Multiple antibiotic resistance as a risk factor for mortality and prolonged hospital stay: A cohort study among neonatal intensive care patients with hospital-acquired infections caused by gram-negative bacteria in Vietnam.

BACKGROUND: Antibiotic resistance (ABR) is an increasing burden for global health. The prevalence of ABR in Southeast Asia is among the highest worldwide, especially in relation to hospital-acquired infections (HAI) in intensive care units (ICU). However, little is known about morbidity and mortality attributable to ABR in neonates. AIM: This study aimed to assess mortality and the length of hospitalization attributable to ABR in gram-negative bacteria (GNB) causing HAI in a Vietnamese neonatal ICU (NICU). METHODS: We conducted a prospective cohort study (n = 296) in a NICU in Hanoi, Vietnam, from March 2016 to October 2017. Patients isolated with HAI caused by GNB were included. The exposure was resistance to multiple antibiotic classes, the two outcomes were mortality and length of hospital stay (LOS). Data were analysed using two regression models, controlling for confounders and effect modifiers such as co-morbidities, time at risk, severity of illness, sex, age, and birthweight. RESULTS: The overall case fatality rate was 44.3% and the 30 days mortality rate after infection was 31.8%. For every additional resistance to an antibiotic class, the odds of a fatal outcome increased by 27% and LOS increased by 2.1 days. These results were statistically significant (p < 0.05). CONCLUSION: ABR was identified as a significant risk factor for adverse outcomes in neonates with HAI. These findings are generally in line with previous research in children and adults. However, heterogeneous study designs, the neglect of important confounders and varying definitions of ABR impair the validity, reliability, and comparability of results.

Delayed Antidepressant Efficacy and the Desensitization Hypothesis.

Many conventional antidepressants can quickly raise the levels of extracellular serotonin, yet their positive effects on mood ensues only weeks later. This delay in efficacy is a clinical problem that has proven difficult to overcome. Early investigation noted that the initial increases in extracellular serotonin engaged strong feedback inhibition of serotonin neurons via 5-HT1A autoreceptors, resulting in a profound reduction in their firing rate. Over the course of chronic treatment, however, firing rate returned to normal and the inhibition via 5-HT1A receptor agonists was attenuated. The coincident timeline of these phenomena led to the influential hypothesis that the relationship was causal and that gradual loss of feedback inhibition mediated by 5-HT1A receptors was critical to the delayed therapeutic onset. Simple and appealing, the desensitization hypothesis has taken strong hold, yet much of the supporting evidence is circumstantial and there are several observations that would refute a causal relationship. In particular, even though 5-HT1A receptors may desensitize, there is evidence that feedback inhibition mediated by remaining receptors persists. That is, baseline serotonin firing rate returns to normal not because of 5-HT1A desensitization but rather despite ongoing feedback inhibition. Thus, while 5-HT1A receptors remain important for emotional behavior, it may be other slow-adaptive changes triggered by antidepressants that allow for therapeutic effects, such as those involving glutamatergic synaptic plasticity.

Evidence for intact 5-HT1A receptor-mediated feedback inhibition following sustained antidepressant treatment in a rat model of depression.

Serotonin (5-HT) neurons are strongly implicated in mood disorders such as depression and are importantly regulated by feedback inhibition mediated by 5-HT1A receptors. These receptors may play a role, albeit a poorly understood one, in the generation of mood disorders, treatment response to antidepressants and delayed therapeutic efficacy. Here we sought to gain insight into the role of 5-HT1A receptor-mediated feedback inhibition in these processes by studying Fos protein expression within serotonin neurons in a rat model of stress-related mood disorder, early life maternal separation (MS), combined with two-week treatment with the antidepressant fluoxetine (FLX) in adulthood. We gauged 5-HT1A receptor-mediated feedback inhibition by the ability of the antagonist, WAY-100635 (WAY), to disinhibit Fos expression in 5-HT neurons. We found that two-week FLX treatment dramatically inhibited Fos expression in serotonin neurons and that this effect was reversed by blocking 5-HT1A receptors with WAY. Together these observations reveal that after prolonged exposure to SSRIs, endogenous 5-HT1A receptors continue to exert feedback inhibition of serotonin neurons. Furthermore we found unique effects of pharmacological treatments after MS in that the WAY effect was greatest in MS rats treated with FLX, a phenomenon selective to the rostral 2/3 of the dorsal raphe nucleus (B7). These results indicate that the balance between activation and feedback inhibition of serotonin neurons in B7 is altered and uniquely sensitive to FLX after early-life stress.