Eradication of Staphylococcus epidermidis within Biofilms: Comparison of Systemic versus Supratherapeutic Concentrations of Antibiotics.

Biofilm-forming bacterial infections result in clinical failure, recurring infections, and high health care costs. The antibiotic concentrations needed to eradicate biofilm require further research. We aimed to model an in vitro prosthetic joint infection (PJI) to elucidate the activity of traditional systemic concentrations versus supratherapeutic concentrations to eradicate a Staphylococcus epidermidis biofilm PJI. We evaluated S. epidermidis high-biofilm-forming (ATCC 35984) and low-biofilm-forming (ATCC 12228) isolates in an in vitro pharmacodynamic biofilm reactor model with chromium cobalt coupons to simulate prosthetic joint infection. Vancomycin, daptomycin, levofloxacin, and minocycline were used alone and combined with rifampin to evaluate the effect of biofilm eradication. We simulated three exposures: (i) humanized systemic dosing alone, (ii) supratherapeutic doses (1,000× MIC), and (iii) and dosing in combination with rifampin. Resistance development was monitored throughout the study. Simulated humanized systemic doses of a lipoglycopeptide (daptomycin), a fluoroquinolone (levofloxacin), a tetracycline (minocycline), and a glycopeptide (vancomycin) alone failed to eradicate a formed S. epidermidis biofilm. Supratherapeutic doses of vancomycin (2,000 µg/mL) and minocycline (15 µg/mL) with or without rifampin (15 µg/mL) failed to eradicate biofilms. However, a levofloxacin supratherapeutic dose (125 µg/mL) with rifampin eradicated the high-biofilm-producing isolate by 48 h. Interestingly, supratherapeutic-dose exposures of daptomycin (500 µg/mL) alone eradicated high- and low-biofilm-forming isolates in established biofilms. The concentrations needed to eradicate biofilms on foreign materials are not obtained with systemic dosing regimens. The failure of systemic dosing regimens to eradicate biofilms validates clinical findings with recurring infections. The addition of rifampin to supratherapeutic dosing regimens does not result in synergy. Supratherapeutic daptomycin dosing may be effective at the site of action to eradicate biofilms. Further studies are needed.

Lucinactant for the treatment of respiratory distress syndrome in neonates.

Respiratory distress syndrome (RDS) is a leading cause of morbidity and mortality in premature neonates. This syndrome is caused by a lack of endogenous surfactant production in the lungs. Surfactant replacement was established as a safe and effective treatment in the 1990s and has become the standard of care for these infants. Surfactant products are either protein-free synthetic phospholipid compounds or animal-derived lung preparations. Currently, about 90,000 infants a year receive treatment with one of the commercially available animal-derived surfactants. Lucinactant (Surfaxin®) is a new synthetic surfactant with a pulmonary surfactant-associated protein B mimic that recently received FDA approval. The clinical trials that have been performed, although underpowered, may indicate that lucinactant is superior to phospholipid synthetic surfactant preparations and at least as effective as animal-derived surfactants in reducing morbidity and mortality from RDS. This review summarizes the current clinical knowledge about lucinactant.

An experimental porcine model of partial ischaemia of the distal colon.

OBJECTIVE: Ischaemia of the colon is a major challenge in aortoiliac surgery. The aim was to establish an animal model of partial distal colonic ischaemia to study interventional strategies. DESIGN: Randomised experiment. SETTING: University Hospital. Department of Experimental Research. MATERIAL: 19 pigs. INTERVENTIONS: 11 Pigs were subjected to ischaemia consisting of total occlusion of the inferior mesenteric artery and partial occlusion of the superior mesenteric artery. Eight animals were sham controls. Dextran was given. MAIN OUTCOME MEASURES: Haemodynamic measurements, intramucosal pH-measurements (pHi) and histological grading. RESULTS: Both ischaemic animals and controls remained haemodynamically stable. It was possible to maintain stable ischaemia in the distal colon in the pHi-range of 6.9-7.1. There was histological mucosal damage of the distal colon in ischaemic animals but not in controls. CONCLUSIONS: The model could be of value when studying interventional strategies to reduce or reverse ischaemia.

Oral phenobarbital given antenatally to reduce neonatal intraventricular hemorrhage. A comparison between maternal and umbilical cord serum levels at delivery.

This investigation was undertaken to compare maternal and neonatal cord serum levels of phenobarbital given orally to mothers anticipated to deliver very low birthweight infants at risk for neonatal intraventricular hemorrhage (IVH). Fifty women anticipated to deliver between 26 and 34 weeks' gestation agreed to receive a daily oral dose of 90 mg of phenobarbital. The umbilical cord to maternal phenobarbital concentration ratio at birth was 1.05 and remained constant after the first day of maternal therapy. Cord phenobarbital concentrations increased rapidly during the first 3 days until reaching a steady state by the end of the first week of therapy. In contrast to recent promising reports using large doses of phenobarbital given parenterally shortly before delivery, lower doses of oral phenobarbital did not reach cord levels reported to be protective against IVH or therapeutic as an anticonvulsant.

Antenatal phenobarbital and bilirubin metabolism in the very low birth weight infant.

Prior studies in term infants have suggested that in utero phenobarbital exposure may accelerate bilirubin metabolism by stimulating hepatocyte glucuronyl transferase activity. This report reviews our experience with maternal phenobarbital therapy and fetal bilirubin conjugation in the very premature fetus. Mothers with arrested premature labor between 26 and 33 weeks' gestation were randomly assigned to receive oral phenobarbital (90 mg daily) or not. Infants in the two groups were similar in race, birth weight, and gestational age. Conjugated bilirubin levels at birth were significantly higher for infants receiving several days of phenobarbital in utero than no therapy (0.31 +/- 0.03 vs 0.16 +/- 0.01 mg dl, p less than 0.01). A smaller portion of infants exposed to phenobarbital in utero required phototherapy (10/23, 43% vs 24/29, 83%, p less than 0.01), which was also more likely to be delayed beyond 48 hours after delivery. Antenatal phenobarbital enhances bilirubin conjugation before delivery of a very low birth weight infant.

Reversing severe hypoglycemia during pregnancy with glucagon therapy.

Glucagon therapy has been used to reverse severe hypoglycemia-induced unconsciousness, but no known study exists which reports its use during pregnancy. Pregnant diabetic women were eligible if they had either a prior hypoglycemic episode requiring intravenous glucose administration or had repeated capillary blood glucose determinations less than 40 mg/dl without any warning adrenergic symptoms. Of 51 insulin-dependent diabetic women, 16 were candidates for glucagon use during a recent 3 1/2-year period. Seven of these 16 persons required an injection on 12 occasions, and an immediate reversal of unconsciousness was encountered in 11 circumstances. No apparent short- or long-term maternal adverse effects were present. We conclude that glucagon therapy is needed infrequently for diabetic women during pregnancy but is helpful in reversing acute episodes of severe hypoglycemia.

Acetaminophen pharmacokinetics: comparison between pregnant and nonpregnant women.

Acetaminophen is the most commonly taken drug during pregnancy, but knowledge about its absorption and disposition is lacking. Six healthy women volunteered to ingest a standard 1000 mg dose at 36 weeks' gestation and 6 weeks post partum. Mean maternal serum concentrations of acetaminophen were consistently less than but not significantly different from the postpartum values. The mean half-life of acetaminophen during pregnancy (3.7 hours) was not significantly different from the nonpregnant value (3.1 hours). The maximum plasma concentration occurred at 0.8 hours and was 20.8 +/- 6.9 micrograms/ml during pregnancy and 23.7 +/- 6.0 micrograms/ml in the nonpregnant state. The absorption, metabolism, and renal clearance of acetaminophen were unchanged. The decrease in the mean area under the curve during pregnancy may be explained by the increase in volume of distribution of acetaminophen. Potentially hepatotoxic metabolites were not measurable in the maternal serum. We conclude that the absorption and disposition of acetaminophen, when used in a standard oral dose, are not affected by pregnancy.

Severe hypoglycemia during pregnancy: its frequency and predisposing factors in diabetic women.

Severe hypoglycemic episodes, as defined as altered consciousness to the extent that self treatment is impossible, were sought prospectively in pregnant diabetic women. One or more episodes were found in none of 21 gestational onset, insulin-requiring women during their 28 pregnancies but were present in 19 (33%) of the 57 already insulin dependent (Type 1) women during 26 (36%) of their 72 pregnancies. The most common predisposing factors included strict glucose control, anorexia, early morning hours (1200-0900), lack of an adrenergic response and time shortly before the next anticipated meal.

Intravenous ritodrine therapy: a comparison between twin and singleton gestations.

The purpose of this study was to determine whether or not guidelines for intravenous ritodrine therapy for singleton pregnancies in premature labor also apply for twin gestations. Between January 1982 and March 1985, 43 (18%) of 239 women admitted in premature labor had twin fetuses. Intravenous ritodrine therapy was used for four or more hours in 23 of these pregnancies. Compared with a matched group of 23 singleton pregnancies, increases in maternal and fetal heart rates and decreases in maternal diastolic blood pressures were not significantly different. Undesired cardiovascular effects were no more common and usually occurred during the initial infusion period when the dose was increased most rapidly. The averaged doses, duration of therapy, and delays in delivery were also similar between the twin and singleton groups.

Changes in insulin therapy during pregnancy.

Care of the diabetic pregnant woman requires a proper understanding of anticipated changes in insulin therapy as a guide for establishing and maintaining strict glucose control. Changes in daily insulin doses were reviewed for 58 pregnancies of 50 insulin-dependent women who were followed for 26 +/- 3 weeks (mean +/- 1 SD) before delivery. By late gestation, insulin was administered on two or three occasions each day using a combination of regular--and intermediate--acting preparations in 55 (95%) pregnancies. Regardless of the metabolic control and duration of diabetes, averaged daily insulin requirements increased twofold from earlier in pregnancy. Following initial hospitalization, insulin requirements often decreased before increasing almost linearly between 2 and 9 months gestation. Fluctuations in insulin requirements were greatest during the last trimester. Insulin demand dropped precipitously after delivery and was two-thirds the averaged prepregnancy insulin dose or one-third the dose at 9 months gestation by the third postpartum day. The total average insulin dose was the same as that before pregnancy by the end of the first postpartum week. Explanations for these changes in prescribing insulin are described.

Comparison of moxalactam and cefazolin as prophylactic antibiotics during cesarean section.

Prophylactic antibiotics have been shown to be effective in decreasing the incidence of febrile morbidity associated with cesarean section after labor. However, the relative effectiveness of different single antibiotics has been studied infrequently, and these investigations have been limited by small patient samples. Several new, broad-spectrum antibiotics are now available, and any further benefit from more traditional antibiotics for surgical prophylaxis remains untested. A randomized prospective double-blind therapeutic trial was therefore undertaken to compare the value of a first-generation cephalosporin (cefazolin) with a new third-generation cephalosporin (moxalactam). Between July 1981 and June 1983, 254 qualifying women who underwent primary cesarean section after labor were randomly chosen for either of the two treatment groups. Although not statistically significant, the rates of febrile morbidity, wound infection, and endometritis were less for those treated with cefazolin (4.0, 3.2, and 0.8%, respectively) than for those treated with moxalactam (9.2, 7.7, and 1.6%, respectively). No serious adverse effects were apparent in the mother and newborn infant from short-term exposure to either drug. Although the newer, more expensive, and broader-spectrum cephalosporin, moxalactam, was associated with a low postoperative febrile morbidity rate and short postpartum hospitalization, it was no more beneficial than cefazolin.

Self-monitoring of blood pressure during pregnancy.

Instruction in self-determination of blood pressure offers a means for managing a pregnant woman who has chronic hypertension. This approach offers patient participation and reinforces compliance to bed rest. If further identifies the anxiety and emotions involved in a visit to the physician's office, since the blood pressure readings are significantly lower when taken by the patient elsewhere. Furthermore, it offers an effective tool to monitor the effect of antihypertensive drugs on blood pressure in a more accurate manner.