A Phase 2 Trial of Oral Solithromycin 1200 mg or 1000 mg as Single-Dose Oral Therapy for Uncomplicated Gonorrhea

Hook, Edward W.; Golden, Matthew R.; Jamieson, Brian; Dixon, Paula; Harbison, Hanne S.; Lowens, Sylvan; Fernandes, Prabhavathi

doi:10.1093/cid/civ478

Cited by 62 publications

(58 citation statements)

References 12 publications

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“…Nevertheless, N. gonorrhoeae strains with high-level resistance to azithromycin (MIC≥256 μg/ml) are likely resistant also to solithromycin (MIC=4–32 μg/ml) (150). A minor Phase 2 single-center, open-label study has also shown that solithromycin (in a single-dose of both 1.0 g and 1.2 g orally) is effective for treating uncomplicated gonorrhea (152). Currently, a multi-centre, open-label, randomized Phase 3 clinical solithromcyin trial is running.…”

Section: Future Treatments For Gonorrheamentioning

confidence: 99%

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

2016

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Neisseria gonorrhoeae is a strictly human pathogen that is typically transmitted by sexual contact. The associated disease gonorrhea has plagued humankind for thousands of years, with a current estimated incidence of 78 million cases per year. Advances in antimicrobial discovery in the 1920s and 1930s leading to the discovery of sulfonamides and penicillin begun the era of effective antimicrobial treatment of gonorrhea. Unfortunately, the gonococcus developed decreased susceptibility or even resistance to these initially employed antibiotics, a trend that continued over subsequent decades with each new antibiotic that was brought into clinical practice. As this pattern of resistance has continued into the 21st century, there is now reason for great concern, especially in an era when few new antibiotics have prospects for use as treatment of gonorrhea. Here, we review the history of gonorrhea treatment regimens and gonococcal resistance to antibiotics, the mechanisms of resistance, resistance monitoring schemes that exist in different international settings, global responses to the challenge of resistance, and prospects for future treatment regimens in the 21st century.

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Section: Future Treatments For Gonorrheamentioning

confidence: 99%

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

2016

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“…Treatment trials of antibiotics for Neisseria gonorrhoeae infections usually enroll primarily men with urethritis, as the diagnosis of acute gonococcal infection in men with urethritis is easily made by Gram stain of the urethral exudate, followed by confirmatory culture or nucleic acid amplification tests (NAATs) [1]. This allows enrollment during the initial clinic visit with subsequent censoring of the very few subjects whose infections will not be confirmed.…”

Section: Introductionmentioning

confidence: 99%

How to Identify Exposed Women Who Are Infected with Neisseria gonorrhoeae

McLaughlin

Griffiss

2019

Neisseria Gonorrhoeae

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Treatment trials of antibiotics for Neisseria gonorrhoeae infections frequently enroll primarily men with urethritis, as the diagnosis of acute gonococcal infection in men with urethritis is easily made by Gram stain of the urethral exudate, followed by confirmatory culture or nucleic acid amplification tests (NAATs). Enrolling women in treatment trials is of great importance, but N. gonorrhoeae cervical infections cause nonspecific symptoms. This makes it difficult to conduct interventional trials, as large numbers of women with nonspecific symptoms need to be screened for infection. Gram stain of cervical secretions has a strikingly low sensitivity, and culture and/or NAAT results are not available at the time of screening. This necessitates recall and delayed treatment of infected women who may not return and who may spread the infection during the interval. In this chapter we present an algorithm, derived from a comparison of women who did, or did not, become infected during exposure, which identifies those women who are highly likely to be infected before culture and/or NAAT results are available. The algorithm provides an efficient way to conduct interventional trials in women without the problem of recall and delayed treatment.

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“…Macrolides continue to be important in the therapeutic treatment of community-acquired pneumonia (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and atypicals Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae), sexually transmitted diseases (Neiserria gonorhoeae, Chlamydia trachomatis, Mycoplasma genitalium), shigellosis, and salmonellosis. With solithromycin heading for a new drug application (NDA) filing in 2016 and having the in vitro potency to treat erythromycin-resistant pneumococci and gonococci (Farrell et al 2015;Hook et al 2015), macrolides/ketolides will continue as an important part of the antibiotic armamentarium.…”

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confidence: 99%

Resistance to Macrolide Antibiotics in Public Health Pathogens

Fyfe

Grossman

Kerstein

et al. 2016

Cold Spring Harb Perspect Med

163

140

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Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome's interaction with the antibiotic. Alternatively, mono-or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) þ msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 2 0 -hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquired genes are regulated by either translation or transcription attenuation, largely because cells are less fit when these genes, especially the rRNA methyltransferases, are highly induced or constitutively expressed. The induction of gene expression is cleverly tied to the mechanism of action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequences of nascent polypeptides to promote transcription or translation of downstream sequences. Macrolide antibiotics are polyketides composed of a 14-, 15-, or 16-membered macrocyclic lactone ring (14-, 15-, and 16-membered) to which several sugars and/or side chains have been attached by the producing organism or as modifications during semisynthesis in the laboratory (Figs. 1 and 2). Newer semisynthetic derivations, like ketolides telithromycin, and solithromycin, have a C3-keto group in place of the C3 cladinose (akin to naturally occurring pikromycin) (Brockmann and Henkel 1950) and an 11,12-cyclic carbamate with an extended alkyl -aryl side chain that increases the affinity of the antibiotic for the ribosome by 10-to 100-fold (Hansen et al. 1999;Dunkle et al. 2010); in the case of solithromycin, a fluorine substituent at C2 provides an additional ribosomal interaction (Llano-Sotelo et al. 2010). Macrolides continue to be important in the therapeutic treatment of community-acquired pneumonia (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and atypicals Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae), sexually transmitted diseases (Neiserria gonorhoeae, Chlamydia trachomatis, Mycoplasma genitalium), shigellosis, and salmonellosis. With solithromycin heading for a new drug application (NDA) filing in 2016 and having the in vitro potency to treat erythromycin-resistant

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A Phase 2 Trial of Oral Solithromycin 1200 mg or 1000 mg as Single-Dose Oral Therapy for Uncomplicated Gonorrhea

Abstract: NCT01591447.

Cited by 62 publications

References 12 publications

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

How to Identify Exposed Women Who Are Infected with Neisseria gonorrhoeae

Resistance to Macrolide Antibiotics in Public Health Pathogens

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