Gram-negative pneumonia: combination therapy and the role of quinolones

6 July, 2022

Dr Tran Thi Phuong Thuy

Infectious disease specialist
Chief of Unit for Tropical diseases
Vinmec Times City International Hospital
Vietnam

Combination antibiotic therapy has been recommended by several medical societies for the treatment of pneumonia, particularly for patients, with invasive infections caused by gram-negative bacteria.¹ Available evidence suggests that empirical use of quinolones in combination therapy may provide beneficial outcomes, owing to their relatively broad spectrum of antimicrobial activity and acceptable safety profile.²

Dr Thuy discusses her experiences in the treatment of gram-negative pneumonia with combination therapy and her insights on the role of the quinolone levofloxacin in combination therapy.

Q1: What is your approach to the treatment of gram-negative pneumonia?

In Vietnam, gram-negative bacteria (GNB) are the most frequently isolated organisms in samples from patients with lower respiratory tract infections. For instance, annual microbiological reports from the Vinmec International Hospital showed that GNB comprised approximately 80–85% of the isolated bacteria from either sputum or bronchoalveolar lavage fluid samples. While GNB are only found in 8–15% cases of community-acquired pneumonia (CAP), these organisms account for acute respiratory failure, severe sepsis or septic shock significantly more frequently compared with gram-positive bacteria.³ Patients with CAP due to GNB infection also require intensive care unit (ICU) admission and mechanical ventilation more frequently.³Moreover, GNB are the most common cause of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP); GNB may be present in up to 90% of cases.⁴ Notably, HAP accounts for the majority (79.4%) of hospital-acquired infection in ICU settings in Vietnam, which leads to prolonged hospital stays, increased expenses and patient mortality.⁵ GNB are the most frequently implicated pathogenic bacteria in HAP, the predominant organisms being multidrug resistant (MDR) Pseudomonas aeruginosa and Acinetobacter baumannii.

Approach to the treatment of gram-negative pneumonia

We follow the American Thoracic Society / Infectious Diseases Society of America (ATS/ IDSA) guidelines in the clinical approach to patients with gram-negative pneumonia.⁶ Based on the guidelines, all hospitalised patients with pneumonia will have lower respiratory tract samples collected before initiating antibiotic treatment. Regular pre-treatment sampling includes sputum specimens and two blood cultures, except in an outpatient setting. Other specimens may also be collected based on the clinical judgement of the physician in charge, such as blood, pleural fluid, bronchoalveolar lavage specimen, bronchoscopic aspirate or endotracheal aspirate. Recommendations for empiric antimicrobial therapy of CAP and HAP/VAP in adult gram-negative pneumonia are summarised as follows.

For patients with suspected CAP:
- As GNB are not commonly isolated from patients with CAP, we do not empirically start specific treatment for MDR-GNB. Treatment will be switched if the culture indicates the presence of GNB.
- Monitoring: Assess response after 48–72 hours and 5–7 days
- Duration of therapy: Usually 5–7 days
For patients with suspected HAP/VAP:
- Empiric treatment must target staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacilli. The choice of antibiotic is based on the severity of infection and risk of MDR pathogens.⁶ Early evaluation of all risk factors for MDR pathogens is performed routinely in our hospital.
- The decision to initiate antibiotic therapy should involve clinical criteria alone, rather than using C-reactive protein (CRP) or serum procalcitonin (PCT) plus clinical criteria. However, PCT levels plus clinical criteria could be used to guide the discontinuation of antibiotic therapy in patients with HAP/VAP.
- Monitoring: Assess response after 48–72 hours and 5–7 days. Consider de-escalation of antibiotics if appropriate, based on the results of culture susceptibility.
- Duration of therapy: Usually 7 days, depending on the clinical symptoms, PCT level and the isolated pathogen. In severe cases or with MDR pathogens, a 14-day duration of treatment is recommended.

Q2: In your experience, what are the key patient, bacterial or disease characteristics that may indicate a need for combination therapy (double coverage) for the treatment of gram-negative pneumonia?

Therapy that incorporates 2 antipseudomonal antibiotics in combination are indicated in cases of:⁴

Patients with high risk of mortality who have septic shock, need for ventilation support due to pneumonia (including CAP and HAP) or VAP.
HAP/VAP patients with risk factors for MDR and local prevalence rates of MDR-GNB of more than 10%. Risk factors for MDR include intravenous antibiotic use within 90 days prior, long ICU stay, and history of MDR-GNB infection.
Patients with infections caused by bacteria that are commonly identified as MDR pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia.

In Vietnam, all HAP/VAP patients with high risk for MDR are empirically treated with double coverage for GNB because of the extremely high prevalence of MDR-GNB causing pneumonia, especially in the ICU setting.

Q3: With the emergence of multidrug-resistant (MDR) gram-negative organisms, what are your opinions regarding combination therapy for the treatment of gram-negative pneumonia?

In Vietnam, the prevalence of antimicrobial resistance is quite alarming. Data published in the 2020 Microbiological report from the VNASS (Viet Nam Antimicrobial Resistance Surveillance System) indicated that approximately 43% of Pseudomonas aeruginosa and 83% of Acinetobacter baumannii were MDR organisms.

I am in agreement with the IDSA guidelines on the use of a combination of antibiotics for the treatment of GNB in severe HAP/VAP cases for several reasons:

In severe cases of HAP/VAP, combination therapy decreases treatment failure and mortality.
The emergence of resistance may be curbed owing to the synergistic activity of the drugs.

However, there are drawbacks to using antibiotic combinations:

Expense.
The potential for more adverse effects.
The potential for overuse of antibiotics if not regulated.

To minimise the risk of overuse, Vinmec hospitals have established antimicrobial stewardship (AMS) teams to regularly monitor antibiotic use in clinical settings. The AMS programme is a coordinated programme that aims to promote the appropriate use of antimicrobials (including antibiotics), improve patient outcomes, reduce microbial resistance, and decrease the spread of infections caused by MDR organisms. An AMS team consists of an infectious disease specialist, a microbiologist and a clinical pharmacist. Specific interventions include:

Stratification of antibiotics according to the potential of developing resistance.
Highly restricted antibiotics must receive prior approval from AMS team before initiation.
Weekly rounds in wards to review patients who have been prescribed highly restricted antimicrobials, with approval for use where the prescription is deemed appropriate.

Q4: What is the role of levofloxacin in combination antimicrobial regimens for gram-negative pneumonia? Please provide an overview of the existing evidence supporting this regimen, including dose selection and duration of treatment.

Levofloxacin is a fluoroquinolone, which is one of the non-β-lactam-base agents recommended for use in combination therapy, and has a broad spectrum of antibacterial activity against numerous gram-positive and gram-negative aerobes and atypical bacteria (Mycoplasma pneumonia, Chlamydia pneumoniae and Legionella pneumophila).⁷

Levofloxacin has pharmacokinetic and pharmacodynamic advantages for treating pneumonia, which include wide distribution in blood and lung tissue (pulmonary distribution is higher than that of ciprofloxacin);⁷ additionally, administration of 500 or 750 mg/day of levofloxacin achieves significantly higher steady-state concentrations in epithelial lining fluid and alveolar macrophages (AMs), obtained by bronchoalveolar lavage, compared to a regimen of 500 mg ciprofloxacin administered twice a day.⁷ In the USA and Canada, levofloxacin is approved for use in the treatment of:

Pneumonia nosocomial (HAP) at a dose of 750 mg/day for 7–14 days.⁷
CAP at a dose of 500 mg/day for 7–14 days or 750 mg/day for 5 days (high-dose, short-course regimen).⁷

In addition, levofloxacin shows advantages over aminoglycosides or polymyxins, other non-β-lactam-base agents, in terms of safety (no renal toxicity), convenient dosing (dose calculation is not required) and the smooth transition to oral therapy (levofloxacin is available in both an oral and injectable formulation).⁷

Q5: Which subgroup(s) of patients with gram-negative pneumonia are most likely to respond to treatment with levofloxacin?

The subgroup(s) of patients with gram-negative pneumonia that are most likely to respond to treatment with levofloxacin can be classified as follows:

For cases of CAP:
- Patients with comorbidities, e.g., diabetes, underlying pulmonary diseases (such as chronic obstructive pulmonary disease and bronchiectasis), immunosuppressive conditions [e.g., human immunodeficiency virus (HIV) and malignancies], elderly patients and patients with chronic alcoholism
- Patients with antibiotic use within 3 months prior, those with prior hospitalization, prior MDR-GNB colonization or infection, or have other risk factors for drug-resistant infection
For cases of HAP/VAP:
- Patients with early-onset infection and without risk factors for MDR pathogens (when receiving levofloxacin as monotherapy)
- Severe patient, late-onset HAP (when receiving combination therapy of levofloxacin plus another antipseudomonal agent)

References