Understanding the Scope of Levofloxacin in Lower Respiratory Tract Infections

LRTI Burden: Demographic Review

LRTI has an incidence of about 20–30% in developing countries and about 3–4% in developed countries. [2] Age, gender, nature of work, environment, and seasons are the risk factors affecting the incidence of LRTIs. As reported by WHO, LRTI causes 5.2% of total deaths worldwide, which is the highest in the Southeast Asian region [3]. Nearly 15.5% of pediatric mortality cases are due to LRTI globally [4]. Even though international efforts like the Millennium Development Goals (MDG) have successfully reduced the disease burden, the results are inconsistent globally [5]. Indian Council of Medical Research (ICMR) has reported data on the total number of culture-positive cases in 2020. Out of 65,561 culture-positive cases, 10,557 were from lower respiratory tract infections [6]. An Indian study published in 2021 found that LRTI and LRTI-associated hospitalization incidences were 248.3 per 1000 person-years among older adults [7].

Definition of LRTI

The European Respiratory Society (ERS), in collaboration with The European Society for Clinical Microbiology and Infectious Diseases (ESCMID), has published updated guidelines on the definitions and management of LRTIs. LRTI is defined as 'an acute illness (present for 21 days or less), usually with cough as the primary symptom, with at least one other lower respiratory tract symptom (sputum production, dyspnoea, wheeze or chest discomfort/pain) and no alternative explanation (e.g., sinusitis or asthma [8]). It is a broad description of a group of disease entities, encompassing acute bronchitis, pneumonia, and exacerbations of chronic lung disease. [8]

LRTIs could be broadly grouped into the following four types [9]:

Community-Acquired pneumonia (CAP)	Acute pulmonary parenchyma infection that is associated with at least symptoms of acute infection, accompanied by the presence of an acute infiltrate on a chest radiograph, or auscultatory findings consistent with pneumonia in a patient not hospitalized or residing in a long-term-care facility for 14 days before the onset of symptoms.
Acute Bronchitis	The acute onset of a cough, with the production of sputum, in a patient with no history of chronic pulmonary disease and without evidence of pneumonia or sinusitis.
Acute Exacerbation of COPD (AECOPD)	A combination of, or all three of; worsening of dyspnoea, increase in sputum purulence and increase in sputum volume as well as one of the following clinical criteria: an upper respiratory tract infection in the past 5 days; fever without another apparent cause; increased wheezing; increased cough or increase in respiratory rate or heart rate by 20% above baseline.
Acute Infectious Exacerbation of Asthma	The acute onset of an increase in asthma symptoms (e.g. dyspnoea, wheeze) and a productive cough (an increase and/or color change in green/yellow of sputum).

What causes LRTI?

There are no explicitly recognized causative agents for LRTIs, and most of them are due to viruses and atypical pathogens secondarily infected by bacteria. Among the bacteria, both gram-positive and negative are the causative agents. [2]

Medical management of LRTIs

As per the published guidelines by the European Respiratory Society (ERS) and The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) on the management of lower respiratory tract infections (LRTI), the following are some of the recommendations [8].

• Recommendation 1: Cough suppressants, expectorants, mucolytics, antihistamines, inhaled corticosteroids, and bronchodilators should not be prescribed in acute LRTI in primary care.
• Recommendations 2: Antibiotic treatment should be prescribed in patients with suspected or definite pneumonia.
• Recommendation 3: Antibiotic treatment should be considered for patients with LRTI and serious co-morbidity like selected exacerbations of COPD, cardiac failure, insulin-dependent diabetes mellitus, or a serious neurological disorder.
• Recommendation 4: An antibiotic should be given in exacerbations of COPD in patients with all three of the following symptoms like increased dyspnoea, sputum volume, and sputum purulence.
• Recommendation 5: Amoxicillin or tetracycline should be the first antibiotic choice. In case of hypersensitivity, a tetracycline or macrolide such as azithromycin, clarithromycin, erythromycin or roxithromycin is a good alternative in countries with low pneumococcal resistance.
• Recommendation 6: The empirical use of antiviral treatment in patients suspected of having influenza is usually not recommended.
• Recommendation 7: Antibiotic treatment should be initiated immediately after diagnosis of Community-acquired pneumonia. Aminopenicillin with or without macrolides, Aminopenicillin or b-lactamase inhibitor with or without macrolide, non-antipseudomonal cephalosporin, Cefotaxime or ceftriaxone with or without macrolide, Levofloxacin, Moxifloxacin, Penicillin G with or without macrolide are the empirical antibiotics of choice.

ICMR Indian Guidelines for CAP [10]:

• All patients with CAP should be risk stratified for the site of care as outpatients or inpatients based on scores such as CURB -65/ CRB-65 (confusion, uremia, respiratory rate, BP, age ≥ 65 years), clinical assessment, and pulse oximetry. The duration of therapy in outpatients is 5 days and 7 days for inpatients based on clinical improvement.
• Antibiotics should be administered as early as possible in severe CAP and the choice of antibiotics depends on various factors including the severity of disease, presence or absence of co-morbidities, likely pathogen, likely resistance pattern, and previous antibiotic use.
• The antibiotic therapy is geared toward covering S. pneumonia the commonest pathogen in CAP.
• The recommended dosage of Levofloxacin, when indicated, is 750 mg once daily PO or IV in adults and 10-15 mg/kg in one or two divided doses PO or IV in pediatric cases.

Levofloxacin:

Levofloxacin is a broad-spectrum, third-generation fluoroquinolone, and optically active L-isomer of Ofloxacin. It is widely used in the treatment of mild-to-moderate respiratory and urinary tract infections due to sensitive organisms. It diffuses through the bacterial cell wall and acts by inhibiting DNA gyrase leading to the blockage of bacterial cell growth [11].

Levofloxacin for LRTIs:

The updated guidelines by ERS and ESCMID recommend Levofloxacin for the following [8]:

• Community-acquired Pneumonia.
• In patients with risk factors for P.aeruginosa infections, 750mg/24 h or 500mg twice daily with or without non-antipseudomonal cephalosporin III.
• For highly resistant S.pnuemonia infections (>8mg/dl), MSSA, Ampicillin-resistant H. influenzae, Mycoplasma pneumonia, Chlamydophila pneumonia, Legionella spp., Coxiella burnetii infections.
• Levofloxacin (750 mg/24 h) over 5 days may be used to effectively treat acute exacerbations of COPD in patients requiring hospitalization and for exacerbations of bronchiectasis.

FDA-approved dosages in the USA, and Canada [12]
Nosocomal Pnuemonia	750 mg/day for 7 -- 14 days
Community-acquired pneumonia	500 mg/day for 7 -- 14 days or 750 mg/ day for 5 days
Acute exacerbations of Chronic Bronchitis	500 mg/day for 7 days
Acute bacterial sinusitis	750 mg/day for 5 days
ERS guidelines
Hospitalized CAP	500 mg twice a day or 750 mg/day
HAP	750 mg/day
Acute exacerbation of Chronic Bronchitis	750 mg/day or 500 mg twice daily in patients with risk of pseudomonas infections.

Levofloxacin in Respiratory Infections: Review of Scientific Literature:

• Antony Torres et al. in their study put forth that Levofloxacin has high levels of susceptibility among Gram-negative, Gram-positive (including penicillin-resistant strains of Streptococcus pneumonia), and atypical pathogens. It is recommended for community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and in the management of acute exacerbations of chronic bronchitis (AECB) as it has good safety, bioavailability, and tissue penetration, thus maintaining adequate concentrations at the site of infection. They suggested a high-dose of 750 mg for a short duration of 5 days for improved treatment, especially in HAP [12].
• Izadi et al. investigated the efficacy of oral Levofloxacin, 750 mg, once daily for five days versus parenteral Ceftriaxone 1gr BD, plus oral Azithromycin (250 mg, once daily) for seven to ten days (standard regimen) in CAP treatment among 150 patients. They found that monotherapy with oral Levofloxacin was as effective as treatment with Ceftriaxone plus Azithromycin combination in patients with CAP who required hospitalization. [13]
• Siva et al. studied the effect of Levofloxacin 500mg once daily for seven days versus placebo on neutrophilic airway inflammation in stable COPD. They concluded that levofloxacin treatment caused a short-term reduction in bacterial load and was associated with a decrease in neutrophilic airway inflammation in patients with high bacterial loads. [14]

Take home points:

• Levofloxacin is the optically active S-isomer of ofloxacin, which is a racemic mixture.
• It is safe and well tolerated with an efficacious pharmacokinetic profile allowing for a single daily dosage and hence a clinically effective antimicrobial agent for the treatment of many infections.
• It penetrates well into the sputum and bronchial secretions and is hence highly effective in patients with respiratory infections.
• It is active against most respiratory pathogens and is the preferred drug for CAP, HAP, and AECOPD.
• Levofloxacin can be used in treating infections where the causative agent is unknown and also in debilitated individuals. It also helps in the short-term reduction of the bacterial load in patients with neutrophilic airway inflammation.
• Levofloxacin has a scientifically demonstrated clinical success rate and favorable pharmacological profile. It helps minimize hospitalizations, thus decreasing the costs and improving the life span of patients.

References:

1. Feldman C, Shaddock E. Epidemiology of lower respiratory tract infections in adults. Expert Rev Respir Med. 2019;13(1):63-77. doi:10.1080/17476348.2019.1555040.
2. Vijay S, Dalela G. Prevalence of LRTI in Patients Presenting with Productive Cough and Their Antibiotic Resistance Pattern. J Clin Diagn Res. 2016;10(1): DC09-DC12. doi:10.7860/JCDR/2016/17855.7082.
3. Thukral S, Saxena S. PREVALENCE OF LOWER RESPIRATORY TRACT INFECTION AMONG PATIENTS IN A TERTIARY CARE HOSPITAL IN NORTH INDIA. Plant Archives. 2019;19(2):2191-94. e-ISSN:2581-6063 (online), ISSN:0972-5210.
4. Ciptaningtyas VR, De Mast Q, De Jonge MI. The burden and etiology of lower respiratory tract infections in children under five years of age in Indonesia. J Infect Dev Ctries
   . 2021;15(5):603-614. Published 2021 May 31. doi:10.3855/jidc.14268
5. Feddema JJ, van der Geest AM, Claassen E, van de Burgwal LHM. Lower Respiratory Tract Infection Trends in East and South-East Asia: In the Light of Economic and Health Care Development. Glob Pediatr Health. 2021;8:2333794X21989530. Published 2021 Jan 24. doi:10.1177/2333794X21989530.
6. AMRSN_annual_report_2020_1.pdf(icmr.nic.in)
   https://main.icmr.nic.in/sites/default/files/upload_documents/AMRSN_annual_report_2020_1.pdf
7. Kumar R, Dar L, Amarchand R, et al. Incidence, risk factors, and viral etiology of community-acquired acute lower respiratory tract infection among older adults in rural north India. J Glob Health. 2021;11:04027. Published 2021 Apr 3. doi:10.7189/jogh.11.04027
8. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections--full version.
   Clin Microbiol Infect. 2011;17 Suppl 6(Suppl 6): E1-E59. doi:10.1111/j.1469-0691.2011.03672.x
9. Greene G, Hood K, Little P, et al. Towards clinical definitions of lower respiratory tract infection (LRTI) for research and primary care practice in Europe: an international consensus study. Prim Care Respir J. 2011;20(3):299-306. doi:10.4104/pcrj.2011.00034
10. Treatment Guidelines for Antimicrobial Use in common syndromes 2019 New Delhi, India.
    https://main.icmr.nic.in/sites/default/files/guidelines/Treatment_guidelines_2019_Final.pdf.

11. National Center for Biotechnology Information. PubChem Compound Summary for CID 149096, Levofloxacin. https://pubchem.ncbi.nlm.nih.gov/compound/levofloxacin. Accessed Aug. 1, 2022.
12. Torres A, Liapikou A. Levofloxacin for the treatment of respiratory tract infections. Expert Opin Pharmacother
    . 2012;13(8):1203-1212. doi:10.1517/14656566.2012.688952
13. Izadi M, Dadsetan B, Najafi Z, et al. Levofloxacin Versus Ceftriaxone and Azithromycin Combination in the Treatment of Community-Acquired Pneumonia in Hospitalized Patients. Recent Pat Antiinfect Drug Discov. 2018;13(3):228-239. doi:10.2174/1574891X13666181024154526.
14. Siva R, Bafadhel M, Monteiro W, Brightling CE, Pavord ID. Effect of levofloxacin on neutrophilic airway inflammation in stable COPD: a randomized, double-blind, placebo-controlled trial.
    Int J Chron Obstruct Pulmon Dis. 2014;9:179-186. Published 2014 Feb 7. doi:10.2147/COPD.S55419