Human recombinant lactoferrin acts synergistically with antimicrobials commonly used in neonatal practice against coagulase-negative staphylococci and Candida albicans causing neonatal sepsis.

Neonatal sepsis causes significant mortality and morbidity. Coagulase-negative staphylococci (CoNS) and Candida frequently cause neonatal sepsis at >72 h of age. Lactoferrin, which is present in human milk, is a component of innate immunity and has broad-spectrum antimicrobial activity. The synergistic effects of lactoferrin with antibiotics against neonatal isolates have not been systematically evaluated. Here, eight clinical strains (seven neonatal) of CoNS and three strains (two neonatal) of Candida albicans were studied. MIC50 and MIC90 values of human recombinant lactoferrin (talactoferrin; TLF), vancomycin (VAN) and nafcillin (NAF) against CoNS, and of TLF, amphotericin B (AMB) and fluconazole (FLC) against C. albicans, were evaluated according to established guidelines. Antimicrobial combinations of TLF with NAF or VAN against CoNS, and TLF with AMB or FLC against C. albicans, were evaluated by a checkerboard method with serial twofold dilutions. Synergy was evaluated by the median effects principle, and combination indices and dose reduction indices were reported at 50, 75 and 90% inhibitory effect at several drug-dose ratios. It was found that TLF acted synergistically with NAF and VAN against CoNS, and with AMB and FLC against C. albicans, at multiple dose effects and drug-dose ratios with few exceptions. In synergistic combinations, drug reduction indices indicated a significant reduction in doses of antibiotics, which may be clinically relevant. Thus TLF acts synergistically with anti-staphylococcal and anti-Candida agents commonly used in neonatal practice and is a promising agent that needs to be evaluated in clinical studies.

Prophylaxis with lactoferrin, a novel antimicrobial agent, in a neonatal rat model of coinfection.

Lactoferrin has broad-spectrum antimicrobial activity, and the authors hypothesized that recombinant human lactoferrin (Talactoferrin alfa [TLF]) would reduce mortality and morbidity in a coinfection model. The MIC 50 (minimum inhibitory concentration required to inhibit the growth of 50% of organisms) of TLF against Candida albicans and Staphylococcus epidermidis was determined. Neonatal Wistar rats were infected with C albicans or S epidermidis or both, at doses of 2 x10(8) colony-forming units (CFUs) given subcutaneously. Rat pups in each group were randomly given TLF intraperitoneally at 40 mg/kg/dose or 300 mg/kg/dose, or saline in 0.2 mL, once a day for 4 d and were monitored for mortality, weight gain, and blood culture positivity. Trough serum levels of TLF were measured at 24, 48, 72, 96, and 144 h. MIC 50 of TLF was 30 microg/mL and 500 microg/mL for C albicans and S epidermidis, respectively. TLF prophylaxis significantly improved survival in the coinfection group at 40 mg/kg/dose (by 16.1%; P=.019) and at 300 mg/kg/dose (by 15.1%; P=.027) and in the S epidermidis group at a dose of 40 mg/kg/dose (by 18.6%; P=.04). Weight gain was not affected by TLF prophylaxis. Serum trough levels of TLF were 1000-fold lower than in vitro MIC 50. The authors conclude that lactoferrin prophylaxis significantly enhanced survival in coinfection and in the subgroup of S epidermidis infection (40 mg/kg/dose) through indirect mechanisms.

Neonatal coinfection model of coagulase-negative Staphylococcus (Staphylococcus epidermidis) and Candida albicans: fluconazole prophylaxis enhances survival and growth.

Coagulase-negative staphylococci (CoNS) and Candida are among the most common causes of single infections and coinfections in neonates after 72 h of age. In neonates, coinfection increases the rate of mortality threefold and results in significantly greater morbidity compared to those that result from single infections. In an effort to better understand this phenomenon, we developed the first neonatal animal model of coinfection (with CoNS and Candida) and evaluated its effects on mortality and morbidity and the impact of antifungal prophylaxis with fluconazole. Neonatal Wistar rats were infected with Candida albicans and/or Staphylococcus epidermidis with doses of 2x10(8) and 2x10(6) CFU subcutaneously in different combinations and were monitored for mortality, weight gain, and bacteremia. The in vitro sensitivity of C. albicans to fluconazole was evaluated and the MIC was determined. A subset of rats in these experiments received fluconazole at 10 mg/kg of body weight/dose intraperitoneally starting 24 h before infection for 4 days, and the serum trough levels of fluconazole were measured. Coinfection in the suckling rat significantly increased the rate of mortality compared to that after infection with a single species (P<0.001) and resulted in deaths even at sublethal doses. Coinfection also impaired weight gain significantly in severely infected pups compared to that achieved after infection with a single species (P<0.001). Fluconazole prophylaxis significantly reduced mortality by 30% in the Candida group and 36% in the coinfection group and improved weight gain in this neonatal model of coinfection (P<0.001). We developed a neonatal model of coinfection with Candida and CoNS, observed significantly greater mortality and morbidity with coinfection, and found that fluconazole prophylaxis significantly reduced the rates of both mortality and morbidity. Further research on neonatal coinfection is urgently needed to improve clinical outcomes.

Prevention and treatment of respiratory syncytial virus infection in infants: an update.

Respiratory syncytial virus (RSV) is a serious pathogen causing significant mortality and morbidity, especially in premature infants and infants with chronic lung disease or significant congenital heart disease. Therapy for RSV infection is essentially supportive, although several new compounds are under investigation. Therefore, immunoprophylaxis to prevent severe RSV disease in high-risk infants assumes great significance. Palivizumab, a humanized monoclonal antibody to RSV, significantly reduces hospitalization in the first 6 months in premature infants born at less than 35 weeks, infants less than 24 months of age with chronic lung disease and requiring treatment in the last 6 months, and in children 24 months or younger with hemodynamically significant heart disease. A new ultrapotent anti-RSV antibody (MEDI-524) appears to be more effective in animals than palivizumab and is undergoing clinical evaluation. There has been considerable progress in the development of vaccines; namely subunit, live attenuated, genetically recombinant virus and polypeptide vaccines. Plasmid DNA vaccines coding for parts of the F and G surface glycoproteins and vaccinia vector vaccines are also being evaluated. Maternal immunization has the potential to prevent RSV disease in early infancy. RSV prophylaxis has seen tremendous progress in the last decade.