Scholarly article on topic 'The solithromycin journey—It is all in the chemistry'

The solithromycin journey—It is all in the chemistry Academic research paper on "Clinical medicine"

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Bioorganic & Medicinal Chemistry
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{Solithromycin / Macrolide / Fluroketolide / Antibiotic-resistance / Pneumonia}

Abstract of research paper on Clinical medicine, author of scientific article — Prabhavathi Fernandes, Evan Martens, Daniel Bertrand, David Pereira

Abstract The macrolide class of antibiotics, including the early generation macrolides erythromycin, clarithromycin and azithromycin, have been used broadly for treatment of respiratory tract infections. An increase of treatment failures of early generation macrolides is due to the upturn in bacterial macrolide resistance to 48% in the US and over 80% in Asian countries and has led to the use of alternate therapies, such as fluoroquinolones. The safety of the fluoroquinolones is now in question and alternate antibiotics for the outpatient treatment of community acquired bacterial pneumonia are needed. Telithromycin, approved in 2003, is no longer used owing to serious adverse events, collectively called the ‘Ketek effects’. Telithromycin has a side chain pyridine moiety that blocks nicotinic acetylcholine receptors. Blockade of these receptors is known experimentally to cause the side effects seen with telithromycin in patients use. Solithromycin is a new macrolide, the first fluoroketolide, which has been tested successfully in two Phase 3 trials and is undergoing regulatory review at the FDA. Solithromycin is differentiated from telithromycin chemically and biologically in that its side chain is chemically different and does not significantly block nicotinic acetylcholine receptors. Solithromycin was well tolerated and effective in clinical trials.

Academic research paper on topic "The solithromycin journey—It is all in the chemistry"

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Bioorganic & Medicinal Chemistry

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The solithromycin journey—It is all in the chemistry

Prabhavathi Fernandes a'*, Evan Martens a, Daniel Bertrand b, David Pereiraa

aCempra Inc., Chapel Hill, NC 27517, USA b HiQScreen Sarl, 1222 Vesenaz, Geneva, Switzerland


The macrolide class of antibiotics, including the early generation macrolides erythromycin, clarithromycin and azithromycin, have been used broadly for treatment of respiratory tract infections. An increase of treatment failures of early generation macrolides is due to the upturn in bacterial macrolide resistance to 48% in the US and over 80% in Asian countries and has led to the use of alternate therapies, such as fluoroquinolones. The safety of the fluoroquinolones is now in question and alternate antibiotics for the outpatient treatment of community acquired bacterial pneumonia are needed. Telithromycin, approved in 2003, is no longer used owing to serious adverse events, collectively called the 'Ketek effects'. Telithromycin has a side chain pyridine moiety that blocks nicotinic acetylcholine receptors. Blockade of these receptors is known experimentally to cause the side effects seen with telithromycin in patients use. Solithromycin is a new macrolide, the first fluoroketolide, which has been tested successfully in two Phase 3 trials and is undergoing regulatory review at the FDA. Solithromycin is differentiated from teli-thromycin chemically and biologically in that its side chain is chemically different and does not significantly block nicotinic acetylcholine receptors. Solithromycin was well tolerated and effective in clinical trials.

© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://


Article history: Received 15 June 2016 Revised 5 August 2016 Accepted 20 August 2016 Available online 22 August 2016







1. Introduction

Macrolide antibiotics have been used successfully to treat respiratory tract and other bacterial infections. This success is due in large part to their (i) spectrum of activity, (ii) safety, (iii) tissue and intracellular activity, and (iv) anti-inflammatory properties. These properties give macrolides an advantage over other classes of antibiotics. Their spectrum of activity in the respiratory tract is targeted to key community-acquired pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and atypical pathogens such as Legionella pneumophila, Mycoplasma pneumoniae and Chlamydophila pneumoniae. The atypical bacteria do not have peptidoglycan in their cell wall and therefore infection caused by these organism cannot be treated with penicillin or other beta-lactam antibiotics, leaving tetracyclines, fluoroquinolones and macrolides as the only single-agent oral treatment options. Although broad spectrum antibiotics such as cephalosporins, aminopenicillins, tetracyclines, and fluoro-quinolones are active against typical community-acquired bacterial pneumonia (CABP) pathogens, their extended spectrum of activity can cause collateral damage by modifying intestinal microflora. Notably, fluoroquinolones such as levofloxacin and moxi-

* Corresponding author. Tel.: +1 919 313 6610. E-mail address: (P. Fernandes).

floxacin are known to cause Clostridium difficile colitis by altering intestinal microbiome. Further, tetracyclines and fluoroquinolones are not used in pediatrics to treat respiratory tract infections because of undesirable side effects. In contrast, macrolides have been generally safe and well tolerated in adults, children, and pregnant women. As a result, a macrolide is frequently the 'go to' antibiotic for empiric treatment of respiratory tract infections.

Many bacteria reside, and replicate intracellularly in phagolyso-somes and cytoplasm. Macrolides also concentrate in alveolar macrophages, extracellular lung fluid (ELF), and some organ tissues such as the lung. Therefore, high concentrations of macrolides can be achieved where needed, including intracellular environments. Lastly, macrolides exhibit a positive immunomodulatory, anti-inflammatory response, likely due to inhibition of cytokine release from inflammatory cells and decreased tissue damage which is considered to provide a clinical benefit and enhancement of clinical efficacy.

2. The need

Since the introduction of the first macrolide, erythromycin in 1957, and the semi-synthetic analogs clarithromycin and azithromycin in the late 1980's, widespread macrolide usage has resulted in increased microbial resistance with resistance rates at an 0968-0896/© 2016 The Authors. Published by Elsevier Ltd.

This is an open access article under the CC BY license (

average of 48% in the US in 2015.1 Macrolide resistance, as with other classes of antibiotics, is higher in Asia.2 No doubt, the overuse of antibiotics in simple upper respiratory tract infections, like sinusitis and bronchitis, and veterinary use for livestock has enhanced the selection for resistance. Simple upper respiratory tract infections are not life threatening; in fact are often due to viral pathogens. Empiric, often indiscriminate antibiotic use increases selection of resistant bacteria. Recognizing this, there is a renewed effort in healthcare to discourage antibiotic use for simple, uncomplicated sinusitis, bronchitis, and other uncomplicated upper respiratory infections.3-5 Macrolide treatment failure of CABP, a leading cause of hospitalization and death among adults in the U.S,6 is possibly the result of infection by macrolide-resistant bacteria.7 Over the past several years, use of fluoroquinolones to treat CABP has steadily increased to cover macrolide-resistant pathogens, including pneumococci.8 Antibiotic-resistant M. pneumoniae has also increased9-12 but exact rates are unknown since this bacterium is difficult to culture and susceptibility testing is done only in specialized laboratories.

The 2007 Infectious Diseases Society and the American Thoracic Society (IDSA/ATS) guidelines for the treatment of CABP recommends treatment with a fluoroquinolone or a beta-lactam plus a macrolide.13 However, fluoroquinolones such as levofloxacin has several downsides including alteration of the intestinal microflora resulting in C. difficile colitis, tendonitis, neuritis, and hallucinations.16 Outpatient treatment failures have increased in recent years leading to an increase in hospitalizations.14,15 Although still indicated for the treatment of CABP, the mounting weight of adverse events prompted the FDA to re-examine the benefit/risk resulting in an update to the US labeling and medication guides for all fluoroquinolones.16 Fluoroquinolones are potent and useful antibiotics, but should be preserved for use in hospitalized critically ill patients where they may be life-saving. Current alternatives to fluoroquinolones for the treatment of hospitalized CABP patients are combination of a beta-lactam antibiotic plus a macro-lide or tetracycline, a treatment regimen supported by studies that showed reduced mortality among patients who received combination antibiotic therapy for bacteremic pneumococcal pneumonia.17 The improved clinical response in CABP patients administered a macrolide together with a third generation cephalosporin18 versus a broad spectrum cephalosporin alone has been reported.19 As an alternative for empiric therapy, a macrolide or tetracycline provides coverage for atypical bacteria. Unfortunately, since all of the third generation cephalosporins are injectable, with no oral alternative, patients cannot be discharged early from the hospital to continue treatment with an oral third generation cephalosporin.

In summary, it is still possible to treat CABP, but with increasing bacterial resistance to oral antibiotics typically used for outpatients, current treatment options are all sub-optimal, requiring hospitalization and/or compromising safety or efficacy.

3. Overcoming macrolide resistance with the ketolides

In recent years, nearly one out of two (50%) strains of pneumo-coccus in the U.S. is now resistant to macrolides.1 Such resistance has led to a substantial increase in both hospitalizations and healthcare costs.20 The second generation macrolides, clar-ithromycin and azithromycin, have chemical modifications in the macrocyclic ring (shown in Fig. 1) that improved bioavailability and pharmacokinetics over that of the first generation macrolide erythromycin but do not confer activity against erythromycin-resistant strains.

All macrolides exert their activity by interacting with the bacterial ribosome, thereby disrupting protein synthesis. Since both macrolide generations share the same single ribosomal binding

site at A2058/A2059 (Escherichia coli numbering) of the 23S RNA of the 50S ribosomal subunit, they have similar potencies and are cross-resistant. Telithromycin is a third generation macrolide with activity against pneumococci resistant to the first and second generation macrolides (shown in Fig. 2).

Telithromycin has a keto group at position 3 of the macrocyclic ring (numbered on the figure) instead of the cladinose sugar of the older macrolides and a side chain at the 11,12 position that interacts with domain II, at A752, of the 23S RNA.21 This second binding site of telithromycin confers activity against macrolide-resistant strains.22 It binds to the bacterial ribosome with high affinity and is bactericidal23 while older macrolides are considered bacterio-static. It is noteworthy that these modifications led to an unusual change in antibacterial development; namely a change in the mode-of action from bacteriostatic to bactericidal within the same class of antibiotic. This feature is clinically relevant since earlier generations of macrolides were considered for use in serious infections caused by pathogens, such as pneumococci only when co-administered with another antibiotic capable of rapid bactericidal activity. Telithromycin received marketing authorization for a number of simple respiratory tract infections as well as CABP by the U.S. Food and Drug Administration in 200424 and was marketed under the brand name Ketek. In late 2006, after reports of various adverse events collectively called the 'Ketek effects', (adverse events that included reversible visual accommodation effects, most frequently noted in young women, syncope, exacerbation of myasthenia gravis, and rarely but most widely reported idiosyncratic hepatic effects that were serious enough to lead to hepatic failure in a select number of patients)25 were discussed at a widely publicized FDA advisory committee meeting. The liver toxicity observed with telithromycin was unusual in that it involved eosinophilic infiltration and inflammatory response that rapidly led to necrotic cell death.26,27 The marketing indication for CABP was retained, but indications for use in simple infections like sinusitis, pharyngitis, bronchitis, etc., and skin infections were removed from the label.27 Telithromycin is no longer actively marketed.

Most antibiotics, including macrolides, can cause reversible liver enzyme elevations because of the large dose of drug administered to patients.28 Antibiotic doses are in the range of 2501000 mg per dose relative to the 1-20 mg doses generally used in the treatment of central nervous system and cardiac diseases.

After the large amount of negative publicity surrounding Ketek, changes were instituted by the FDA for antibiotic approval. New guidelines which excluded upper respiratory tract infections that could be self-limited or of a viral etiology were developed to encourage the development of antibiotics for serious infections, such as CABP.29 These new guidelines encourage stewardship of new antibiotics to decrease the possibility of resistance selection by limiting use in simpler upper respiratory tract infections with the aim of extending the clinical useful period of new antibiotics.

Many, if not all, large pharmaceutical companies had invested in macrolide and ketolide research into the early 2000s. These efforts led to macrolide/ketolide compounds that were as potent as or better than telithromycin. Some of these compounds are described in a recent review.30 One compound, cethromycin, was out-licensed by Abbott Labs (Chicago, IL) and developed by a start-up company, Advanced Life-Sciences.31 Cethromycin was a ketolide like telithromycin, but the location of the side chain is at the 6 position (shown in Fig. 3).

Although microbial activity was similar to telithromycin, cethromycin was highly protein bound and was a CYP3A4 inducer, which led to poor oral bioavailability. Larger doses of cethromycin could not be used as they resulted in unacceptable increased gastrointestinal motility. Although no safety concerns were revealed in the Phase 3 trials, cethromycin was not non-inferior to




Figure 1. Chemical structures of first generation (erythromycin) and second generation (clarithromycin and azithromycin) macrolide antibiotics.


Figure 2. Chemical structure of telithromycin.

clarithromycin in the sicker CABP patient (possibly due to poor bioavailability). A New Drug Application (NDA) submitted in 2008 failed to gain approval by FDA.32

The mechanism behind the Ketek adverse events were unknown and differentiation of other macrolide/ketolide compounds from Ketek could not be determined pre-clinically. As a result, no other macrolide/ketolide reached late clinical development and all programs were terminated.

Figure 3. Chemical structure of cethromycin.

4. Development of a new, effective and a well tolerated macrolide

In 2003-2005, at the time when a large number of pharmaceutical companies were trying to discover a lead macrolide that would be competitive with telithromycin, Optimer Pharmaceuticals in San Diego made and tested hundreds of macrolides and ketolides. Working with scientists from the Scripps Institute, they used copper click chemistry to synthesize a novel 5-membered 1,2,3-triazole ring which was incorporated into the side chain of the 11-12 carbamate at the position of the imidazole in the side chain of telithromycin. Control of the stereo chemical substitution on the 1,2,3-triazole ring via copper(I) catalysis had never been accomplished before the discovery by Professor Sharpless33 as well as by Tornoe.34 Unlike imidazoles that are metabolically unstable in vivo, the 1,2,3-triazole ring has the advantage of being metabol-ically stable. Cempra Pharmaceuticals was founded by in-licensing the entire macrolide program from Optimer Pharmaceuticals with the hope of finding a suitable lead candidate to develop. Among the several hundred molecules made at Optimer, one, which was coded 0P-1068, showed the best activity both in vitro and in animal infection models. After licensing the macrolide program, discussion at Cempra focused on three lead molecules; 0P-1068, 0P-1055, the des-2-fluorine analog of 0P-1068, and a third molecule that had only a phenyl group at the terminus of the side chain instead of the aminophenyl group of 0P-1068 (shown in Fig. 4).

We noted that 0P-1068, recoded CEM-101 and later named solithromycin by Cempra, was the most potent in vitro and the only one of the three molecules that had activity against telithro-mycin-resistant bacterial strains. In addition to activity against tel-ithromycin-resistant strains, it was predicted to be chemically stable owing to the 1,2,3-triazole and the 2F.

Testing many analogs with and without the 2-F revealed that there was complementarity in the ribosome interactions between the 2-F and the aminophenyl in the side chain. The binding of soli-thromycin to bacterial ribosomes with multiple and strong interactions has been confirmed by X-ray crystallography studies (shown in Fig. 5).35

The aminophenyl as well as the 1,2,3, triazole provided multiple ribosomal interactions for solithromycin that were not observed in the telithromycin-ribosome complex. The desosamine sugar of solithromycin interacted with the ribosome in the same manner as all macrolides. The 2-Fluorine of solithromycin also has an interaction with the ribosome resulting in a third interaction site and is believed to contribute to improved pharmacokinetics. In addition to enhancing its activity against telithromycin-resistant strains and pharmacokinetics, the 2-F prevents the 3-keto from enoliza-tion previously observed with telithromycin and other ketolides as noted in solution by nuclear magnetic resonance (NMR) (as shown in Fig. 6).36

Solithromycin OP-1055

Figure 4. Chemical structure of solithromycin (0P-1068) and 0P-1055.

Figure 5. Crystallographic structure of solithromycin bound to the E. coli ribosome at 3.2 A. (A) Solithromycin (pink) and telithromycin (yellow) positions of the macro-lactone ring and the alkyl aryl side chain in interactions with the ribosome; (B) Solithromycin alkyl aryl side chains interactions with the ribosome; (C) Solithromycin and telithromycin interactions with the ribosome; (D) Proximity of solithromycin's fluorine to base pair C2611-G2057 of the ribosome (Antimicrobial Agents and Chemotherapy, 2010, 54(12), 4965 (only Fig. 5 part D is reproduced), doi:, reproduced with permission from American Society for Microbiology.

Figure 6. Reversible conversion of Keto to Enol in telithromycin.

Thus, solithromycin is the first 'pure' ketolide. The importance of the 2-F addition, which enhanced the activity against telithro-mycin-resistant strains, was recognized by naming solithromycin as a fourth generation macrolide and the first fluoroketolide.

Since reservation was expressed by expert advisors on developing a drug that had an aniline moiety (aminophenyl), extensive metabolic stability experiments were conducted on solithromycin to determine if the aminophenyl would be metabolized to reactive metabolites or be cleaved to release aniline. Even with very sensitive detection methods, down to 1.0 nM, no aniline was detected after metabolism by hepatocytes. These studies provided reassurance to concerns about aniline or aminophenyl related toxicities recognized in other marketed medications such as sulfamethoxa-zole, sulfanilamide, and para-aminosalicylic acid. Cempra then conducted three in vitro genetic toxicology assays; bacterial reverse mutation assay (the Ames test) with and without S9 activation, mouse lymphoma forward mutation assay and chromosomal aberration in human peripheral blood lymphocytes assay that are used to show that a drug is not mutagenic in vitro. In addition, solithromycin was also tested in the in vivo rat bone marrow micronu-cleus assay. Solithromycin was not mutagenic or clastogenic in any of these studies. As a result, the aminophenyl was no longer considered to have any aniline-associated side effects of mutagenicity or toxicity.

Solithromycin was well tolerated in one-, and three-month oral toxicology studies conducted in rats and monkeys. In the 3-month toxicology studies, with doses up to 125 mg/kg administered once per day, all animals survived and during the 3 month recovery period after completion of dosing most tissue and organ changes noted during dosing resolved. Following these studies, clinical Phase 1 single and multiple dose escalation studies commenced.37 Pharmacokinetics data from these studies were used in pharmacokinetics and pharmacodynamics (PK/PD) assessments to select for the Phase 2 study in CABP patients a dosing regimen of a single 800 mg oral loading dose on day 1 followed by a single dose of 400 mg (maintenance dose) on the following four days.

The Phase 2 trial, which was a double blind, multicenter study in moderate to moderately severe CABP, was conducted as a two arm 1:1 randomization study using 750 mg levofloxacin as the comparator. Since monotherapy was going to be tested in moderate to moderately severe CABP patients, azithromycin was considered inappropriate since pneumococcal azithromycin resistance had risen to over 30% as early as 2012. In this Phase 2 trial, the first time that a macrolide was tested as monotherapy in moderate to moderately severe CABP, solithromycin had an acceptable safety profile and was statistically non-inferior to levofloxacin.38

5. Telithromycin's pyridine—The smoking gun

In 2012 when Cempra completed Phase 2 development, many experts stated that telithromycin also had not shown adverse events in clinical development. However, a review of the telithro-mycin clinical literature, revealed that in published telithromycin trials, as early as Phase 1, subjects reported visual effects at high doses (although other major adverse events that were later noted were not observed).24 We examined the structure of telithromycin for clues that could explain the reported serious adverse events. Telithromycin contains a pyridine ring at the terminus of the side chain as illustrated in Figure 7.

Pyridine moieties are generally employed by medicinal chemists working in the CNS area to obtain activity against nicotinic acetylcholine receptors (nAChRs).39,40 Extensive experiments conducted by Dr. Daniel Bertrand, an expert in nicotinic acetylcholine receptors (nAChRs), and his staff tested telithromycin, solithromy-cin, and the older macrolides against human nAChRs expressed in


Figure 7. Similarity of nicotine and the pyridine of telithromycin.

Xenopus oocytes.41 These experiments demonstrated that telithro-mycin blocked the nAChRs found in the ciliary ganglion of the eye, in particular the a7 and a3p4 receptors. These receptors are involved in visual accommodation; blockade of these receptors causes reversible visual disturbance. The finding that young women were more often than men to have visual disturbances after treatment with telithromycin could be explained by progesterone sensitization of these receptors.42 These data offer a mechanistic explanation for blurry vision due to interference of visual accommodation. The possible reason for syncope was proposed to be caused by inhibition of the a3p4 nAChRs with decreased vagal activity caused by the pyridine-containing piece of the teli-thromycin side chain cleaved at the imidazole. In order to explain the adverse event finding of myasthenia gravis, the nAChRs at the neuromuscular junction were examined. The a3p2 pre-synaptic nAChR and the post neuromuscular junction ap5e receptors were shown to be antagonized by telithromycin, thereby explaining the exacerbation of myasthenia gravis seen in some patients treated with telithromycin. We next thought about the cause for teli-thromycin-associated hepatic toxicity.

Branches of the vagus nerve terminating in the liver and hepatic macrophages express a7 nAChRs. These receptors are identical to the a7 nAChRs in the ciliary ganglion in the eye. Tracey et al. has demonstrated that when stimulated, hepatic a7 nAChRs block cytokines, like TNFa release by the cholinergic cytokine pathway.43,44 Thus, the a7 nAChRs have a protective function in the liver. Activation of a7 nAChRs blocks liver injury from an acute inflammatory response while blockade promotes a cytokine rush, potentially causing liver injury and apoptosis. Telithromycin blocks the cholinergic anti-inflammatory response, allowing macrophages to release a number of cytokines, including TNFa. Thus, a patient who is predisposed to liver inflammation, for example from alcohol or acetaminophen, might develop centrilobular necrosis and eosinophilic infiltration, also seen in patients with hepatic failure, and is strongly suggestive of acute liver injury related to hypersensitivity.26,27 In the rat model, direct electrical stimulation of the vagus nerve in vivo during endotoxemia inhibited TNF synthesis in the liver, and prevented development of shock.44,45 In other animal models, loss of vagal regulation of hepatic inflammation (by vagotomy) has been demonstrated to increase the lethality of pro-inflammatory insults to the liver.43,46 Through its inhibition of nAChRs, telithromycin may dampen feedback inhibition of systemic inflammation, perhaps explaining the unique hepatotoxicity of that molecule in comparison with the older macrolides.

In summary, all of the Ketek effects could be readily explained by telithromycin-related inhibition of nAChRs (shown in Fig. 8).

Unlike telithromycin, the aryl-alkyl side chain of solithromycin does not have a pyridine moiety, does not significantly block a7 nAChRs, and thus is chemically and biologically differentiated from telithromycin (shown in Fig. 9).

6. Intravenous dosing formulation for solithromycin

In addition to the oral formulation used in previous trials, a soli-thromycin intravenous formulation was developed to allow dosing of hospitalized patients with CABP or seriously ill patients with CABP requiring 1-2 doses of an antibiotic administered in the emergency room. Solithromycin intravenous toxicology studies for up to 28 days showed that daily solithromycin administration was well tolerated in both dogs and monkeys. Unlike all the older macrolides, solithromycin did not prolong the QT interval which allowed safe administration of large intravenous doses without risk of causing arrhythmias.47 Although an intravenous formulation of telithromycin had been made, Phase 3 trials with a telithro-mycin IV infusion formulation were not published.48 Solithromycin was shown to be safe and well tolerated in a Phase 1 safety trial

which allowed Cempra to eventually conduct a Phase 3 IV to oral CABP trial.49

7. Phase 3 clinical trials

The solithromycin oral and intravenous formulations have been tested in two global Phase 3 trials which demonstrated that oral and IV solithromycin is well tolerated and non-inferior to moxi-floxacin, a potent, broad spectrum fluoroquinolone.49,50 Two New Drug Applications (one for oral solithromycin and one for IV solithromycin) for the use of solithromycin in the treatment of moderate to moderately-severe CABP have been submitted to the FDA. Solithromycin has received Priority Review and Fast Track designation from the FDA and, if approved, Cempra plans to market the antibiotic in the U.S.

8. Solithromycin in pediatrics

New drugs need to be developed for use in children. To this end, two U.S. laws have been enacted. The first is the Pediatric Research Equity Act (PREA), which requires pharmaceutical companies to study the drug product in children for the same indication for

a3|32 & a|38e nAChRs

oc7 & a3|34 nAChRs

a7 & a3p4 nAChRs

Figure 8. Nicotinic acetylcholine receptors and their distribution in various organs. Nicotine binds and activates nicotinic acetylcholine receptors in the eye, muscle, liver and brain. (A) Variety of nACh receptors; (B) nACh receptors in the ciliary ganglion of the eye; (C) nACh receptors at the neuromuscular junction; (D) The brain and autonomic response via the a7 nACh receptor at the vagus nerve and macrophages in the liver whose function is to inhibit damaging cytokine release, such as TNF-a in the liver. Inhibition of these a7 nACh receptors and this autonomic response results in FAS activation and apoptotic cell death in the liver. The brain also contains the a3p4 nACh receptors at the vagus nerve nucleus at the base of the brain, wherein the subsequent blocking of its signal could result in syncope.

Telithromycin versus Solithromycin

Figure 9. Chemical differentiation of solithromycin from telithromycin.

which it is approved in adults. The second is the Best Pharmaceuticals for Children Act (BPCA), which provides the pharmaceutical company with an additional six months of marketing exclusivity as an incentive to conduct FDA-requested pediatric studies. Prior to these laws, most drugs approved for adult use in the US were used '''off-label' in children without demonstration of safety, effectiveness or appropriate pharmacokinetics in children. Children, especially newborns to 8 years, metabolize and eliminate drugs quite differently than adults, and hence the pharmacokinetics can be drastically different. In the last decade only new antibiotics with IV formulations, such as ceftaroline, have been tested in children with CABP. Since oral formulations of these antibiotics are not available, pediatricians do not have convenient oral formulations to prescribe, and so they must resort to injectable antibiotics requiring hospitalization for children with CABP. Although there are oral tetracycline and fluoroquinolone formulations, these are not recommended for use in children because of safety, leaving amoxicillin and amoxicillin/clavulanic acid as the only oral treatment alternatives for CABP in children. While these antibiotics are effective against pneumococcus and many H. influenzae, they have no activity against Mycoplasma, leaving a treatment gap for children.51,52

Historically, macrolides were commonly used to treat CABP and other respiratory infections in pediatrics. The safety, efficacy and targeted spectrum of activity of macrolides have been useful in treating respiratory tract infections in children, but in recent times have lost their utility because of increasing resistance. The safety and tolerability of solithromycin in adult CABP studies led to funding from The Biomedical Advanced Research and Development Authority (BARDA) to support the development of oral capsules, oral suspension, and IV solithromycin formulations, as well as clinical studies in pediatric age groups for newborns to children 17 years of age. Initial safety and pharmacokinetic data on the oral and intravenous formulations have been reported in some of the age groups.53,54 A pivotal Phase 2/3 trial in children with CABP (from neonates to age 17) has been initiated with oral capsules, oral suspension and intravenous formulations.

9. Additional indications

Neisseria gonorrhoeae has become resistant to all oral antibiotics. The current recommended treatment is intramuscular ceftriaxone and 1000 mg of azithromycin orally (the latter to treat Chlamydia, which is frequently a co-infection).55 A single dose of oral solithromycin was shown to be clinically effective and micro-biologically active against N. gonorrhoeae in a Phase 2 study of

patients with uncomplicated gonorrhea with or without chlamydia infection.56 Due to this unmet need, a single, oral 1000 mg dose of solithromycin is being evaluated in a Phase 3 trial to treat gonorrhea with or without concomitant chlamydia infection.

Solithromycin did not show untoward effects in Segment I, Segment II and Segment III reproductive and developmental toxicology studies, which will facilitate an evaluation of solithromycin use during pregnancy. In Australia, studies in pregnant ewes, a surrogate model for human pregnancy, demonstrated solithromycin achieved potentially useful concentrations in amniotic fluid, cord blood and placenta.57,58 In an ex vivo placental perfusion model, solithromycin was efficiently transferred across the human placenta.59 These features, coupled with the potent activity against Group B Streptococcus,60 Ureaplasma,61,62 Mycoplasma hominis63 and Gardnerella vaginalis64 could make it a very useful antibiotic for this special population.

The anti-inflammatory benefit from macrolides has led to chronic administration to patients with Chronic Obstructive Pulmonary Disease (COPD) and cystic fibrosis.65,66 The antiinflammatory effects are proposed to be through the upregulation of HDAC-2 promoter (histone deacetylase-2) which results in a subsequent downregulation of important cytokines, such as TNFa.65,67 In vitro, studies, including those with macrophages from COPD patients demonstrate that solithromycin is also capable of modulating the immune response, perhaps to a greater extent than the older macrolides.68 It was also more active than the older macrolides in a mouse model for COPD, where mice were exposed to cigarette smoke to induce pulmonary disease reminiscent of COPD.65 Since solithromycin does not enter the mammalian nucleus (unpublished observations, P. Tulkens, Université Catholique de Louvain), the mechanism of HDAC-2 promoter activation could be indirectly through inhibition of Akt phosphorylation.67 The particular target in the pathway for Akt phosphorylation inhibition has not yet been identified but has been shown not to be through the inhibition of PI3K enzymes.67 Further studies are expected to determine if solithromycin could provide benefit to COPD patients.

10. Conclusions

There is an increasing need for a new macrolide as a result of increasing resistance associated with older antibiotics as well as safety issues associated with fluoroquinolones. Based on the chemical structure, safety and tolerability of solithromycin was anticipated, and then confirmed by pre-clinical and clinical studies. The side chain and the 2-fluorine of solithromycin imparts potency to the macrolide pharmacophore. If solithromycin receives

marketing approval, intravenous and oral formulations are expected to provide flexibility in dosing CABP patients, and allow patients to be switched from IV to oral drug. Treatment with solithromycin in the outpatient may allow for a complete hospitalization avoidance or reduce the patient's length of stay. Development of a pediatric suspension for treating children unable to swallow oral capsules, and an intravenous formulation will provide dosing flexibility to pediatricians and their patients. Assuming solithromycin obtains marketing approval, the shadow of Ketek will be left behind, to bring a much needed antibiotic to the market.


The authors acknowledge the Cempra staff as well as its investors, especially those who have traveled the 'Solithromycin Journey' with Cempra over the last decade during the development of solithromycin. Special thanks are due to Dr. Gary Horwith of Cempra who carefully edited the manuscript.

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