Associate Professor Dr Lee Wen-Sen
Division of Infectious Diseases, School of Medicine,
College of Medicine, Taipei Medical University,
Taiwan Director, Department of Medical Affairs,
New Taipei City Hospital, Taiwan

Penicillin non-susceptible Streptococcus pneumoniae (PNSP) is one of the most important antimicrobial threats worldwide.^{1, 2} With the widespread emergence of antimicrobial resistance, combination regimens appear to be promising alternatives to monotherapy for combating PNSP-associated pneumonia.

Associate Professor Dr Lee Wen-Sen shares his insights on PNSP-associated pneumonia in Taiwan, and strategies for the optimisation of antimicrobial regimens to combat multidrug resistant (MDR) strains.

Q1: In Taiwan, what is the current antimicrobial resistance profile of pneumococci and the prevalence of PNSP in patients with pneumonia and meningitis?

There has been increasing data about the development of resistance of pneumococci to penicillin, third generation cephalosporins, erythromycin and new macrolides. The Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART) program demonstrated that the overall prevalence of PNSP was 85.7% and 27.4% in meningitis and non-meningitis groups, respectively, from 2017 to 2019 in Taiwan.³ According to the same study, the incidence rate of PNSP in the meningitis group was reported to be >80% (82.8%–90.1%, mean 85.7%), which was higher than the reported non-susceptibility rates toward penicillin (68.2%–83.9%) from 2011 to 2015 in Taiwan.³

Q2a: Please provide an overview of recommended diagnostic and treatment strategies for the management of patients with pneumonia caused by PNSP?

Early diagnosis and appropriate treatment are very important for PNSP infections. The diagnosis of pneumococcal pneumonia is usually based on clinical and radiographic evidence of pneumonia, combined with microbiological results of blood and sputum samples and detection of pneumococcal antigens in urine. At present, the current ‘gold standard’ for serotyping S. pneumoniae is the Quellung reaction, which is based on the antigenic specificity of different capsular polysaccharides (CPSs), with marked serotype-specific difference in disease prevalence.⁴ The recommended techniques or applications are the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), Quellung capsular typing using multiplex polymerase chain reaction (PCR) and antimicrobial susceptibility testing. MALDI-TOF and multiplex PCR technology are reliable in providing rapid and accurate bacterial and serotype identification.

The selection of antimicrobial regimens for empiric therapy is based upon a number of factors, including most likely pathogen(s), clinical evidence demonstrating efficacy, risk factors for antimicrobial resistance, medical comorbidities and epidemiological factors. For patients with pneumonia caused by PNSP, newer fluoroquinolones, fifth generation cephalosporins and glycopeptides are recommended for treatment.

Q2b: Are there any specific clinical guidelines available for the management of patients with pneumonia caused by PNSP?

Breakpoints are minimum inhibitory concentrations (MICs) that define penicillin susceptibility according to the site of infections and route of drug administration. In non-meningitis cases, penicillin MIC ≤2 μg/mL was defined as susceptible, while 4 μg/mL was defined as intermediate and ≥8 μg/mL as resistant.^{5, 6} Several guidelines are available for the management of patients with pneumonia who have risk factors for penicillin resistance or who have documented infections caused by S. pneumoniae with MIC of penicillin of ≥4 µg/mL.

Identification of patients with pneumococcal bacteremia at low risk of having higher-level penicillin resistance can assist physicians in selecting fluoroquinolone-sparing regimens for initial empiric therapy (e.g., beta-lactams and/or macrolides or tetracyclines). This may help to delay the development of fluoroquinolone resistance in S. pneumoniae.

According to the Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy (IMPACT) guidelines published in Hong Kong, the use of newer fluoroquinolones should be reserved for selected patients with community-acquired pneumonia (CAP) with higher-level penicillin resistance (MIC ≥4 μg/mL).⁵ Other indications for use of fluoroquinolones in CAP include failure of the first-line treatment regimen and allergy to alternate antibiotics.⁵ Patients with pneumococcal pneumonia caused by strains with penicillin MIC ≤1 μg/mL can be treated appropriately with optimal dosages of intravenous (IV) penicillin and other oral or IV beta-lactams.⁵

The 2017 Guidelines Recommendations for Evidence-based Antimicrobial agents use in Taiwan (GREAT) working group, formed by the Infectious Diseases Society of Taiwan (IDST), recommend beta-lactam antibiotics, including penicillin, a penicillin derivative, or a second- or third-generation cephalosporins for penicillin-susceptible S. pneumoniae.⁶ Fluoroquinolone and doxycycline are alternative choices for patients who are allergic to beta-lactams.⁶ For adult patients with CAP caused by S. pneumoniae, the guidelines recommend that physicians choose regimens based on susceptibility testing for cefotaxime, ceftriaxone, fluoroquinolones (levofloxacin or moxifloxacin), vancomycin, linezolid, high-dose amoxicillin (3 g/day) with penicillin MIC ≤4 μg/mL.⁶

According to the current American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) CAP guidelines, there is evidence to support amoxicillin-clavulanic acid for the treatment of adults with CAP in countries with a high prevalence of penicillin-resistant S. pneumoniae.⁷

The IDST 2017 guidelines also provide recommendations for antimicrobial treatment of paediatric pneumonia (refer below).⁶

Target therapy for CAP caused by S. pneumoniae in paediatric patients

MIC for penicillin ≤2 μg/mL (susceptible)

Preferred: Penicillin G, ampicillin and amoxicillin

Alternative: Ceftriaxone

Duration of treatment: 7–10 days

MIC for penicillin ≥4 μg/mL (intermediate)

Preferred: Cefotaxime, ceftriaxone

Alternative: Vancomycin, linezolid and levofloxacin (for levofloxacin, the physician must weigh the risks and benefits of fluoroquinolones use; growth and maturation should also be considered)

Duration of treatment: 7–10 days

Q3: Based on your clinical experience, please indicate your antimicrobial selection criteria for pneumonia caused by PNSP. What microbial, disease or patient factor(s) dictate your choice?

For adult patients with comorbidities (such as diabetes mellitus and chronic obstructive pulmonary disease), or who are immunocompromised or have COVID-19 co-infection with bacterial pneumonia, my recommendations for antimicrobial therapy for pneumonia caused by PNSP are fluoroquinolones and fifth generation cephalosporins, based on my clinical experience. For patients with renal insufficiency, glycopeptides should be avoided.

Q4: What is your treatment experience with fluoroquinolones (e.g. levofloxacin) for pneumonia caused by PNSP? Please provide common indications for use of conventional dose or high-dose levofloxacin in your clinic, and observed patient responses in terms of efficacy and safety.

Based on my clinical experience, levofloxacin therapy of high-dose (750 mg) and short course (rapid de-escalation from IV to oral route) is preferred owing to the treatment’s favourable efficacy and safety in patients with pneumonia caused by PNSP. This therapeutic approach is especially important in the era of the COVID-19 pandemic and co-infection with bacterial pneumonia, in order to combat the emergence and transmission of MDR strains.

References

1. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. Atlanta, GA: Centers for Disease Control and Prevention.
2. World Health Organization. Citing websites: Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics. Available at: https://www.aidsdatahub.org/sites/default/files/resource/who-global-priority-list-antibiotic-resistant-bacteria.pdf. Accessed 27 October 2022.
3. Tsai YT, et al. J Microbiol Immunol Infect 2022;55(2):215–
4. Zhou ML, et al. J Microbiol Immunol Infect 2022;55(5):870–
5. PL Ho, et al. Reducing bacterial resistance with IMPACT. 5^th Hong Kong: 2017.
6. Chou CC, et al. J Microbiol Immunol Infect 2019;52(1):172–
7. Metlay JP, et al. Am J Respir Crit Care Med 2019;200(7):e45–