A New, Potent, and Placenta-Permeable Macrolide Antibiotic, Solithromycin, for the Prevention and Treatment of Bacterial Infections in Pregnancy

Abstract

Intrauterine infection–inflammation is a major cause of early preterm birth and subsequent neonatal mortality and acute or long-term morbidity. Antibiotics can be administered in pregnancy to prevent preterm birth either prophylactically to women at high risk for preterm delivery, or to women with diagnosed intrauterine infection, prelabor rupture of membranes, or in suspected preterm labor. The therapeutic goals of each of these scenarios are different, with different pharmacological considerations, although effective antimicrobial therapy is an essential requirement. An ideal antibiotic for these clinical indications would be (a) one that is easily administered and orally bioactive, (b) has a favorable adverse effect profile (devoid of reproductive toxicity or teratogenicity), (c) is effective against the wide range of microorganisms known to be commonly associated with intra-amniotic infection, (d) provides effective antimicrobial protection within both the fetal and amniotic compartments after maternal delivery, (e) has anti-inflammatory properties, and (f) is effective against antibiotic-resistant microorganisms. Here, we review the evidence from clinical, animal, and ex vivo/in vitro studies that demonstrate that a new macrolide-derived antibiotic – solithromycin – has all of these properties and, hence, may be an ideal antibiotic for the treatment and prevention of intrauterine infection-­related pregnancy complications. While this evidence is extremely encouraging, it is still preliminary. A number of key studies need to be completed before solithromycin’s true potential for use in pregnancy can be ascertained.

Comparison of Bacterial DNA Profiles in Mid-Trimester Amniotic Fluid Samples From Preterm and Term Deliveries

“…(Urushiyama et al, 2017;Kayem et al, 2018;Zhu et al, 2018). Interestingly, bacterial species typically associated with ascending intrauterine infection and preterm labor were not detected in this study (Keelan et al, 2016). This supports the view that invasion by such species represents a pathological event that likely occurs after 20 weeks' gestation, whereas potential colonization by the species identified in this study occurs much earlier and is non-pathogenic.…”

Current understanding and treatment of intra‐amniotic infection with Ureaplasma spp.

“…Compared with other existing macrolides, it has a higher rate of transplacental passage . Animal studies have shown that the risk of developmental toxicity and/or teratogenesis was low with no mutagenic or clastogenic effects and with low hepatotoxicity …”

Applying Precision Public Health to Prevent Preterm Birth

“…Many of the trials of prophylactic antibiotic therapy given to pregnant women to prevent PTB have failed to employ robust inclusion criteria or delivered poorly effective antibiotic regimens (95, 96). Identifying women who will benefit from treatment is a key requirement for primary prevention: prescribing antibiotics to large numbers of women in pregnancy in order to prevent PTB in a small percentage of recipients is not justifiable in light of the emerging recognition of the potential developmental effects of disrupting the maternal and neonatal microbiomes with antibiotics in pregnancy (97–100). …”

“…It remains to be determined whether more refined and selective molecular techniques may help to improve diagnostic discrimination (109). It is likely that a combination of clinical risk factors (e.g., prior PTB, cervical imaging, and abnormality detection), high-resolution microbial profiling (possibly including bacterial strain identification), and immunological/inflammatory biomarker assessment will be needed, in combination with a highly effective antimicrobial regimen (97, 126), to enable a truly effective maternal “screen and treat” program to achieve the desired level of precision and effectiveness required for a primary prevention public health program (127–133). …”