Journal of Experimental Pharmacology Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Investigational and Experimental Drugs for Community-Acquired Pneumonia: the Current Evidence This article was published in the following Dove Press journal: Journal of Experimental Pharmacology Juilia Sellarès-Nadal Abstract: Community-acquired pneumonia (CAP) is a common infection with a constantly Joaquin Burgos evolving etiological spectrum. This changing etiology conditions the adequate selection of Vicenç Falcó optimal therapeutic regimens, both in empirical and definitive treatments. In recent years, Benito Almirante new antimicrobials have been approved by regulatory authorities for use in CAP, although it is necessary to continue incorporating new antimicrobial agents that improve the activity Infectious Diseases Department, Hospital profile in relation to the appearance of bacterial resistance in certain pathogens, such as Universitari Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain pneumococcus, Staphylococcus aureus or Pseudomonas aeruginosa. Delafloxacin, omada­ cycline and lefamulin are the most recently approved antibiotics for CAP. These three antibiotics have shown non-inferiority to their comparators for the treatment of CAP with an excellent safety profile. However, in the 2019 ATS/IDSA guidelines, it has been con­ sidered that more information is needed to incorporate these new drugs into community- based treatment. New antimicrobials, such as solithromycin and nemonoxacin, are currently being studied in Phase III clinical trials. Both drugs have shown non-inferiority against the comparators and an acceptable safety profile; however, they have not yet been approved by the regulatory authorities. Several drugs are being tested in Phase I and II clinical trials. These include zabofloxacin, aravofloxacin, nafithromycin, TP-271, gepotidacin, radezolid, delpazolid, and CAL02. The preliminary results of these clinical trials allow us to assure that most of these drugs may play a role in the future treatment of CAP. Keywords: community-acquired pneumonia, new antimicrobial drugs, fluoroquinolones, macrolides, tetracyclines, oxazolidinones Introduction Community-acquired pneumonia (CAP) continues to be an important challenge in the field of infectious diseases because is one of the most common infections that require hospitalization, especially in the elderly population and persons with co- morbid conditions.1–5 In the case of a patient with CAP, doctors have to decide which tests should be performed in order to determine the cause of pneumonia, which is the appropriate location to treat the patient and which is the best antibiotic therapy for this patient. Correspondence: Benito Almirante Understanding the burden and the etiology of CAP is critical to making these decisions. Infectious Diseases Department, Hospital Initial treatment of patients with CAP is empirical so the antibiotics chosen should Universitari Vall d’Hebron, Avda. Vall d’Hebron, 119-129, Barcelona 08035, cover the most common pathogens causing CAP but also those uncommon pathogens Spain that may cause CAP in certain patients. This is one of the most important challenges in Tel +34 274 60 90 Email benitoalmirante@gmail.com patients with CAP because the microbial etiology of CAP is constantly changing. The submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2020:12 529–538 529 DovePress © 2020 Sellarès-Nadal et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/ http://doi.org/10.2147/JEP.S259286 terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Sellarès-Nadal et al Dovepress main features that have contributed to these changes in the contribute to the diagnosis of CAP, raising the level of last years are the widespread introduction of the pneumococ­ microbiological diagnosis up to 85%. Therefore, these new cal conjugate vaccine, the emergence of resistant pathogens methods have pointed out that mixed infections can represent such as Pseudomonas aeruginosa or methicillin-resistant 10–25% of all CAP.8,11 In the latest studies, etiologies of Staphylococcus aureus (MRSA) and the increased recogni­ CAP include Gram-negative bacilli, such as Escherichia coli tion of the role of viral pathogens. (11.5%), Klebsiella pneumoniae (4%) or P. aeruginosa Numerous antibiotics have been approved for the treat­ (2.8%), and S. aureus (10.2%).12 ment of CAP by the Food and Drug Administration (FDA); Finally, multidrug-resistant organisms (MDRO), however, it is necessary to continue the research of new drugs including MRSA and extended-spectrum beta-lactamase that are able to cover the entire etiological spectrum of CAP (ESBL) Enterobacteriaceae and P. aeruginosa, represent and with novel mechanisms of action that can overcome the 6% of pathogens isolated in CAP, mostly in older patients increase of resistances and the emergence of resistant patho­ with previous exposure to antibiotics, and they are asso­ gens. In this article, we will perform a narrative review about ciated with higher mortality.13 In North America, commu­ the existing treatments for CAP and we will focus on the new nity-acquired MRSA, specially the USA300 clone, can drugs that are currently being investigated. cause a severe CAP presenting with rapid progression and hemoptysis.14 Etiology of CAP Knowledge of the pathogens causing CAP is essential to select Current Treatment of CAP correct empirical treatments. The etiology of CAP is condi­ Several guidelines for the diagnosis and treatment of CAP tioned by several factors. The presence of underlying condi­ have been published, each one taking into account local tions, such as chronic lung disease or immunosuppression, epidemiology, health system particularities, drug side local epidemiology or previous exposure to antibiotics is the effects and cost-effectiveness. In this part, we assess gen­ most important. eral and most updated recommendations for the treatment In any textbook, the pathogen referred as the main of CAP in adults. cause of CAP is Streptococcus pneumoniae, accounting Most recommendations take into consideration the level for up to two-thirds of bacteremic cases and for 30% of of care (inpatient or outpatient) and severity of the disease. all CAP. Other pathogens include Haemophilus influenzae, Severity can be assessed by scores, such as IDSA criteria, for which represents 12% and atypical microorganisms such severe pneumonia or by clinical judgment supported by as Mycoplasma pneumoniae, Chlamydiophila pneumoniae CURB65, as recommended in British guidelines.9,15 and Legionella spp. that account for 20% of CAP.1,6,7 The recommended treatment for healthy outpatients with Despite S. pneumoniae is the main bacterial microorgan­ CAP is amoxicillin, doxycycline or, in areas with low pre­ ism isolated in CAP, in the latest studies its proportion is valence of macrolide-resistant S. pneumoniae, a macrolide. decreasing. This may partially be due to the introduction On the other hand, outpatients with co-morbidities, such as of the conjugated anti-pneumococcal vaccine in the United chronic lung disease, diabetes mellitus or alcoholism should States and other countries.2 be treated with amoxicillin-clavulanate acid plus a macrolide Moreover, recent studies point out that respiratory virus or with a respiratory fluoroquinolone.9 should also be taken into account. In these studies, viral Treatment of hospitalized patients depends on severity. isolates represent 20–30%, with influenza and rhinovirus in Patients with severe CAP should be treated with combined the head of viral pathogens.8 In fact, 2019 Infectious therapy with β-lactam plus macrolide or β-lactam plus fluor­ Diseases Society of America (IDSA) guidelines suggest oquinolone. Several studies and meta-analysis support com­ that when influenza viruses are circulating, their presence bined therapy for critically ill patients with CAP.16,17 In should be investigated in patients with CAP.9 Such informa­ hospitalized patients with non-severe CAP, combination of tion has an impact, since a meta-analysis showed a higher a β-lactam plus a macrolide or a respiratory fluoroquinolone risk of death in patients with viral-bacterial co-infection is recommended. Evidence of superiority of combined treat­ compared to patients with non-dual infection.10 ment with β-lactam plus macrolide over β-lactam monother­ On the other hand, with usual microbiological methods, apy in non-critically ill patients with CAP is less robust and pathogen detection is achieved in less than 50%.11 New studies have drawn contradictory conclusions on this diagnostic tools such as molecular techniques could issue.18,19 530 submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2020:12 DovePress Dovepress Sellarès-Nadal et al Finally, previous guidelines defined “healthcare- hypoglycemia, adverse psychiatric events, QT prolongation associated pneumonia” (HCAP) as a pneumonia occurring or aortic rupture and dissection). For these reasons FDA has in patients with higher risk of MDRO. Risk factors con­ suggested that fluoroquinolones should be reserved for those sidered are residence in nursing homes, recent hospitaliza­ patients who have no other treatment options.30 tion, or chronic conditions, among others.20 The latest guidelines recommend avoiding the term as it leads to an New Antimicrobials Recently increase in the use of broad-spectrum antibiotics without Approved for CAP better results.21 Therefore, the current recommendation is to individually assess clinical probability of resistant- Delafloxacin Delafloxacin is a novel fluoroquinolone with a broad spec­ pathogens and to adjust treatment to local epidemiology.9 trum that includes Gram-positive and Gram-negative organisms, including MRSA and P. aeruginosa.31 It is Do We Need New Antibiotics for also active against atypical microorganisms causing CAP. CAP? Delafloxacin differs from other fluoroquinolones in that The constant epidemiological changes have raised some delafloxacin exerts a minimal effect on cytochrome P450 issues that justify the research of new antibiotics for CAP. enzymes and on the corrected QT interval so there does not Although penicillin resistance has been a matter of concern seem to be a risk of QT prolongation. The efficacy of for many years, currently we have learned that levels of β- delafloxacin for CAP was demonstrated in a Phase 3, ran­ lactam resistance in most settings generally do not result in domized double-blind trial.32 In this study iv delafloxacin, treatment failure for patients with pneumococcal pneumonia with potential to switch to oral delafloxacin, was compared when appropriate agents and doses are used.22–24 On the to iv moxifloxacin, with potential to switch to oral moxi­ contrary, resistance of S. pneumoniae to macrolides is sig­ floxacin and potential to switch moxifloxacin to iv linezolid nificant, with a prevalence of 20 to 40% in some settings.25,26 for confirmed MRSA. A total of 860 patients with CAP in In the same way, resistance of M. pneumoniae to macrolides PORT risk class of II to V were planned to be enrolled and is also emerging worldwide.27 For these reasons, macrolide finally 859 were included in the intention-to-treat (ITT) monotherapy, that was recommended for outpatients in the population. Overall, 88.9% of patients who received dela­ 2007 American Thoracic Society (ATS)/IDSA guidelines, floxacin and 89.0% of patients who received moxifloxacin has evolved to a conditional recommendation because of met the primary end-point of statistical non-inferiority for concerns on resistance levels to macrolides in the 2019 early clinical response at 96 hours. Delafloxacin was well- ATS/IDSA guidelines.9,28 tolerated. The most common adverse events (≥2%) were On the other hand, the emergence of MDRO, including diarrhea and increases in transaminase levels, which were MRSA and P. aeruginosa, requires consideration in the generally mild and did not lead routinely to treatment dis­ empirical treatment coverage in some patients with risk continuation. As a consequence of these results, the FDA factors for these etiologic agents.29 Although infection by approved delafloxacin for the treatment of adults with CAP S. aureus is still uncommon in most patients with CAP, its the past 10/24/2019.33 incidence is increasing in pediatric population and during the influenza season. Enterobacteriaceae and P. aeruginosa Omadacycline accounts in <2% of cases of CAP, but they are increasing in Omadacycline is a new aminomethylcycline, a derivate of elderly patients with co-morbidities. So, appropriate ther­ tetracycline, with a mechanism of action based on its bind­ apy for these pathogens may be necessary for selected ing to the primary tetracycline site on bacterial 30S riboso­ patients, since the impact of failing in initial treatment mal subunit with high specificity. An advantage over older may be high, especially in critically ill patients.2 tetracyclines is that it is able to overcome the efflux and Finally, the description of adverse events related to the ribosomal protection mechanisms of tetracycline resistance. use of fluoroquinolones has raised concerns regarding its Omadacycline is active against pathogens that cause CAP, generalized use in all patients with CAP. While some of including S. pneumoniae, H. influenzae, S. aureus, and aty­ these adverse events, such as tendinopathy and tendon rup­ pical pathogens.34 The efficacy of omadacycline was ture were already known since years ago, others have evaluated in the OPTIC trial, a double-blind trial in which become relevant more recently for their severity (severe once-daily omadacycline was compared to moxifloxacin for submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2020:12 531 DovePress Sellarès-Nadal et al Dovepress the treatment of adults with CAP in PORT risk class II to patients with moderate to severe CAP.38 The LEAP 2 study IV.35 The ITT population included 386 patients in the oma­ compared the safety and efficacy of oral lefamulin twice dacycline group and 388 patients in the moxifloxacin group. daily for 5 days versus oral moxifloxacin once daily for 7 Omadacycline showed non-inferiority to moxifloxacin for days in 738 adult patients with moderate CAP, and also early clinical response (81.1% and 82.7%, respectively), and demonstrated non-inferiority between the two therapeutic for the rates of investigator-assessed clinical response at the options.39 On August of 2019, based on the results of these post-treatment evaluation (87.6% and 85.1%, respectively). trials, the FDA announced the approval of lefamulin for the The most frequent events were gastrointestinal side effects treatment of CAP.40 Despite this approval the ATS and the (10.2% and 18.0%, respectively). Although FDA approved IDSA demand further validation in the outpatient setting.9 omadacycline for CAP the 10/02/2018,36 recent ATS/IDSA guidelines state that omadacycline needs further validation Investigational Drugs Currently in in the outpatient setting.9 Phase III Clinical Trials The phase III clinical trials including these drugs for Lefamulin patients with CAP are listed in Table 1. Lefamulin is a semi-synthetic agent that belongs to the pleuromutilin class of antibiotics. The precise mechanism Solithromycin of action is based on the binding to the peptidyl-transferase Solithromycin is a fourth-generation macrolide and the center of the 50S ribosomal subunit of the bacteria. first fluroketolide in development. Solithromycin acts Lefamulin has a potent antimicrobial activity against Gram- binding to three different sites of 50S ribosomal unit, positive microorganisms, including S. pneumoniae, and resulting in a potent antibacterial activity and a low ten­ some Gram-negative pathogens (H. influenzae, Moraxella dency to select for resistant mutants.41 This drug has catarrhalis and Neisseria spp.), as well as against mycoplas­ activity against the most common typical and atypical mas and intracellular organisms, such as Chlamydia spp. and CAP pathogens, including fluoroquinolone-, macrolide-, Legionella pneumophila.37 It has a good oral bioavailability and penicillin-resistant isolates.41 Two phase III trials, and an excellent penetration into epithelial lining fluid of the SOLITAIRE-ORAL and SOLITAIRE-IV, have evaluated lung. The clinical efficacy of lefamulin in patients with CAP the safety and efficacy of oral and iv solithromycin, was evaluated in two multicentre, randomized, double-blind, respectively, for the treatment of CAP.42,43 Both trials double-dummy, phase 3 trials, the Lefamulin Evaluation have shown non-inferiority compared with moxifloxacin Against Pneumonia (LEAP 1 and 2) trials. The LEAP 1 for the early clinical response meeting the FDA's primary study demonstrated the clinical efficacy and safety of iv-to- end-point (SOLITAIRE-ORAL, difference = −0.19, 95% oral lefamulin compared to moxifloxacin ± linezolid in adult CI, −5.8 to 5.5, and SOLITAIRE-IV, difference = −0.46, Table 1 Antimicrobials in Phase III Clinical Trials Drug Name Drug Class Development Study Results * Data Approval Phase by FDA Omadacycline Aminomethylcycline (derivate of Phase III Clinical response: 81.1% (313/386) vs 82.7% 10/02/2018 tetracyclines) (321/388) comparator. Delafloxacin Fluoroquinolone Phase III Clinical response: 90.5% (390/431) vs 89.7% 10/24/2019 (384/428) comparator Lefamulin Pleuromutilin Phase III Clinical response: 89.3% (577/646) vs 90.2% 8/19/2019 (582/645) comparator Solithromycin Macrolide Phase III Clinical response: 78.7% (677/860) vs 78.8% Not yet approved (680/863) comparator Nemonoxacin Non-fluorinated quinolone Phase III Clinical cure: 89.1% (542/608) vs 88.5% (261/ Not yet approved 295) Note: * Expressed in percentage and number. 532 submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2020:12 DovePress Dovepress Sellarès-Nadal et al 95% CI, −6.1 to 5.2). In SOLITAIRE-ORAL, side effects clinical testing. Of this, ACH-702, WCK-771, WCK-2389 were comparable between both groups. However, in and KPI-10 are new quinolones with activity against com­ SOLITAIRE-IV more than 50% of patients in the solithro­ mon respiratory pathogens, including resistant isolates, and mycin arm had drug-related adverse events, compared with potential to treat respiratory tract infections. with 35% in the moxifloxacin arm. This difference was Nevertheless, these drugs have not yet been studied in driven mainly by infusion reactions, more common in the phase I clinical trials. The next groups of antibiotic are solithromycin group (31.3%) compared to the moxifloxa­ tetracyclines and ketolides, with three drugs in study. cin group (5.4%).43 Nevertheless, hepatic safety remains Oxazolidinones are also an important class, with two com­ a concern, with 5–10% of patients experiencing mild pounds currently in clinical trials. Finally, a non-antibiotic asymptomatic transaminase elevations. Given the rela­ drug with antitoxin activity completes the compounds under tively small sample sizes (<1000 patients) in which soli­ investigation. The targets of most of these drugs are not only thromycin was studied, the FDA recommended that the patients with CAP but also patients with other types of company initiates a new clinical study with a greater infections. The phase I and II clinical trials including these number of patients to better evaluate its safety profile drugs for patients with CAP are listed in Table 2. before formally granting approval.44 Zabofloxacin Zabofloxacin is a novel fluoroquinolone with identical Nemonoxacin mechanism of action than other quinolones and with Nemonoxacin is a recently developed non-fluorinated quino­ a broad-spectrum against respiratory pathogens. It has lone antibiotic. Nemonoxacin has a broad spectrum of activ­ proven bactericidal efficacy both in vitro and in vivo ity against Gram-positive, Gram-negative, and atypical against Gram-positive and Gram-negative pathogens, pathogens, and a reduced resistance profile compared with including S. pneumoniae, S. aureus, H. influenzae, and other fluoroquinolones. It displays good in vitro activity M. catarrhalis. By contrast, zabofloxacin has no activity against MRSA, penicillin-resistant S. pneumoniae, and erta­ against major pathogens associated with hospital-acquired penem-non-susceptible Enterobacteriaceae.45–47 This is pneumonia, such as P. aeruginosa and Acinetobacter achieved by its targeting to both topoisomerase II and IV. baumannii.52,53 Scarce clinical data exist regarding the Different Phase II and III clinical trials have investigated efficacy of this drug in pneumonia. Only, a phase II clin­ the clinical efficacy and safety of nemonoxacin in the treat­ ical trial to evaluate the safety and efficacy of oral zabo­ ment of CAP in comparison with levofloxacin.48–51 A recent floxacin compared with oral levofloxacin in CAP has been meta-analysis of most recent phase III trial found that nemo­ performed, and although it was finished in 2012, results noxacin and levofloxacin had similar clinical cure rates in the have not been yet published.54 treatment of CAP (OR = 1.05, 95% CI, 0.67–1.64). Nemonoxacin also had a similar microbiologic response rate than levofloxacin (OR = 0.89, 95% CI, 0.44 to 1.81). The Aravofloxacin (JNJ-Q2) Aravofloxacin (JNJ-Q2) is a novel fifth-generation fluoroqui­ safety/tolerability of nemonoxacin was also comparable with nolone that has excellent in vitro and in vivo activity against levofloxacin, so no significant differences were found in a variety of Gram-positive and Gram-negative organisms. In adverse events between the two drugs (OR = 1.08, 95% CI, vitro studies that included 3757 isolates indicate that aravo­ 0.81 to 1.43). In subgroup analysis of dose of nemonoxacin floxacin has potent activity against pathogens responsible for (500 or 750 mg) and individual pathogens, results remained CAP, such as S. aureus (MIC50, 0.12 μg/mL) and unchanged.47 It has received priority review status by the FDA S. pneumoniae (MIC50/90, 0.008/0.015 μg/mL), being >16- as a “qualified infectious disease product” once further phase fold more potent than moxifloxacin and levofloxacin. The III studies are available documenting its safety and efficacy. activity of avarofloxacin was equivalent to that of moxiflox­ acin against Gram-negative microorganisms.55,56 Investigational Drugs in Phase I and Aravofloxacin has also been shown to have a higher barrier II Clinical Trials to resistance compared to other agents in the class and it Several drugs for the treatment of CAP are currently being remains highly active against drug-resistant organisms, investigated in phase I and phase II clinical trials. Quinolone including MRSA, ciprofloxacin-resistant S. aureus, and are the leading antibiotic class, with 6 compounds under drug-resistant S. pneumonia.55,56 A Phase II, randomized, submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2020:12 533 DovePress Sellarès-Nadal et al Dovepress Table 2 Compounds in Phase I and II Clinical Trials Drug name Drug Class Development Study Results * NCT Reference Phase Zabofloxacin Fluoroquinolone Phase II No results available NCT00640926 Aravofloxacin Fluoroquinolone Phase II Clinical cure: 87.5% (14/16) vs 81.3% (13/16) NCT01198626 57 comparator Nafithromycin Ketolide Phase II Clinical response: 91.9% (68/74) vs 87% (67/77) NCT02903836 61 comparator TP-271 Tetracycline Phase I No results available NCT02724085 Gepotidacin Tetracycline Phase I No results of efficacy available NCT02853435 64 Radezolid Oxazolidinone Phase II Clinical cure: 78% (103/132) NCT00640926 66 Delpazolid Oxazolidinone Phase I No results of efficacy available NCT01842516 68 CAL02 Antitoxin agent Phase II Clinical cure: 100% (12/12) vs 100% (5/5) comparator NCT02583373 70 Note: * Expressed in percentage and number. double-blind, multicenter study evaluating the efficacy of in lung tissue, a good penetration in alveolar macrophages, aravofloxacin (150 mg iv every 12 hours, followed by and it seems to have an acceptable hepatic safety.60 A phase 250 mg orally every 12 hours) versus that of moxifloxacin II, randomized, placebo-controlled study evaluated the (400 mg iv or orally every 24 hours) for the treatment of CAP safety, tolerability, pharmacokinetics, and efficacy of oral has been published.57 The study was designed to enroll 120 nafithromycin (800 mg 3 days and 5 days) versus oral moxi­ subjects to ensure ability to detect non-inferiority of aravo­ floxacin in the treatment of CAP in adults. The primary end- floxacin to moxifloxacin; however, this was not feasible due point (clinical response at day 4, tested in the ITT population) to the strict inclusion criteria. Clinical cure was achieved in was achieved in 91.9% (68/74), 89% (65/73) and 87% (67/ 87.5% (14/16) and 81.3% (13/16) of patients treated with 77) of patients in the nafithromycin 3 days, nafithromycin 9 aravofloxacin and moxifloxacin, respectively (OR = 1.66, days and moxifloxacin groups, respectively. Rates of serious 95% CI, 0.23 to 11.75). However, the small sample sizes adverse events were similar between groups (around 1–2%), preclude to have sufficient power to detect non-inferiority for nevertheless, nafithromycin had more non-serious adverse clinical test of cure. Adverse events were comparable events, mainly gastrointestinal disorders (14.9% versus between aravofloxacin and moxifloxacin, with the exception 12.5% versus 7.9%, respectively).61 of nausea and vomiting.57 Considering its early stage of development, the definitive role of aravofloxacin against TP-271 these infections and its safety profile will have to be deter­ TP-271 is a promising new tetracycline with in vitro activity mined in future phase III studies. against the major pathogens associated with CAP.62 TP-271 is currently under assessment in phase I trial, single ascend­ Nafithromycin ing-dose, in order to evaluate its safety, tolerability, and Nafithromycin (WCK 4873) is a novel antimicrobial agent of pharmacokinetics in patients with pneumonia.63 the ketolide class that interacts at multiple positions on the ribosome, thus allowing for activity against macrolide- Gepotidacin resistant organisms.58 In a collection of 4739 clinical isolates, Gepotidacin is a broad-spectrum antibacterial agent with compiled worldwide, the antibiotic showed in vitro potency a novel mechanism of action. It inhibits the B subunit of against S. pneumoniae (MIC50/90, 0.015/0.06 μg/mL), DNA gyrase. Initial phase I studies with escalating oral S. aureus (MIC50/90, 0.06/>2 μg/mL), and comparable dosing have demonstrated a safety profile similar to those in vitro activities against H. influenzae and M. catarrhalis of other marketed antibiotics.64 Its antibacterial activity isolates (MIC90 0.25 μg/mL).59 This drug has also an attrac­ and its properties make it have a potential role in the tive pharmacokinetic profile, a good absorption, high levels treatment of CAP. 534 submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2020:12 DovePress Dovepress Sellarès-Nadal et al Radezolid CAL02 group compared with placebo, with similar rates Radezolid (RX-1741) is a novel oxazolidinone antibiotic of side effects.70 The results of this study support further agent and is the first biaryloxazolidinone in clinical develop­ clinical development of CAL02 and provide a solid basis ment. It is being developed for the treatment of serious for a larger clinical study. MDRO infections, including infections caused by linezolid- resistant strains. Radezolid has shown excellent activity Conclusion against a number of key CAP pathogens, including The treatment of CAP is a continuous challenge due to the S. pneumoniae, S. aureus, H. influenzae, and atypical respira­ constant changes in its etiological spectrum and the tory pathogens.65 It is 11 times more active in comparison to appearance of bacterial resistances. In recent years, new linezolid against a series of bacterial species capable of antimicrobials have been approved for use in CAP therapy, surviving intracellularly, such as Staphylococcus, both at the hospital and community levels. Currently, Chlamydia, and Legionella species. A phase II clinical trial several antimicrobials are being evaluated in phase III has been completed evaluating radezolid in mild-to-moderate clinical trials and their results allow their possible incor­ CAP at three different doses: 300 mg once daily, 450 mg poration into the treatment of CAP. Several drugs are once daily, and 450 mg twice daily for 7–10 days. The study being evaluated in preclinical phases with the aim of showed comparable efficacy across all three doses, with demonstrating efficacy against the majority of pathogens clinical cure rates ranging from 78 to 92%.66 However, its causing CAP. Quinolone are the leading antibiotic class, safety profile has not been established and its advantages with more compounds under clinical testing. However, over linezolid and tedizolid are not clear at present. increasing concerns exist about its safety due to the report­ Redezolid is ready for entering a phase III trial. ing of some rare adverse events as tendinopathies or aortic dissection. On this basis, tetracyclines and ketolides could be interesting drugs to explore. Delpazolid Delpazolid (LCB01-0371) is a new oxazolidinone with Funding good in vitro and in vivo activities against Gram-positive The authors are supported by Plan Nacional de I+D+I bacteria, similar to linezolid.67 The drug has also interest­ 2013–2016. They are also supported by the Instituto de ing properties such as high aqueous solubility and good Salud Carlos III, Subdirección General de Redes y Centros absorption, distribution, metabolism, excretion, and toxi­ de Investigación Cooperativa, Ministerio de Economía, city and PK profiles.68 There are no phase II studies Industria y Competitividad, and the Spanish Network for ongoing; however, its characteristics make it have Research in Infectious Diseases [REIPI RD16/0016/0003], a potential role in the treatment of CAP. which is co-financed by European Development Regional Fund ‘A way to achieve Europe’ and Operative program CAL02 Intelligent Growth 2014–2020. CAL02 is a non-antibiotic drug, a novel antitoxin agent with a singular mechanism of action. CAL02 consists of Disclosure a mixture of liposomes that capture bacterial toxins known J. Burgos has received honoraria for speaking at educa­ to dysregulate inflammation, cause organ damage, and tional events from Janssen Pharmaceuticals, Merck Sharp impede immune defense. Preclinical data show that when and Dohme (MSD) and ViiV Healthcare and has received combined with antibiotics, CAL02 substantially improves research funding from MSD. V. Falco has received honor­ survival outcomes in mice with severe pneumonia and aria for speaking at educational events for Janssen bacteremia.69 A randomized, phase II, double-blind, multi­ Pharmaceuticals, MSD, ViiV Healthcare, has received centre, placebo-controlled trial was done in patients with research funding from Gilead Sciences, MSD and ViiV severe pneumococcal CAP who required ICU admission. Healthcare, and reports grants and personal fees from Nineteen patients were randomly assigned, resulting in 14 Merck Sharp Dhome, ViiV, and Gilead and personal fees patients in the CAL02 groups (3 assigned to low-dose from Janssen Pharmaceuticals, outside the submitted work. CAL02 and 11 assigned to high-dose CAL02) and 5 in B. Almirante has received honoraria for speaking at edu­ the placebo group. Despite the limited number of patients, cational events from MSD, Pfizer Inc, Gilead Sciences and better patient outcomes were observed in the high-dose Angellini and has received research funding from Gilead submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2020:12 535 DovePress Sellarès-Nadal et al Dovepress Sciences, MSD and Pfizer Inc. The authors have no other 18. Lee JS, Giesler DL, Gellad WF, Fine MJ. Antibiotic therapy for adults hospitalized with community-acquired pneumonia relevant affiliations or financial involvement with any a systematic review. 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