Faropenem: A Breakthrough in the Fight against Community-Acquired Pneumonia and Drug-Resistant Respiratory Tract Infections Pathogens

Understanding The Common Bacterial Pathogens in CAP: Recent Insights from India: CAP is commonly caused by Streptococcus pneumoniae, which is responsible for almost 50% of cases. Other common causes include respiratory viruses, such as influenza A, and atypical bacteria like Chlamydophila pneumoniae and Mycoplasma pneumoniae. Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, and Legionella pneumophila are less frequent bacterial causes. The lungs can be infected by these microorganisms through inhalation of droplets or micro aspiration after colonisation of the nasopharynx with culprit pathogens. [2]

According to a systematic review conducted in India, S. pneumoniae was the primary pathogen responsible for CAP, accounting for 19% of cases with a pooled proportion of 12-26% (95% confidence interval) and I^.2 (I squared statistic) value of 94.5% (P<0.01). Other pathogens identified included M. pneumoniae (15.5%), Klebsiella.pneumoniae (10.5%), and L. pneumophila (7.3%). [3]

Alarming Rise in Resistant Respiratory Tract Infections Pathogens, Extended-spectrum β-lactamases

The emergence of antibiotic-resistant pathogenic organisms has become a major obstacle to the effective treatment of infectious diseases globally, both in community and healthcare settings. Multidrug-resistant pathogens, including Escherichia coli, K.pneumoniae, Acinetobacter baumannii, Streptococcus pneumoniae, Enterococcus, and extensively drug-resistant Mycobacterium tuberculosis, are of significant concern.

The frequent use of β-lactam antibiotics has led to the continuous development and mutation of β-lactamases, including extended-spectrum β-lactamases (ESBLs), which can inactivate newly developed β-lactam antibiotics. The rise in ESBL-related infections worldwide presents a significant scientific challenge for the treatment of these multidrug-resistant organisms. [4] ESBLs are a group of enzymes that can degrade antibiotics, making them less effective in treating bacterial infections. These enzymes are encoded by genes that can move between different bacteria, resulting in the spread of antibiotic resistance. There are different types of enzymes that can cleave the chemical bonds present in antibiotics, making them ineffective. Moreover, some pathogenic bacteria can also modify antibiotics through oxidation or reduction processes. [4]

Current Antibacterial Agents for CAP: Clinical Efficacy and Failure Rates

Macrolides, amoxicillin, fluoroquinolones, and third-generation cephalosporins are commonly used to treat CAP. However, antimicrobial resistance is increasing globally, making these treatments less effective. S. pneumoniae and atypical pathogens are increasingly resistant to macrolides, emphasising the need for new antibiotics. There is a lack of newly developed oral antimicrobial therapies for CAP, and while fluoroquinolones remain an option, their tolerability and safety profiles may be inconsistent across patient populations. [5]

The emergence of antibiotic-resistant strains of Staphylococci and S. pneumoniae has made the treatment of CAP more challenging. This has led to the failure of initial empiric therapy for CAP, which is linked to poor clinical outcomes. The development of new antimicrobial agents offers a promising avenue for improving the management of resistant CAP pathogens and enhancing initial empiric therapy. [5]

Faropenem: Meeting Unmet Needs & Rationale for Use in the Treatment of CAP

S. pneumoniae strains have developed resistance to penicillin, making it necessary to develop new antimicrobials for community-acquired respiratory tract infections. Faropenem, a novel β-lactam with a penem structure, is being developed as an oral therapy. Studies have shown that it has broad-spectrum antibacterial activity, and there is a growing interest in its efficacy against respiratory pathogens such as S. pneumoniae, H. influenzae, and M. catarrhalis. [6]

The chiral tetrahydrofuran substituent present in Faropenem is responsible for its improved stability and decreased CNS effects. It has good bioavailability after oral administration and is stable to hydrolysis. Faropenem has been seen to have postantibiotic effect which means that it has better and more bacteriological eradication outcomes. It does not induce AmpC β-lactamase production in Enterobacteriaceae. [7]

Key Features of Faropenem: A Safe and Effective Oral Penem with ESBL Stability

Faropenem exhibits resistance to hydrolysis by nearly all β-lactamases and shows broad-spectrum in vitro antimicrobial activity against various Gram-positive and Gram-negative bacteria. Prior research conducted with faropenem using a broad range of multidrug-resistant Gram-positive and Gram-negative bacterial species revealed satisfactory effectiveness overall, except for methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium, and Acinetobacter spp., which were predominantly resistant.[8]

Faropenem is a unique carbapenem that can be taken orally, which sets it apart from other carbapenems that are restricted to intravenous administration. Pharmacokinetic studies have shown faropenem levels in blood can reach up to 14 mg/L using two daily doses of 300 mg. Faropenem also appears to have stable bactericidal activity in serum, making it a potential option for the treatment of susceptible bacterial pathogens. [8]

Clinical Application of Faropenem in India

Clinicians in India often prescribe faropenem, an oral antibiotic belonging to the penems class, as a treatment option for ESBL-producing Enterobacteriaceae, despite the availability of carbapenems. This has led to a significant increase in the consumption of faropenem in India, surpassing the consumption of carbapenems. [9] Faropenem is currently registered for use in India.[10]

Clinical Evidence of Faropenem in Treatment of CAP and RTI Pathogens

A study determined the in vitro activities of Faropenem and other antimicrobial agents against 4,725 S.pneumoniae isolates, 2,614 H.influenzae isolates, and 1,193 M. catarrhalis isolates. Faropenem minimal inhibitory concentrations (MICs) at which 90% of isolates are inhibited were 0.008, 0.25, and 1 μg/ml for penicillin-susceptible, -intermediate, and -resistant S. pneumoniae strains, respectively; 0.5 and 1 μg/ml for β-lactamase-positive and H. influenzae strains, respectively; and 0.12 and 0.5 μg/ml for β-lactamase-negative and β-lactamase-positive M. catarrhalis strains, respectively. Faropenem holds promise as an oral therapy for community-acquired respiratory tract infections.[6]

In a multicenter noninferiority trial conducted in multiple regions, the effectiveness and safety of faropenem medoxomil and amoxicillin in treating community-acquired pneumonia were compared. Patients were randomly assigned to either faropenem 300 mg twice daily for 10 days or amoxicillin 1000 mg three times daily for 10 days. The primary outcome was clinical cure within 6-16 days after finishing the treatment regimen. The study concluded that faropenem was noninferior to amoxicillin in treating community-acquired pneumonia as both had similar cure rates (91.5% vs 88.4%). The cure rates remained comparable even after 28-35 days post-treatment. Adverse effects were mild gastrointestinal events and occurred similarly between both groups. [11]

A pooled analysis of 5023 subjects from Phase 2 and 3 trials was conducted to evaluate the safety profile of faropenem medoxomil. The most commonly reported adverse events were gastrointestinal, but the incidence did not differ between faropenem and other antibiotics. Additionally, there were no significant differences in the risk of serious adverse reactions or death between faropenem and the other used antibiotics. Overall, the authors concluded that the benefit–risk ratio of faropenem makes it a reasonable choice for first-line treatment of community-acquired infections. [11]

Case Studies on Faropenem

• A patient with community-acquired pneumonia was diagnosed with Streptococcus infection, which was resistant to most drugs. The patient's co-morbidities and drug resistance of the organism made treatment challenging. Faropenem was prescribed orally for one week, and the patient showed significant improvement within two days and complete resolution of symptoms by day five. [10]
• In a case report by Tanaka et al., a 63-year-old hepatitis C-positive patient with a recurrent pulmonary infection caused by Mycobacterium abscess was successfully treated with faropenem. The patient showed improvement within two weeks of initiating faropenem and clarithromycin and continued the regimen for 12 months without incident. The isolate showed susceptibility to both faropenem and clarithromycin, prompting the initiation of this treatment.[11]

Conclusion

CAP is a significant cause of morbidity and mortality in India, with increasing antibiotic resistance, particularly the production of ESBLs in respiratory tract infections, posing a challenge for clinicians. Current antibiotics have variable clinical success rates, leading to an unmet need for effective and convenient oral treatment options. Faropenem, a new oral penem antibiotic with a hybrid structure providing intrinsic stability against ESBLs, shows promise in treating respiratory tract infections. Faropenem presents a potentially valuable consideration to address the limitations of current treatment options and combat antibiotic resistance.

References

1. Preeti Nagkumar, K., Bhadra Reddy, C., Hima Bindu, M., & Mallikarjuna Reddy, C. (2021). Risk factors of community acquired pneumonia among the elderly population: A study in a semi urban area. Indian Journal of Immunology and Respiratory Medicine, 6(2), 125–129.

2. Brown, J. S. (2012). Community-acquired pneumonia. Clinical Medicine (London, England), 12(6), 538–543.

3. Eshwara, V. K., Mukhopadhyay, C., & Rello, J. (2020). Community-acquired bacterial pneumonia in adults: An update. The Indian Journal of Medical Research, 151(4), 287–302.

4. Shaikh, S., Fatima, J., Shakil, S., Rizvi, S. M. D., & Kamal, M. A. (2015). Antibiotic resistance and extended spectrum beta-lactamases: Types, epidemiology and treatment. Saudi Journal of Biological Sciences, 22(1), 90–101.

5. Sharma, R., Sandrock, C. E., Meehan, J., & Theriault, N. (2020). Community-acquired bacterial pneumonia-changing epidemiology, resistance patterns, and newer antibiotics: Spotlight on delafloxacin. Clinical Drug Investigation, 40(10), 947–960.

6. Critchley, I. A., Karlowsky, J. A., Draghi, D. C., Jones, M. E., Thornsberry, C., Murfitt, K., & Sahm, D. F. (2002). Activities of Faropenem, an Oral β-Lactam, against Recent U.S. Isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrobial Agents and Chemotherapy, 46(2), 550–555.

7. Schurek, Kristen N; Wiebe, Ryan; Karlowsky, James A; Rubinstein, Ethan; Hoban, Daryl J; Zhanel, George G (2007). Faropenem: review of a new oral penem. Expert Review of Anti-infective Therapy, 5(2), 185–198.

8. Feng, X.-W., Shao, J.-D., Ji, Z.-K., Fang, H., Ding, C., Wang, S.-T., Shang-Guan, Y.-W., Shi, P., Li, L.-J., & Xu, K.-J. (2020). Faropenem susceptibility of multidrug-resistant contemporary clinical isolates from Zhejiang province, China. Infectious Microbes & Diseases, 2(1), 26–29.

9. Gandra, S., Klein, E. Y., Pant, S., Malhotra-Kumar, S., & Laxminarayan, R. (2016). Faropenem consumption is increasing in India. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 62(8), 1050–1052.

10. Balamurugan, S. (2015). Management of the community acquired respiratory tract infections with co-morbidities. Indian Journal of Case Reports, 1(1), 24–27

11. Gettig, J. P., Crank, C. W., & Philbrick, A. H. (2008). Faropenem medoxomil. The Annals of Pharmacotherapy, 42(1), 80–90. https://doi.org/10.1345/aph.1G23