diseases

Global Surveillance Report on *H. influenzae* Antimicrobial Resistance: A Sustainable Development Goal Perspective

Introduction: Aligning Antimicrobial Stewardship with SDG 3

Continuous monitoring of Haemophilus influenzae resistance is a critical component of antimicrobial stewardship, directly supporting the achievement of Sustainable Development Goal 3 (Good Health and Well-being) by combating communicable diseases and strengthening global health security. A 10-year longitudinal surveillance study provides crucial data on antimicrobial resistance and β-lactamase production across Asia, the West Pacific, Europe, and the Americas. The study’s robust methodology enhances the reliability of global health data, which is essential for managing health risks as outlined in SDG Target 3.d.

• Scope: The research represents a decade-long surveillance effort across five continents.
• Methodology: It is the first global study to analyze BLNAR, BLNAI, BLPACP, and BLPACI resistance types using the broth microdilution method, the reference standard recommended by both CLSI and EUCAST.
• Consistency: The consistent application of updated 2024 CLSI and EUCAST breakpoints across all isolates ensures high reliability and comparability of results over time.
• Centralized Testing: All isolates were sent to a central laboratory for standardized testing, eliminating discrepancies that arise from varied local practices and outdated breakpoints, thereby preventing misclassifications that can lead to ineffective therapy and adverse patient outcomes.

Analysis of Key Findings on Antimicrobial Susceptibility

The study reveals significant findings regarding the susceptibility of H. influenzae to various antibiotics, highlighting discrepancies between international testing standards that complicate global surveillance efforts. Addressing these differences is vital for fostering the international cooperation required by SDG 17 (Partnerships for the Goals).

Discrepancies Between CLSI and EUCAST Standards

• Susceptibility to ceftriaxone and piperacillin-tazobactam was 100% according to CLSI breakpoints but fell to 99.1% and 99.8%, respectively, under the more conservative EUCAST breakpoints.
• These differences in interpretation have significant implications for clinical decision-making, global surveillance data, and the harmonization of laboratory methods.
• A recent meta-analysis on multidrug-resistant (MDR) H. influenzae reported a global prevalence of 34.9%, with MDR strains at 23.1%. However, this analysis lacked data from the Americas and did not provide specific rates for key resistance phenotypes like BLNAR.

Cross-Resistance Patterns

• β-lactamase-producing isolates showed higher susceptibility to fluoroquinolones but lower susceptibility to trimethoprim-sulfamethoxazole, tetracycline, and macrolides.
• Conversely, BLPACR and BLNAR isolates exhibited reduced susceptibility to fluoroquinolones, suggesting that alterations in penicillin-binding protein 3 (PBP3) may be a more significant driver of fluoroquinolone resistance than β-lactamase production.

The Rise of Resistant Strains: A Challenge to Global Health Equity (SDG 3 & SDG 10)

The emergence and spread of β-lactamase-negative ampicillin-resistant (BLNAR) strains pose a severe threat to public health and challenge the goal of ensuring healthy lives for all. The dramatic increase in BLNAR rates and significant regional variations underscore the health inequalities highlighted in SDG 10 (Reduced Inequalities).

Global and Regional BLNAR Prevalence Trends

• Global Trend: The study observed a significant increase in BLNAR rates, rising from 0.9% in 2013 to 14.3% in 2016 and reaching 87% in 2021.
• Regional Disparities:
  • Japan: Prevalence increased sharply from 5.8% in 2000 to 60% in 2016.
  • Canada: Rates varied, averaging 14.6% between 2007 and 2014.
  • Europe: Rates remained relatively stable at around 9% but showed significant variation between countries, from 0% to 33.9%.
  • Asia and West Pacific: The study confirmed a high prevalence of BLNAR, BLNAI, BLPACP, and BLPACI in this region, consistent with other reports.

These resistant strains, particularly BLNAR and BLPACR, were also significantly less susceptible to other critical antibiotics, including carbapenems, cephalosporins, fluoroquinolones, and macrolides. This multi-drug resistance narrows treatment options and complicates clinical management, necessitating heightened vigilance and investment in alternative therapeutic strategies to protect global health.

Implications for Diagnostics, Treatment, and Antimicrobial Stewardship

The study’s findings have profound implications for clinical microbiology, treatment guidelines, and antimicrobial stewardship programs, which are foundational to achieving SDG 3.

1. Diagnostic Challenges: Standard laboratory methods, such as nitrocefin β-lactamase testing, are inadequate as they fail to detect BLNAR and BLPACR isolates. This can lead to an overestimation of susceptibility to amoxicillin and amoxicillin-clavulanate, resulting in treatment failures.
2. Empiric Therapy Risks: CLSI recommendations for empiric treatment of respiratory infections could lead to very major errors (VMEs) exceeding the acceptable threshold of 1.5%. The study found potential VMEs of 5.7% for amoxicillin-clavulanate and 13.1% for clarithromycin, indicating that empiric use of these agents carries a significant risk of failure, especially in high-prevalence regions like Asia.
3. Informed Antibiotic Choice: The data showed higher in vitro susceptibility to azithromycin (98.4%) compared to clarithromycin (87.2%). Azithromycin is therefore a more reliable option for empiric therapy where necessary, though susceptibility testing remains essential for guiding effective treatment.

Conclusion: A Call for Global Partnership (SDG 17) to Combat Antimicrobial Resistance

The emergence of BLNAR and BLPACR strains of H. influenzae is a global health challenge that threatens progress towards the Sustainable Development Goals. The high prevalence of these strains, particularly in Asia and the West Pacific, combined with growing resistance to other antibiotic classes, demands an urgent, coordinated global response. Achieving this requires strengthening international partnerships in line with SDG 17.

Recommendations

1. Enhance Global Surveillance: Strengthen and expand surveillance programs to include underrepresented regions to provide a more accurate picture of the global resistance landscape and address health inequalities (SDG 10).
2. Harmonize International Standards: Promote collaboration between standards organizations like CLSI and EUCAST to harmonize breakpoints. This will ensure data comparability and support a unified global strategy against antimicrobial resistance (SDG 17).
3. Improve Diagnostic Capacity: Invest in the global availability of accurate and accessible susceptibility testing methods to prevent misclassification of resistant isolates and ensure effective treatment.
4. Strengthen Antimicrobial Stewardship: Utilize robust surveillance data to inform and update national and international treatment guidelines. Empirical therapy, particularly with clarithromycin, should be approached with caution, and stewardship programs must be reinforced to mitigate the spread of resistant strains.

Analysis of Sustainable Development Goals in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

The article primarily addresses issues related to one Sustainable Development Goal:

• SDG 3: Good Health and Well-being

Explanation: The entire article focuses on antimicrobial resistance (AMR) in Haemophilus influenzae, a significant global health challenge. It discusses the surveillance of drug-resistant bacteria, the effectiveness of antibiotics, and the need for optimized treatment protocols. These topics are central to ensuring healthy lives and promoting well-being, as the spread of resistant strains can lead to “ineffective therapy and adverse patient outcomes,” directly threatening public health and the ability to treat common infections.

2. What specific targets under those SDGs can be identified based on the article’s content?

Based on the article’s focus on AMR and global health surveillance, the following specific targets under SDG 3 are identified:

1. Target 3.3: By 2030, end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases.
   • Explanation: Antimicrobial resistance is a major threat to combating communicable diseases. The article details the rising resistance of H. influenzae, a bacterium causing respiratory and other infections. The study’s conclusion that “the emergence of BLNAR and BLPACR strains presents a global challenge” and the “urgent need for effective containment strategies” highlights how AMR undermines efforts to control and treat such diseases, making this target highly relevant.
2. Target 3.d: Strengthen the capacity of all countries, in particular developing countries, for early warning, risk reduction and management of national and global health risks.
   • Explanation: The article is an example of this target in action. It describes a “10-year longitudinal surveillance study” covering multiple continents, which serves as a global early warning system for AMR trends. The text emphasizes that “Continuous monitoring of H. influenzae resistance trends is critical” and discusses the importance of standardized testing methods (CLSI and EUCAST) and centralized laboratories. This entire framework is about building and utilizing capacity to manage the global health risk of AMR. The study itself, as part of the “SENTRY Antimicrobial Surveillance Program,” is a mechanism for risk reduction and management.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

Yes, the article mentions and implies several indicators that can be used to measure progress:

• Indicator for Target 3.3: Prevalence and trends of antimicrobial resistance in specific pathogens.
  • Explanation: The article is replete with quantitative data that serves as a direct measure of this indicator. It provides specific resistance rates, such as “global rates of BLNAR varied over the years, with 0.9% resistance to ampicillin in 2013, 14.3% in 2016, and 87% in 2021.” It also cites another study’s findings on “Antibiotic resistance rates to ampicillin, azithromycin, and ceftriaxone were 36%, 15.3%, and 1.4%, respectively.” Tracking these percentages over time is a direct way to measure the challenge of AMR in relation to communicable diseases.
• Indicator for Target 3.d: Implementation of standardized global antimicrobial surveillance and reporting.
  • Explanation: The study’s methodology implies this indicator. The article describes how “all H. influenzae isolates were sent to a central laboratory for standardized testing using reference testing methods, ensuring consistency and reliability.” The detailed discussion about the differences between CLSI and EUCAST breakpoints and their implications for resistance reporting (“The discrepancy between the CLSI and EUCAST breakpoints has significant implications for the interpretation of antimicrobial susceptibility”) underscores the importance of standardized systems for accurate global health risk management. The existence and findings of the “SENTRY Antimicrobial Surveillance Program” itself is a measure of this capacity.

4. Summary Table of SDGs, Targets, and Indicators

Source: bmcinfectdis.biomedcentral.com