Community-acquired pneumonia: Insights into macrolide resistance and a review of levofloxacin use

5 July, 2021

Dr Ton That Viet Hung
Vice Director, Chief of Department of Examination
Tam Tri Da Nang Hospital
Vietnam

According to the Survey of Antibiotic Resistance (SOAR) – an ongoing surveillance study of key respiratory pathogens – susceptibility to macrolides in South Korea was relatively low at 20% and 50% to 60% in other Asian countries (Thailand, India and Singapore).¹ The Asian Network for Surveillance of Resistant Pathogens (ANSORP) has also reported a high prevalence of macrolide resistance in Streptococcus pneumoniae isolates.²Levofloxacin is a well established treatment option for respiratory tract infections (RTI) particularly since it is active against some macrolide-resistant respiratory pathogens.³

Dr Ton That Viet Hung – Vice Director of the Tam Tri Da Nang Hospital – provides an overview of macrolide resistance in respiratory pathogens in Vietnam and discusses the efficacy and safety of levofloxacin for the treatment of RTI.

Q1. Please describe the aetiology and epidemiology profiles of community-acquired pneumonia (CAP) in Vietnam.

CAP is a leading cause of morbidity and mortality worldwide.⁴ The clinical presentation of CAP varies – ranging from mild pneumonia characterised by fever and productive cough to severe pneumonia characterised by respiratory distress and sepsis. Owing to its wide spectrum of clinical features, the differential diagnosis of CAP is included in nearly all respiratory illnesses.

Vietnam is one of the developing countries with a high annual rate of CAP – especially among children under five years old and adults over 65 years old.^5,6 The risk factors for CAP include:

Old age (65 years and above)
Chronic comorbidities, including chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, chronic heart disease (particularly congestive heart failure), stroke, diabetes mellitus, malnutrition, and immunocompromising conditions
Viral respiratory tract infection
Impaired airway protection
Smoking and alcohol overuse
Other lifestyle factors such as crowded living conditions (e.g., prison, shelters for homeless), residence in low income settings, and exposure to environmental toxins (e.g., solvents, paints, and gasoline)

Streptococcus pneumoniae is the most common bacterial cause of CAP.⁶ Other causative pathogens include Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus. Atypical bacteria such as Mycoplasma pneumoniae, Legionella spp and Chlamydia pneumoniae,⁵ respiratory viruses including Influenza A and B, as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are also implicated in CAP cases.

Q2. In Vietnam, what is the susceptibility profile of macrolide-resistant CAP pathogens?

Strategies for the empirical treatment of CAP are often complicated by the shifting aetiologies and the emergence of drug-resistant pathogens. S. pneumoniae has long been identified as the most important causative pathogen in adult CAP, followed by H. influenzae, M. catarrhalis, and S. aureus.⁶ However, recent studies have documented an increased incidence of pneumonia due to atypical pathogens (e.g., L. pneumophila, M. pneumoniae and C. pneumoniae) and Gram negative bacteria.⁵ Of additional concern is the increasing incidence of resistance to previously effective antimicrobial agents. The incidence of S. pneumoniae cases that are multidrug-resistant (MDR; i.e., resistant to ≥3 antimicrobial classes) has increased. The most common MDR phenotype identified in S. pneumoniae exhibits resistance to penicillin, azithromycin (macrolides) and trimethoprim-sulfamethoxazole.¹

In Vietnam, macrolides (azithromycin and clarithromycin), amoxicillin, doxycycline, respiratory fluoroquinolones (levofloxacin and moxifloxacin) are used as first-line treatment for outpatients with CAP; macrolides are not recommended for the treatment of hospitalised patients with CAP.

The ANSORP study demonstrated a high prevalence of antimicrobial resistance among clinical S. pneumoniae isolates in Asia.² The rate of erythromycin resistance were relatively high in Vietnam (92.1%), Taiwan (86%), Korea (80.6%), Hong Kong (76.8%) and China (73.9%). The minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC₉₀) value for erythromycin was >32 mg/L. As a result, erythromycin has largely been replaced with clarithromycin (a newer macrolide) and azithromycin (an azalide). However, it is important to note that most pneumococci that are resistant to erythromycin are also resistant to the newer macrolides and azalides.

Q3. What are the next steps after treatment failure with macrolides in CAP? Is levofloxacin (as monotherapy or combination therapy) typically used?

For most patients with CAP in which aetiology is unknown at the time of diagnosis, empiric treatment directed at common causative pathogens is appropriate. The causative pathogens of CAP vary with the severity of illness, local epidemiology, and patients’ risk factors for infection with drug-resistant organisms. For instance, the range of potential pathogens causing mild CAP in patients who are otherwise healthy in the ambulatory setting is limited whereas a more diverse range of pathogens is often implicated in patients with severe CAP requiring hospitalisation. As such, the initial treatment regimens for severe CAP are often broader.

The selection of antibiotic therapy for outpatients largely depends on the safety profiles of available agents, potential drug interactions, patients’ allergy reactions, and other patient-specific factors:

For patients aged below 65 years who are otherwise healthy and have no recently used antibiotics, we typically prescribe oral amoxicillin plus a macrolide (azithromycin or clarithromycin) or doxycycline.
For patients with major comorbidities (e.g., chronic heart, lung, kidney, or liver disease, diabetes mellitus, alcohol dependence or immunosuppression) who are smokers and have used antibiotics within the past three months, we suggest oral extended-release agents such as amoxicillin-clavulanate plus either a macrolide or doxycycline.
For patients who cannot use beta-lactams, we select a respiratory fluoroquinolone (e.g., levofloxacin, moxifloxacin and gemifloxacin); for patients with structural lung disease, we prefer using a respiratory fluoroquinolone.

Generally, clinicians ensure that all patients improve on therapy and are afebrile for at least 48 hours before stopping antibiotics. In cases of treatment failure with macrolides, we prefer using fluoroquinolone as an alternative.

For inpatients, we initiate antibiotic therapy as soon as we are confident that CAP is the appropriate working diagnosis – ideally within four hours of presentation. A delay in antibiotic treatment exceeding four hours has been associated with increased mortality.

For patients without suspicion of methicillin-resistant aureus (MRSA) or Pseudomonas, we use one of two regimens: combination therapy with a beta-lactam and a macrolide or monotherapy with a respiratory fluoroquinolone.
For patients with known colonisation or prior infection with Pseudomonas and recent hospitalisation with intravenous (IV) antibiotic use, we typically use combination therapy with both antipseudomonal beta-lactam (e.g., piperacillin-tazobactam, cefepime, cetazidime and meropenem) plus an antipseudomonal fluoroquinolone (e.g., ciprofloxacin and levofloxacin).
For patients with know colonisation or prior infection with MRSA, we add an agent with anti-MRSA activity, such as vancomycin and linezolid.

Q4. What are the common indications for high-dose and conventional dose levofloxacin in Vietnam? Are there any differences in both dosing regimens in terms of efficacy and safety?

Levofloxacin is a concentration-dependent antimicrobial agent, with therapeutic outcomes most closely linked to the ratio of the area under the concentration-time curve (AUC) to MIC for the organism rather than the time of concentration greater than MIC.⁷ Furthermore, a high peak plasma concentration (C_max) to MIC ratio has been associated with the emergence of antimicrobial resistance. By exploiting these pharmacodynamic parameters in terms of dose increment, i.e. increasing the C_max and AUC, the duration of treatment can be shortened without compromising efficacy:

For hospitalised patients with mild to moderate CAP who cannot take combination therapy of beta-lactam plus macrolide, we suggest monotherapy with a high-dose levofloxacin (750 mg) for five days.
For hospitalised patients with severe CAP or requiring ICU care, we suggest an initial combination therapy with an antipneumococcal beta-lactam (ceftriaxone, cefotaxime, amoxicillin-sulbactam) plus a respiratory fluoroquinolone (i.e., levofloxacin) – either with a 500 mg or 750 mg dose depending on the patient’s condition.
For patients at risk of Pseudomonas or drug-resistant pathogen infections, coverage for these pathogens should be included i.e., piperacillin-tazobactam, ceftazidime or meropenem plus an antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin 750 mg).
For patients with MRSA infection risk factors, we suggest the addition of either vancomycin or linezolid.

It is noteworthy that there are no differences in both dosage of levofloxacin (500 mg and 750 mg) in terms of efficacy and safety profile.

Q5. Is the high-dose, short course levofloxacin beneficial for CAP patients with comorbidities and those with non-severe CAP? What are your considerations when prescribing this regimen?

The high dose, short course levofloxacin is beneficial for CAP patients with comorbidities and those with non-severe CAP. In a multicentre, randomised, double-blind investigation comparing levofloxacin dosages of 750 mg per day for five days with 500 mg per day for 10 days for the treatment of mild to severe CAP, the clinical success rates were 92.4% for the 750 mg group and 91.1% for the 500 mg group (95%CI -7.0–4.4).⁸ Microbiologic eradication rates were 93.2% and 92.4% in the 750mg and 500mg group, respectively. These findings suggest that levofloxacin 750 mg per day for five days is as effective as the 500 mg per day for 10 days regimen for the treatment of mild to severe CAP. As such, it is possible to increase peak concentration of levofloxacin by increasing the daily dose to take advantage of its pharmacodynamic properties while shortening the duration of drug exposure and total dose exposure – without compromising the efficacy and safety profile of levofloxacin in the management of CAP. This is in line with our clinical practice, in which levofloxacin 750 mg per day for five days is commonly used for the treatment of patients with mild to severe CAP.