A Review Article on Recent Advances in Drug Therapy for Pneumonia

Abstract

Reusing current medications to increase treatment options and creating new kinds of antibiotics to combat resistance are the two main areas of recent advancements in pneumonia treatment. One novel cephalosporin, cefiderocol, enters and kills bacteria by using their own iron-uptake mechanism. Against hardy, drug-resistant Gram-negative bacteria, including those resistant to carbapenems, it works incredibly well. With its ability to combat both Gram-positive (like MRSA) and Gram-negative bacteria, delafloxacin is a next-generation fluoroquinolone that performs particularly well in acidic environments, like infected lung tissue. Newer antibiotics that can be taken orally or intravenously include lefamulin, a pleuromutilin, and omadacycline, a modified tetracycline. They efficiently enter the lungs and treat both common and uncommon bacteria that cause pneumonia that is acquired in the community. New treatment options for resistant Gram-negative infections are made possible by combination therapies like imipenem-relebactam (Recarbrio) and meropenem-vaborbactam (Vabomere), which restore the effectiveness of carbapenems against the majority of resistant Enterobacterales. New antifungals such as rezafungin and ibrexafungerp represent important developments in the management of fungal pneumonias. Ibrexafungerp is an oral glucan synthase inhibitor that effectively combats invasive Candida species, while Rezafungin is a second-generation echinocandin with a long half-life that allows weekly dosing.

Keywords

Introduction

In most parts of the world, community-acquired pneumonia (CAP) is one of the major causes of death, contributing to more than 4 million deaths and about 450 million cases each year^[1]. Pneumonia has three types: hospital-acquired pneumonia (CAP), ventilator-acquired pneumonia (VAP), and hospital-acquired pneumonia (HAP). The predominant etiologies of HAP and VAP are gram-negative organisms, such as Acinetobacter baumannii, Enterobacterales, and Pseudomonas aeruginosa.In contrast, CAP is caused mostly by Streptococcus pneumoniae ^[2]. New agents and combination regimens designed to enhance tissue delivery, transcend resistance, and optimize pharmacokinetics are a result of recent medicinal chemistry advancements.This overview examines mechanisms of action and the medicinal chemistry basis for numerous notable drugs, including cefiderocol, delafloxacin, omadacycline, remdesivir, ibrexafungerp, rezafungin, ivermectin, Recarbrio, Vabomere, and lefamulin.

A possible antimicrobial therapy for HAP, especially those initiated by MDR and carbapenem-resistant gram-negative bacilli, is cefiderocol, a new-generation siderophore cephalosporin. Ceftazidime and cefepime, third- and fourth-generation cephalosporins, respectively, have molecular properties similar to cefiderocol.

Cefiderocol, however, has an exclusive catechol moiety on the C3 position of the side chain with the ability to enter the bacteria through iron chelation ^[3].

The wide range of the anionic fluoroquinolone delafloxacin encompasses unusual, gram-positive, and gram-negative animals.

The recently developed aminomethylcycline omadacycline is a semisynthetic agent of the tetracycline class. Similar to its predecessors, omadacycline has antibacterial action against a diverse group of bacteria, including gram-positive, gram-negative, anaerobic, and atypical pathogens. Methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Spneumoniae, vancomycin-resistant enterococci, and extended-spectrum b-lactamase-producing Enterobacteriaceae are all subject to the strong in vitro activity of omadacycline. The clinical safety and efficacy of madacycline for the treatment of adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infection (ABSSSI) have recently been evaluated in a number of randomized trials ^[4].

Remdesivir (GS-5734) is a ribonucleic acid (RNA)-dependent RNA polymerase inhibitor nucleoside analog that inhibits RNA-dependent RNA polymerase of SARS-CoV-27. Its broad-ranging inhibition of RNA viruses, including the Middle East Respiratory Syndrome, initially positioned it as an effective treatment for COVID-19 ^[5].

Inhibitors of the synthesis of β-(1,3)-D-glucan, a component of the cell walls of most fungi, can have highly effective, all-encompassing activity.

These compounds act on an enzyme, β-(1,3)-D-glucan synthase specific to lower eukaryotes and restrict their activity in humans ^[6]. The echinocandins were the initial glucan synthase inhibitors to be approved for use in 2001^[7].

An echinocandin derivative with longer duration of action that also acts on β-glucan synthase is named rezafungin (CD101). Its advances in medicine chemistry counteract the deficiencies of traditional echinocandins by offering enhanced solution stability, increased tissue penetration. Recarbrio™, or imipenem/cilastatin/relebactam, is an intravenous fixed-dose combination of imipenem, a carbapenem, cilastatin, a renal dehydropeptidase-I inhibitor, and relebactam, a new β-lactamase inhibitor ^[8,9]. Imipenem/cilastatin/relebactam is licensed in the United States ^[8] and European Union ^[9] for the treatment of adults with ventilator-associated bacterial pneumonia (VABP), hospital-acquired bacterial pneumonia (HABP), and other gram-negative infections, including complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs), including pyelonephritis.Two Phase III clinical trials established the clinical efficacy and tolerable safety profile of Lefamulin in oral and intravenous (IV) form as a treatment for CABP. Lefamulin is extremely effective against both Gram-positive (Streptococcus pneumoniae & Staphylococcus aureus) and Gram-negative (Moraxella catarrhalis, Neisseria spp. & Haemophilus influenzae) fastidious microorganisms, intracellular pathogens, and mycoplasmas, like Chlamydia spp. and Legionella pneumophila. Experiments on lefamulin's antibacterial activity have also been tested on the most common bacteria causing STDs ^[10]. To maximize effectiveness against resistant organisms, Vabomer (meropenem/vaborbactam) pairs a very effective β-lactamase inhibitor with a carbapenem.Although individual data for pneumonia might be shifting, its combination strategy aligns with the penetrating resistance (generalizable concept) objectives of contemporary medicinal chemistry ^[11].

Table no: 1: Types of Pneumonia

Based on ethiology	Based on site of acquisition	Based on clinical course
Bacterial pneumonia	Community-acquired pneumonia	Acute pneumonia
Viral pneumonia	Hospital-acquired pneumonia	Chronic pneumonia
Parasitic pneumonia	Ventilator-associated pneumonia
Aspiration pneumonia	Healthcare-associated pneumonia
Chemical pneumonitis

Chemical Classification of Anti-Pneumonia Drugs

I.β Lactam antibiotics: Cefiderocol, Amoxicillin, ceftriaxone,

II.Fluoroquinolones: Delafloxacin, Levofloxacin

III. Tetracyclines: Doxycycline, omadacycline

IV. RNA polymerase inhibitors: Remdesivir

V. Antiviral agent: Nirsevimab

VI. Antifungals agent: Ibrexafunger p

VII. Echinocandins:  Rezafungin

VIII. Antiparasitic: ivermectin

 IX. Pleuromutilin antibiotic: Lefamulin

X. β Lactam inhibitor: Recarbrio, vabomere

1. Cefiderocol

Fig. no. 1: Structure of Cefiderocol

Cefiderocol consists of a cephalosporin nucleus, which is a β-lactam-dihydrothiazine bicyclic ring system. Cefiderocol act by binding to penicillin-binding proteins (PBPs), especially PBP3.This inhibits transpeptidation, a key step in peptidoglycan cross-linking for bacterial cell wall synthesis. The result is cell wall instability, osmotic lysis, and bacterial cell death. It is used to treat pneumoni, serious gramnegative infections, especially those caused by multi-drug resistant (MDR) and carbapenem-resistant organisms.^[12]

2. Delafloxacin

Fig. no. 2: Structure of Delafloxacin

Delafloxacin contains a quinolone nucleus, specifically a fluoroquinolone core structure. Delafloxacin inhibits bacterial DNA replication enzymes, specifically: DNA gyrase (Topoisomerase II) – mainly in Gram-negative bacteria Topoisomerase IV – mainly in Gram-positive bacteria. These enzymes are essential for: Supercoiling and relaxation of bacterial DNA during replication, Separation of replicated DNA strands during cell division. By inhibiting these enzymes, delafloxacin prevents DNA replication and transcription, leading to bacterial cell death. it is used to treat Acute Bacterial Skin and Skin Structure Infections (ABSSSI). Community-Acquired Bacterial Pneumonia (CABP). ^[13]

3. Omadacycline

Fig. no. 3: Structure of Omadacycline

Omadacycline has a tetracycline nucleus (a four-ringed naphthacene core), specifically:> 4-ring fused tetracyclic nucleus: Known as naphthacene carboxamide. It acts by Binding to the 30S ribosomal subunit of bacteria. Blocks the binding of aminoacyl-tRNA to the mRNA-ribosome complex. Inhibits bacterial protein synthesis, resulting in bacteriostatic action.it is used to treat Community-Acquired Bacterial Pneumonia (CABP), Acute Bacterial Skin and Skin Structure Infections (ABSSSI).^[14]

4. Remdesivir

Fig. no 4: Structure of Remdesivir

Remdesivir is a nucleotide analog prodrug. Its active form mimics adenosine monophosphate (AMP). It consists of Purine base nucleus Specifically, adenine-like (purine ring structure) Remdesivir is a 1′-cyano-substituted adenosine analog. Remdesivir targets viral replication machinery: Inhibits viral RNA-dependent RNA polymerase (RdRp). Incorporated into the viral RNA chain as an adenosine triphosphate analog. Causes premature termination of viral RNA synthesis (delayed chain termination). Acts specifically against single-stranded RNA viruses. It does not inhibit human DNA or RNA polymerases, offering selective antiviral activity. It is used in treatment of COVID-19 (caused by SARS-CoV-2).^[15]

5.Ibrexafunger P

Fig. no. 5: Structure of Ibrexafunger P

Ibrexafunger p is a semisynthetic triterpenoid antifungal agent. It consists of Triterpenoid nucleus. Consists of a five-ring (pentacyclic) fused triterpene scaffold, structurally distinct from azoles or echinocandins. Ibrexafungerp inhibits fungal 1,3-β-D-glucan synthase, an enzyme required for the synthesis of β-1,3-D-glucan, a key structural component of the fungal cell wall. This leads to: Disruption of fungal cell wall integrity, Osmotic instability, Cell lysis and death. It is used to treat Vulvovaginal Candidiasis (VVC). Active against Candida albicans, C. glabrata, C. krusei, and some azole-resistant Candida species.^[16]

6. Rezafungin

Fig. no. 6: Structure of Rezafungin

Rezafungin is a semisynthetic echinocandin antifungal. It consists of Cyclic hexapeptide nucleus with a lipophilic side chain. Rezafungin inhibits the fungal enzyme 1,3-β-D-glucan synthase, which is crucial for building the β-1,3-D-glucan polymer in the fungal cell wall. Thereby Inhibits fungal cell wall synthesis, leads to osmotic instability, cell wall weakening, and ultimately fungal cell death. Fungicidal against Candida spp. and fungistatic against Aspergillus spp. Treatment of Candidemia and Invasive Candidiasis.^[17]

7. Ivermectin

Fig. no. 7: Structure of Ivermectin

Ivermectin is a macrocyclic lactone derived from avermectin, a natural product of Streptomyces avermitilis. Ivermectin binds selectively and with high affinity to glutamate-gated chloride ion channels found in invertebrate nerve and muscle cells. This binding causes an increase in the permeability of the cell membrane to chloride ions, leading to hyperpolarization, paralysis, and ultimately death of the parasite. It may also interact with GABA-gated chloride channels, but these are present mainly in the central nervous system of mammals and are protected by the blood-brain barrier, contributing to ivermectin’s safety in humans. It is used to treat Onchocerciasis (River Blindness), Strongyloidiasis, Scabies Pediculosis (head lice), Lymphatic filariasis (in mass drug administration), Rosacea (topical form).^[18]

8. Recarbrio

Fig. no. 8: Structure of Recarbrio

It is combination of Imipenem (carbapenem nucleus), cilastatin, relebactam (diazabicyclooctane nucleus). Inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), leading to cell lysis and death. It has broad-spectrum activity against Gram-positive and Gram-negative bacteria. Treat Complicated urinary tract infections, Complicated intra-abdominal infections, Hospital-acquired bacterial pneumonia (HABP), Ventilator-associated bacterial pneumonia (VABP), Infections caused by carbapenem-resistant Enterobacteriaceae (CRE).^[19]

9. Lefamulin

Fig. no. 9: Structure of Lefamulin

It consists of Pleuromutilin nucleus, a tricyclic diterpene structure. Inhibits bacterial protein synthesis by binding to the peptidyl transferase center (PTC) of the 50S ribosomal subunit. Specifically, it binds to the A- and P-site of the ribosome and prevents the correct positioning of tRNA, thus blocking peptide bond formation. Treat Community-Acquired Bacterial Pneumonia (CABP), Acute Bacterial Skin and Skin Structure Infections (ABSSSI) – investigated in clinical trials, Effective against: Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus (including MRSA), Mycoplasma pneumoniae.^[20]

10. Vabomere

Fig. no. 10: Structure of Vabomere

 Vabomere is a combination of meropenem (a carbapenem β-lactam antibiotic) and vaborbactam (a cyclic boronic acid β-lactamase inhibitor). Meropenem acts by Binding to PBPs and inhibits the final transpeptidation step of peptidoglycan cross-linking in bacterial cell walls and weakens cell wall finally causes cell lysis and bacterial death. Vaborbactam forms a reversible covalent bond with the active site serine residue in β-lactamase enzymes and prevents them from hydrolyzing the β-lactam ring of meropenem and protects meropenem from enzymatic degradation. Treat Complicated Urinary Tract Infections (cUTI), including pyelonephritis, caused by susceptible strains of: Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae species complex, Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) in multidrug-resistant cases.^[21]

CONCLUSION

Recent therapeutic advances in pneumonia reflect the strategic optimization of drug structures to overcome resistance mechanisms, improve pharmacokinetics, and enhance target specificity. Cefiderocol, a siderophore cephalosporin, employs a “Trojan horse” strategy to penetrate Gram-negative bacteria via iron transport channels, resisting β-lactamases. Delafloxacin, a novel fluoroquinolone, is designed with an anionic character to improve activity in acidic infection sites. Omadacycline and doxycycline represent modern tetracycline derivatives optimized for oral and intravenous bioavailability while evading common efflux and ribosomal protection resistance. Remdesivir, a nucleoside analog prodrug, is structurally tailored for efficient intracellular activation, inhibiting viral RNA-dependent RNA polymerase in viral pneumonia. Nirsevimab, a long-acting monoclonal antibody, is engineered with Fc region modifications to extend half-life and neutralize RSV by targeting its prefusion F protein. Ibrexafungerp, a triterpenoid glucan synthase inhibitor, and rezafungin, a long-acting echinocandin, expand antifungal coverage in aspiration or immunocompromised pneumonia. Ivermectin, though primarily antiparasitic, demonstrates broad binding to parasite glutamate-gated chloride channels, with emerging interest in respiratory disease adjunct use. Lefamulin, a pleuromutilin derivative, inhibits bacterial protein synthesis through a unique binding site on the 50S ribosome, minimizing cross-resistance. Recarbrio (imipenem–cilastatin–relebactam) and Vabomere (meropenem–vaborbactam) combine β-lactam antibiotics with novel β-lactamase inhibitors, restoring efficacy against carbapenem-resistant pathogens. Collectively, these agents exemplify how rational drug design, structural modification, and combination strategies continue to drive innovation in pneumonia therapy, providing clinicians with potent options against an increasingly resistant microbial landscape.

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