It has been known for decades that intrauterine infection accompanied by intraamniotic inflammation is a major cause of early preterm birth (PTB) and its associated neonatal morbidity and mortality. However, clinical trials of antenatal antibiotic therapy to prevent PTB have, to a large extent, been unsuccessful. Recent microbiome studies have profiled the bacteria associated with intrauterine infection, finding the presence of many different bacteria in the amniotic cavity with preterm deliveries; they have also reinforced the fact that inflammation can occur without the presence of bacteria in the amniotic cavity, and that bacterial infection is much more benign in the absence of an inflammatory response.
Collectively, these studies highlight the essential therapeutic requirements for successfully preventing infection-inflammation associated PTB: 1) antibiotic therapy that effectively treats the intrauterine infection, and 2) anti-inflammatory therapy that suppresses the sterile or anti-bacterial inflammatory response. Few researchers have appreciated the clinical importance of delivering dual antimicrobial/anti-inflammatory therapy and the risks of treating one but not the other.
The antibiotics that have been evaluated to date have either lacked the ability to treat the major organisms known to cause PTB, or have lacked the ability to reach fetal and amniotic tissues and fluids and treat the infection at its source. Moreover, while several anti-inflammatory therapeutic strategies have been proposed and evaluated in animal models, concerns regarding therapeutic efficacy and safety have hindered major advances in this area.
We have conducted studies of a novel 4th generation macrolide antibiotic, solithromycin, which we believe it is the first antibiotic capable of effectively treating all major PTB-associated bacteria within the amniotic cavity while also supressing inflammation. We have also evaluated the benefits of intraamniotic delivery of cytokine signalling inhibitors in conjunction with antibiotics, using a pregnant sheep model. The combination of these two therapies may at last provide a successful pharmacological strategy for preventing a significant proportion of preterm deliveries.