The Cochrane database of systematic reviews | Year: 2013
Invasive fungal infection is an important cause of mortality and morbidity in very low birth weight infants. Early diagnosis is difficult and treatment is often delayed. Systemic antifungal agents (usually azoles) are increasingly used as prophylaxis against invasive fungal infection. To assess the effect of prophylactic systemic antifungal therapy on mortality and morbidity in very low birth weight infants. We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 3), MEDLINE, EMBASE, and CINAHL (to August 2012), conference proceedings, and previous reviews. Randomised controlled trials or quasi-randomised controlled trials that compared the effect of prophylactic systemic antifungal therapy versus placebo or no drug or another antifungal agent or dose regimen in very low birth weight infants. We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors. We identified 11 eligible trials enrolling a total of 1136 infants. Seven trials (involving 880 infants) compared systemic antifungal prophylaxis versus placebo or no drug. These trials were generally small but of good methodological quality. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection in infants who received systemic antifungal prophylaxis (typical risk ratio (RR) 0.41, 95% confidence interval (CI) 0.27 to 0.61; risk difference (RD) -0.09, 95% CI -0.14 to -0.05). The average incidence of invasive fungal infection in the control groups of the trials (16%) was much higher than that generally reported from large cohort studies (< 5%). Meta-analysis did not find a statistically significant difference in the risk of death prior to hospital discharge (typical RR 0.74, 95% CI 0.52 to 1.05; RD -0.04, 95% CI -0.08 to 0.01). Very limited data on long-term neurodevelopmental outcomes were available. Two trials that compared systemic versus oral or topical non-absorbed antifungal prophylaxis did not detect any statistically significant effects on invasive fungal infection or mortality. Two trials that compared different dose regimens of prophylactic intravenous fluconazole did not detect any significant differences in infection rates or mortality. Prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in very low birth weight infants. This finding should be interpreted and applied cautiously since the incidence of invasive fungal infection was very high in the control groups of most of the included trials. Meta-analysis does not demonstrate a statistically significant effect on mortality. There are currently only limited data on the long-term neurodevelopmental consequences for infants exposed to this intervention. In addition, there is a need for further data on the effect of the intervention on the emergence of organisms with antifungal resistance.
News Article | September 14, 2016
Postpartum depression is the most common complication of pregnancy and childbirth, affecting up to 15 percent of all women within the first three months following delivery. Research has shown that mothers of infants born prematurely have almost double the rates of postpartum depression, particularly during their time in the neonatal intensive care unit (NICU).
A new study of gut bacteria in premature infants reveals the vast scope of the problem of antibiotic resistance and gives new insight into the extreme vulnerability of these young patients, according to researchers at Washington University School of Medicine in St. Louis. The study appears online March 7 in the journal Nature Microbiology. The gut microbiome has emerged in recent years as a vital player in human health, affecting factors as diverse as nutritional status, bone development and immune function. The new study shows that the microbes colonizing the gastrointestinal tracts of babies born prematurely are not health-promoting or even benign organisms, but close relatives of bacteria known to cause hospital-acquired infections, including Escherichia coli (E. coli), Klebsiella and Enterobacter. The researchers sequenced all of the DNA in the bacterial communities living in the preterm babies’ guts. Using new techniques they developed, the investigators identified almost 800 genes in these bacterial communities that confer resistance to antibiotics. They noted that about 80 percent of these genes had not previously been associated with antibiotic resistance. “Our study demonstrates that even well-studied bacteria — the ones that we know cause disease or their close relatives — have many genes associated with antibiotic resistance that have not been characterized before,” said senior author Gautam Dantas, Ph.D., associate professor of pathology and immunology. “Premature babies do not always get bacterial infections that need treatment, but we have known for a long time that they are at higher risk for infection than babies born full term. Now, we know that preterm-infant guts are attracting exactly the wrong kinds of bacteria.” Because of this increased risk of infection, almost all preterm infants cared for in neonatal intensive care units (NICUs) receive antibiotics in the first two days of life, regardless of their health status. And a majority of those receive many more days of treatment. “Extremely preterm infants often have multiple medical problems, with symptoms of prematurity overlapping with other conditions like infection,” said co-author Barbara B. Warner, M.D., a professor of pediatrics and neonatologist at St. Louis Children’s Hospital. “The conventional wisdom has been antibiotics can’t hurt and they might help. But our new study demonstrates that wide-scale use of antibiotics in this population does not come without cost.” The study included babies cared for in the NICU of St. Louis Children’s Hospital, where the investigators collected 401 fecal samples from 84 preterm infants over the first three months of life. By sequencing all of the bacterial DNA in these fecal samples, the investigators identified resistance genes to 16 different antibiotics. The babies that received antibiotics only in the first few days of life served as a comparison group to the babies that received antibiotics early plus subsequent treatments later. On average, the babies that continued receiving antibiotics had a total of 21 days of treatment. All babies were born before 33 weeks’ gestation. In general, research from this and other groups suggests it is better to have a high diversity of bacterial species living in the gut. Compared with babies born full term, preterm infants were found to have 10-fold fewer species of bacteria colonizing the gut. And among the preterm babies, those receiving the most antibiotics showed the least species diversity. Giving breast milk was associated with increased bacterial diversity, as was each baby’s increasing age, perhaps simply from having more time for exposure. The specific antibiotics associated with the lowest species richness were drugs called meropenem, cefotaxime and ticarcillin-clavulanate. Dantas said the meropenem finding is particularly alarming, as it’s part of the carbapenem class of drugs that are considered antibiotics of last resort. They are used to treat infections caused by bacteria closely related to the species most commonly found in these infants’ GI tracts. “Consider what is going on in terms of selection pressure,” Dantas said. “As with any antibiotic, giving carbapenems encourages the selection of bacteria resistant to this drug. And if these microbes, which dominate these babies’ guts, become resistant to carbapenems, the microbes go on the highest urgency threat list at the Centers for Disease Control and Prevention.” According to the CDC, carbapenem-resistant Enterobacteriaceae (CRE) are resistant to nearly all existing antibiotics and about half of patients in intensive care units who contract a bloodstream infection from CRE die from that infection. Enterobacteriaceae is a large family of bacteria that includes E. coli, Klebsiella and Enterobacter. In the new study, the two antibiotics most commonly given to the preterm infants were found to be vancomycin and gentamicin, which both had divergent effects on species richness. The researchers were able to predict the direction of this effect with high accuracy, based on the sequences of bacteria present and the resistance genes they carried in samples taken before treatment. The researchers also showed that treating with one antibiotic can dial up resistance to seemingly unrelated antibiotics. Dantas said this surprising finding makes sense because they found the majority of these microbes were resistant to multiple drugs, showing that resistance genes tend to cluster together in the same organisms. “This data demonstrates the collateral damage these drugs can do,” Dantas said. “If doctors give penicillin, it makes sense that you will see enrichment in the proportion of bacteria resistant to penicillin. But perhaps a vancomycin-resistant gene is nearby. A doctor may not even be giving vancomycin, but vancomycin resistance increases because the genes happen to be grouped together. “This is a consequence of our history of antibiotic use,” he added. “We’ve given these bacteria powerful reasons to collect all these resistance genes together.” Warner expressed hope that clinicians will use this information to make decisions about the best ways to treat these vulnerable patients. “While antibiotics can certainly still be lifesaving, we are becoming more aware of the risks they pose,” she said. “This study arms us with information that may help us push toward shorter antibiotic treatment courses and minimizing the use of broad-spectrum antibiotics.” Dantas expressed concern over the dwindling numbers of effective antibiotics and the fact that few new drugs are in development. He also suggested a shift in strategy for the design of new generations of antibiotics. “If we can stop these bacteria from producing toxins, rather than kill them outright, we won’t see the same selection pressure,” he said. “We don’t necessarily need to kill these bacteria, we just need to stop them from killing us.”
News Article | September 7, 2016
A factor found in umbilical cord blood could become the basis for developing a new therapy to fight harmful inflammation, University of Utah School of Medicine researchers report. When given to mice, the newly discovered factor countered signs of inflammation and sepsis, such as fever, fluctuations in respiratory rate, and death. The factor circulates in the blood of newborns for about two weeks after birth and is not found in older babies or adults, according to the study published online Sept. 6, 2016, in The Journal of Clinical Investigation. "We found something we weren't expecting, and it has taken us to new strategies for therapy that didn't exist before," says Guy Zimmerman, M.D., professor of internal medicine and senior author who carried out the investigation in collaboration with lead author and associate professor of pediatrics, Christian Con Yost, M.D., and their colleagues at the University of Utah School of Medicine. Anyone who has twisted an ankle or been stung by a bee is familiar with inflammation and its telltale redness, pain, and swelling, all positive signs that the body is mounting defenses against the insult. But under certain circumstances, inflammation can turn against us, causing damage to healthy tissue. An out-of-control inflammatory response is thought to be behind a diverse spectrum of conditions from rheumatoid arthritis to sepsis, an overreaction to infection and common cause of in-hospital deaths. Yost and colleagues isolated a cord blood factor, called neonatal NET inhibitory factor (nNIF), based on its ability to inhibit production of a specific component of the inflammatory response, called NETs (neutrophil extracellular traps). While NETs are thought to ordinarily help the body ward off infectious bacteria and viruses, they can also damage blood vessels and organs during sepsis. As physicians who have treated critically ill patients with the condition, Zimmerman and Yost immediately saw the therapeutic potential of nNIF. "We knew we were onto something that could be very meaningful," recalls Yost. To test whether the cord blood factor could control sepsis, the scientists treated groups of mice in which the condition had been induced in different ways. Without treatment, only 20 percent survived longer than two to four days. Mice treated with nNIF had triple the chance for survival, with 60 percent remaining after the same amount of time. "Sepsis is a case where the body's reaction to infection is lethal," says Yost. "nNIF is offering insights into how to keep the inflammatory response within prescribed limits." He adds that they will carry out additional studies to test the therapeutic properties of nNIF. One of the most intriguing observations is that the factor is present for just a brief window of time at the beginning of life. nNIF circulates in cord blood, persists in the baby's own bloodstream for up to two weeks after birth, and then disappears. Yost's team found that the placenta also harbors a similar, but less potent, anti-inflammatory agent. The transient nature of these factors could indicate that inflammation must be under tight control during this time. Keep in mind that normally, inflammation is a way to stave off infectious microbes in healthy individuals. Considering that young babies are so fragile, it seems counterintuitive that nature would make a factor that could lower their defenses. Yost, a NICU doctor, speculates that doing so could potentially keep a baby from mounting an inflammatory attack against its mother, who could be perceived as a foreign invader. It could also allow a baby to tolerate the wealth of bacteria it encounters at birth, an event proving to be important for subsequent development. "The beginning of life is a delicate balance," says Yost. "Our work is showing that it is important to have the right defenses, but they have to be controlled."
The Cochrane database of systematic reviews | Year: 2013
Invasive fungal infection is an important cause of mortality and morbidity in very preterm or very low birth weight infants. Uncertainty exists about the effect of prophylactic oral/topical non-absorbed antifungals to reduce mucocutaneous colonisation and so limit the risk of invasive fungal infection in this population. To assess the effect of prophylactic oral/topical non-absorbed antifungal therapy on the incidence of invasive fungal infection, mortality and morbidity in very preterm or very low birth weight infants. We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL: The Cochrane Library, 2012, Issue 3), MEDLINE, EMBASE, and CINAHL (to August 2012), conference proceedings, and previous reviews. Randomised controlled trials or quasi-randomised controlled trials that compared the effect of prophylactic oral/topical non-absorbed antifungal therapy versus placebo or no drug or another antifungal agent or dose regimen in very preterm or very low birth weight infants. We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors. Four trials, in which a total of 1800 infants participated, compared oral/topical non-absorbed antifungal prophylaxis (nystatin or miconazole) with placebo or no drug. These trials had various methodological weaknesses including quasi-randomisation, lack of allocation concealment, and lack of blinding of intervention and outcomes assessment. The incidence of invasive fungal infection was very high in the control groups of three of these trials. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection [typical risk ratio 0.20 (95% confidence interval 0.14 to 0.27); risk difference -0.18 (-0.21 to -0.16)] but substantial statistical heterogeneity was present. We did not find a statistically significant effect on mortality [typical risk ratio 0.87 (0.72 to 1.05); risk difference -0.03 (-0.06 to 0.01)]. None of the trials assessed posthospital discharge outcomes.Two trials (N = 265) assessed the effect of oral/topical non-absorbed versus systemic antifungal prophylaxis. Meta-analyses did not find any statistically significant differences in the incidences of invasive fungal infection or all-cause mortality. The finding of a reduction in risk of invasive fungal infection in very low birth weight infants treated with oral/topical non-absorbed antifungal prophylaxis should be interpreted cautiously because of methodological weaknesses in the included trials. Further large randomised controlled trials in current neonatal practice settings are needed to resolve this uncertainty. These trials might compare oral/topical non-absorbed antifungal agents with placebo, with each other, or with systemic antifungal agents and should include an assessment of effect on long-term neurodevelopmental outcomes.