OECD 414 supplementary prenatal developmental toxicity study of sodium molybdate dihydrate in the rat and benchmark dose evaluation.

In a continuing investigation of the potential for reproductive and developmental toxicity of molybdenum (Mo), consequent to the previous published OECD studies [1,2] and as directed by the European Chemicals Agency [3], a supplemental rat GLP-compliant Prenatal Developmental Toxicity (PNDT) study was conducted to investigate higher dose levels of sodium molybdate dihydrate (SMD) in an identical study design (OECD 414)[4] to Murray et al. 2014a [1], at dietary concentrations calculated to provide target Mo levels of 80 and 120 mg/kg bw/day (the maximum-tolerated dose). There was no effect on post-implantation loss, litter size, sex ratio or the incidence of external, visceral or skeletal fetal malformations or variations. Fetal weight was reduced proportionate to maternal dose. Minimal differences observed in the ossification status of some extremities of fetuses from females receiving 120 mg Mo/kg bw/day were confirmed as transient by skeletal examination of PND 21 pups from a further group of females receiving the same dose regime. There was no evidence of copper depletion in serum, placenta or liver. A benchmark dose evaluation using continuous and dichotomous approaches by combining the fetal body weight data from this study and the previous study determined that the BMD05 ranged from 47 to 57 mg Mo/kg bw/day, depending on the modelling approach and the BMDL05 estimates ranged from 37 to 47 mg Mo/kg bw/day. These levels are considered a more statistically robust point of departure for risk assessment for reproductive effects than the established NOAEL of 40 mg Mo/kg bw/day.

Toward a comparative retrospective analysis of rat and rabbit developmental toxicity studies for pharmaceutical compounds.

Based on a proposal made at the ICH Workshop in Tallinn, Estonia (2010), the value of the rabbit embryo-fetal development (EFD) versus the rodent EFD was examined by the HESI DART group. A cross-industry data survey provided anonymised EFD and toxicokinetic data from EFD studies on over 400 marketed and unmarketed drugs (over 800 studies) that were entered by experts at RIVM into US EPA's ToxRefDB style database. The nature and severity of findings at the lowest observed adverse effect level (LOAEL) are being reviewed to quantitate the frequency with which lesser signs of embryo-fetal effects (e.g., delays in ossification, minor changes in frequency of variants) are driving the LOAELs. Interpretation was based on exposure rather than administered dose. This paper provides an update of this ongoing project as discussed during a workshop of the European Teratology Society in Ispra, Italy (2013). This was the first presentation of the initial data set, allowing debate on future directions, to provide a better understanding of the implications of either delaying a rabbit EFD or waiving the need in particular circumstances.

Oral (drinking water) two-generation reproductive toxicity study of dibromoacetic acid (DBA) in rats.

In a two-generation study of dibromoacetic acid (DBA), Crl SD rats (30 rats/sex/group/generation) were provided DBA in drinking water at 0 (reverse osmosis-deionized water), 50, 250, and 650 ppm (0, 4.4 to 11.6, 22.4 to 55.6, and 52.4 to 132.0 mg/kg/day, respectively; human intake approximates 0.1 microg/kg/day [0.0001 mg/kg/day]). Observations included viability, clinical signs, water and feed consumption, body and organ weights, histopathology, and reproductive parameters (mating, fertility, abortions, premature deliveries, durations of gestation, litter sizes, sex ratios and viabilities, maternal behaviors, reproductive organ weights, sperm parameters and implantation sites, sexual maturation). Histopathological evaluations were performed on at least 10 P and F1 rats/sex at 0 and 650 ppm (gross lesions, testes, intact epididymis; 10 F1 dams at 0, 250, and 650 ppm for primordial follicles). Developmental observations included implantations, pup numbers, sexes, viabilities, body weights, morphology, and reproductive performance. At 50 ppm and higher, both sexes and generations had increased absolute and relative liver and kidneys weights, and female rats in both generations had reduced absolute and relative adrenal weights; adrenal changes were probably associated with physiological changes in water balance. The livers and kidneys (10/sex/group/generation) had no histopathological changes. Other minimal effects at 50 ppm were reduced water consumption and a transient reduction in body weight. At 250 and 650 ppm, DBA reduced parental water consumption, body weight gains, body weights, feed consumption, and pup body weights. P and F1 generation male rats at 250 and 650 ppm had altered sperm production (retained step 19 spermatids in stages IX and X tubules sometimes associated with residual bodies) and some epididymal tubule changes (increased amounts of exfoliated spermatogenic cells/residual bodies in epididymal tubules, atrophy, and hypospermia), although inconsistently and at much lower incidences. Unilateral abnormalities of the epididymis (small or absent epididymis) at 650 ppm in four F1 generation male rats were considered reproductive tract malformations. The no-observable-adverse-effect level (NOAEL) and reproductive and developmental NOAELs for DBA were at least 50 ppm (4.5 to 11.6 mg/kg/day), 45,000 to 116,000 times the human adult exposure level. Reproductive and developmental effects did not occur in female rats exposed to DBA concentrations as high as 650 ppm. Based on the high multiples of human exposure required to produce effects in male rats, DBA should not be identified as a human reproductive or developmental risk.

Oral (drinking water) two-generation reproductive toxicity study of bromodichloromethane (BDCM) in rats.

Bromodichloromethane (BDCM) was tested for reproductive toxicity in a two-generation study in CRL SD rats. Thirty rats/sex/ group/generation were continuously provided BDCM in drinking water at 0 (control carrier, reverse osmosis membrane-processed water), 50,150, and 450 ppm (0, 4.1 to 12.6, 11.6 to 40.2, and 29.5 to 109.0 mg/kg/day, respectively). Adult human intake approximates 0.8 microg/kg/day (0.0008 mg/kg/day). P and F1 rats were observed for general toxicity (viability, clinical signs, water and feed consumption, body weights, organ weights [also three weanling Fl and F2 pups/sex/litter], histopathology [10/sex, 0- and 450-ppm exposure groups]) and reproduction (mating, fertility, abortions, premature deliveries, durations of gestation, litter sizes, sex ratios, viabilities, maternal behaviors, reproductive organ weights [also three weanling Fl and F2 pups/sex/ litter], sperm parameters, and implantations. F1 rats were evaluated for age at vaginal patency or preputial separation. Ten P and F1 rats/sex from the 0- and 450-ppm exposure groups and rats at 50 and 150 ppm with reduced fertility were evaluated for histopathology (gross lesions, testes, intact epididymis, all F1 dams for number of primordial follicles). Developmental parameters in offspring included implantation and pup numbers, sexes, viabilities, body weights, gross external alterations, and reproductive parameters (Fl adults). Toxicologically important, statistically significant effects at 150 and/or 450 ppm included mortality and clinical signs associated with reduced absolute and relative water consumption, reduced body weights and weight gains, and reduced absolute and relative feed consumption (P and F1 rats). Significantly reduced body weights at 150 and 450 ppm were associated with reduced organ weights and increased organ weight ratios (% body and/or brain weight). Histopathology did not identify abnormalities. Small delays in sexual maturation (preputial separation, vaginal patency) and more Fl rats with prolonged diestrus were also attributable to severely reduced pup body weights. Mating, fertility, sperm parameters, and primordial ovarian follicular counts were unaffected. The no-observable-adverse-effect level (NOAEL) and the reproductive and developmental NOAELs for BDCM were at least 50 ppm (4.1 to 12.6 mg/kg/day), 5125 to 15,750 times the human adult exposure level, if delayed sexual maturational associated with severely reduced body weights is considered reproductive toxicity. If considered general toxicity, reproductive and developmental NOAELs for BDCM are greater than 450 ppm (29.5 to 109.0 mg/kg/day), or 36,875 to 136,250 times the human adult exposure level. Regardless, these data indicate that BDCM should not be identified as a risk to human reproductive performance or development of human conceptuses.

Short term oral cefixime therapy for treatment of bacterial conjunctivitis.

BACKGROUND: There have been few controlled studies evaluating treatment of bacterial conjunctivitis beyond the newborn period. Topical therapy of bacterial conjunctivitis achieves a clinical cure but does not prevent acute otitis media (AOM). OBJECTIVES: The aim of this study was to compare systemic antibiotic therapy (cefixime) with topical therapy with polymyxin-bacitracin for treatment of acute bacterial conjunctivitis with regard to clinical and bacteriologic cure and prevention of AOM. METHODS: This study was a randomized, double blind, placebo-controlled trial of polymyxin-bacitracin ointment and oral placebo vs. topical placebo and oral cefixime in children with presumed acute bacterial conjunctivitis. Topical therapy was administered for 7 days; oral therapy was administered for 3 days. Bacterial cultures were obtained at entry and on Day 3 of treatment. Children were examined on Days 3 and 10 or if they worsened within 15 days of entry. RESULTS: Eighty children were enrolled in the study. Bacterial cultures of the conjunctiva were positive in 70% of children: Haemophilus influenzae (53.7%); Streptococcus pneumoniae (13.8%); H. influenzae and S. pneumoniae (1.2%); and Moraxella catarrhalis (1.3%). There were 7 (17.5%) bacteriologic failures among children receiving topical antibiotic and oral placebo and 15 (37.5%) bacteriologic failures among children receiving topical placebo and oral cefixime (P = 0.07 with Yates correction). There was no difference between study groups with regard to either clinical cure or the development of AOM. Nine children (11%), 5 who received active topical therapy and 4 who received active oral drug, developed AOM either during or within 15 days of study entry. CONCLUSION: Cefixime was not more effective than topical polymyxin-bacitracin in either the eradication of conjunctival colonization with respiratory pathogens or the prevention of AOM in children with acute bacterial conjunctivitis.

Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media.

OBJECTIVES: To determine the bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate (90/6.4 mg/kg/day) against common bacterial pathogens causing acute otitis media (AOM), including penicillin-resistant Streptococcus pneumoniae (PRSP). METHODS: In this open label multicenter study, 521 infants and children with AOM [mean age, 18.6 months; age < 24 months, n = 375 (72%)] were treated with amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses for 10 days. Bilateral otitis media, previous episodes of AOM, antibiotic treatment within 3 months and day-care attendance were recorded in 60.1, 35.7, 50.2 and 38.2% of the children, respectively. Tympanocentesis was performed before the first dose and repeated on Days 4 to 6 for all children with S. pneumoniae at 22 centers and for all children with any pathogen at 3 centers. Clinical response was assessed at end of therapy. RESULTS: Pathogens were isolated from 355 (68%) of 521 enrolled children; 180 children underwent repeat tympanocentesis and were bacteriologically evaluable. Baseline pathogens were S. pneumoniae (n = 122 enrolled/93 bacteriologically evaluable), Haemophilus influenzae (n = 160/51), both (n = 37/32) and others (n = 36/4). Pathogens were eradicated from 172 (96%) of 180 bacteriologically evaluable children. Overall 122 (98%) of 125 isolates of S. pneumoniae were eradicated, including 31 (91%) of 34 PRSP isolates (penicillin MICs 2 to 4 micrograms/ml). Seventy-eight (94%) of 83 isolates of H. influenzae were eradicated. Symptoms and otoscopic signs of acute inflammation were completely resolved or improved on Days 12 to 15 in 263 (89%) of 295 clinically evaluable children with bacteriologically documented AOM. CONCLUSIONS: On the basis of bacteriologic outcome on Days 4 to 6 and clinical outcome on Days 12 to 15, we found that high dose amoxicillin/clavulanate (90/6.4 mg/kg/day) was highly efficacious in children with AOM, including those most likely to fail treatment, namely children < 24 months of age and those with infectious caused by PRSP.

Oral (drinking water) developmental toxicity studies of bromodichloromethane (BDCM) in rats and rabbits.

Crl:CD(SD)IGS BR VAF/Plus (Crl SD) rats and Hra(NZW) SPF rabbits were tested for potential developmental toxicity from bromodichloromethane (BDCM) provided continuously in the drinking water during gestation (gestation days [GDs] 6 to 21 in rats and GDs 6 to 29 in rabbits). Concentrations of 0, 50, 150, 450, or 900 ppm of BDCM were used for rats; 0, 15, 150, 450, or 900 ppm were used for rabbits (in dose range-finding studies, 1350 ppm was excessively maternotoxic to both species). Investigated maternal parameters included viability, clinical signs, water and feed consumption, and body weights. Maternal gross lesions, gravid uterine weights, abnormal placentas, and numbers of corpora lutea, implantation sites, live and dead fetuses, and early and late resorptions were observed at time of Caesarean sectioning (GD 21 in rats; GD 29 in rabbits). Body weights, sex ratios, and morphological abnormalities (external, soft tissue, and skeletal) were noted in the fetuses. Mean consumed doses of BDCM were calculated to be 0, 2.2, 18.4, 45.0, or 82.0 mg/kg/day for the rats, and 0, 1.4, 13.4, 35.6, or 55.3 mg/kg/day for the rabbits (approximate human intake is 0.8 microg/kg/day [0.0008 mg/kg/day] in adults). In pregnant rats, toxicologically important, statistically significant effects included reduced absolute (g/day) and relative (g/kg/day) water consumption values at > or =50 ppm (2.2 mg/kg/day) and reduced body weight gains (also when corrected for gravid uterine weight) and absolute (g/day) and relative (g/kg/day) feed consumption values at >450 ppm (45.0 mg/kg/day). These parameters were also significantly reduced at > or =450 ppm (35.6 mg/kg/day) in pregnant rabbits (significant weight loss occurred in the rabbits at 900 ppm, i.e., 55.3 mg/kg/day). Thus, the maternal no-observable-adverse-effect level (NOAEL) for BDCM was 150 ppm, i.e., 18.4 and 13.4 mg/kg/day in rats and rabbits, respectively. No adverse effects on embryofetal viability, growth, sex ratio, gross external, soft tissue, or skeletal morphology occurred at 900 ppm in rats or rabbits. Minimal delays in the ossification of forepaw phalanges and hindpaw metatarsals and phalanges occurred in rat fetuses at 900 ppm; delays were considered marginal, reversible, and associated with severely reduced maternal weight gain. Therefore, the developmental NOAEL for rats was 450 ppm (45.0 mg/kg/day), whereas in rabbits it was 900 ppm (55.3 mg/kg/day). These NOAELs are 56,250 and 69,120 times the human adult exposure level of 0.0008 mg/kg/day, respectively. Based on the results of these studies, BDCM should not be identified as a risk to development of human conceptuses.

Biodisposition of dibromoacetic acid (DBA) and bromodichloromethane (BDCM) administered to rats and rabbits in drinking water during range-finding reproduction and developmental toxicity studies.

Dibromoacetic acid (DBA) and bromodichloromethane (BDCM), by-products of chlorine disinfection of water, were provided in drinking water in range-finding reproductive/developmental toxicity studies (rats) and a developmental toxicity study (BDCM) in rabbits. Studies included absorption and biodisposition of DBA and BDCM, including passage into placentas, amniotic fluid, fetuses (rats and rabbits), or milk (rats). The DBA and BDCM range-finding reproductive/developmental toxicity studies each included 50 Sprague-Dawley rats/sex/group. DBA (0, 125, 250, 500, or 1000 ppm) or BDCM (0, 50, 150, 450, or 1350 ppm) was provided in drinking water 14 days premating through gestation and lactation (63 to 70 days). The developmental toxicity range-finding study included 25 time-mated New Zealand white rabbits/group given 0, 50, 150, 450, or 1350 ppm BDCM in drinking water on gestation days (GDs) 6 through 29. Satellite groups (6 male, 17 female rats/group/study and 4 rabbits/group) were used for bioanalytical sampling. Rats and rabbits had exposure-related reduced water consumption caused by apparent taste aversion to DBA or BDCM, especially in the parental animals at the two highest exposure levels (500 and 1000 ppm DBA; 450 and 1350 ppm BDCM). Female rats consumed slightly higher mg/kg/day doses of DBA than male rats, especially during gestation and lactation; weanling rats consumed the highest mg/kg/day doses. DBA produced detectable and quantifiable concentrations in plasma, placentas, amniotic fluid, and milk. Plasma samples confirmed that rats drink predominately during the dark; this drinking pattern, not accumulation, produced detectable plasma concentrations for 18 to 24 hours/day. No quantifiable concentrations of BDCM occurred in plasma, placentas, amniotic fluid, or milk, suggesting that BDCM is rapidly degraded or metabolized in vivo. DBA (500 and 1000 ppm, rats) and BDCM (450 and 1350 ppm, rats and rabbits) produced secondary toxicity in the parental generation by reducing water consumption, which caused severe exposure-related apparent dehydration, reduced feed intake and weight gain. Reproductive and developmental parameters were essentially unaffected (mating possibly reduced [DBA at 1000 ppm]; exposure-related decreases in body weights of pups secondary to reduced water and feed consumption [DBA at 250, 500, and 1000 ppm; BDCM at 150, 450, and 1350 ppm]). No effects on development of rabbit fetuses occurred at BDCM concentrations as high as 1350 ppm. Results from these preliminary studies, in which DBA and BDCM were provided in the drinking water at concentrations thousands of times higher than those to which humans are exposed, suggest that neither DBA nor BDCM are reproductive/developmental risks for humans.

Vaccine prevention of acute otitis media.

The incidence of acute otitis media (AOM) in infants and young children has increased dramatically in recent years in the United States. AOM often follows upper respiratory tract infections due to pathogens such as respiratory syncytial virus (RSV), influenza virus, and parainfluenza virus (PIV). These viruses cause eustachian tube dysfunction that is critical to the pathogenesis of AOM. Vaccines against these viruses would likely reduce the incidence of AOM. In three previous studies, influenza virus vaccines reduced the incidence of AOM by 30% to 36%. Vaccines to prevent infections with RSV and PIV type 3 are undergoing clinical testing at this time. Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis are the three most common AOM pathogens. Heptavalent pneumococcal conjugate vaccine is effective in preventing invasive disease and AOM caused by serotypes contained in the vaccine. Vaccine candidates for NTHi and M. catarrhalis are under development.

Developmental toxicity study of pentachlorophenol in the rabbit.

The potential for developmental toxicity of pentachlorophenol (penta) was studied in New Zealand white rabbits at doses of 0 (corn oil), 7.5, 15, and 30 mg/kg/day administered by gavage on days 6 to 18 of gestation. The rabbits were sacrificed on day 29 of presumed gestation and necropsied. Measurements included number of corpora lutea, pregnancy, number and distribution of implantations, early and late resorptions, live and dead fetuses, fetal weight, gender, and gross external, soft tissue, and skeletal alterations. The mid and high doses reduced maternal body weight gain; the high dose caused transient weight loss and reduced feed consumption. There were no effects on embryofetal development at any of the doses evaluated. Based on these data, the maternal no-observable-adverse-effect level (NOAEL) is 7.5 mg/kg/day, while the developmental NOAEL is 30 mg/kg/day. Penta is not a developmental toxicant in a nonrodent animal model.

A study of the developmental toxicity potential of pentachlorophenol in the rat.

Pentachlorophenol (penta, CAS #87-86-5) is primarily used as a wood preservative. As part of the USEPA pesticide reregistration process, the developmental toxicity (embryo-fetal toxicity and teratogenic potential) of commercially available penta was studied following oral gavage to presumed pregnant female Sprague-Dawley rats (Crl:CD BR VAF/Plus Subdivision F, 83-3). Both study design and penta purity met the requirements of the USEPA. Doses of 0 (corn oil), 10, 30, and 80 mg/kg/day were administered to the rats at concentrations of 0, 2, 6, and 16 mg/ml, respectively from day 6 to day 15 of presumed gestation. The dosage volume was 5 ml/kg, adjusted on each day of dosage based on individual body weights recorded immediately before intubation. The rats were sacrificed on day 20 of presumed gestation and necropsied. The number of corpora lutea in each ovary was recorded. The uterus was examined for pregnancy, number and distribution of implantations, early and late resorptions and live and dead fetuses. Each fetus was weighed, sexed, and examined for gross external, soft tissue and skeletal alterations. The no-observable-adverse-effect-level (NOAEL) for maternal toxicity in rats was determined to be 30 mg/kg/day of penta. The developmental NOAEL for penta in rats was also found to be 30 mg/kg/day. The lowest-observable-adverse-effect-level (LOAEL) for penta developmental toxicity (80 mg/kg/day) was associated with increased resorptions, reduced live litter size and fetal body weights, and caused increased malformations and variations. These NOAELs, derived using USEPA approved study designs, are higher than those previously reported using penta that is no longer commercially available in studies with non-approved experimental designs. Penta should not be identified as a selective developmental toxicant in the rat because adverse effects on development of rat conceptuses occurred only at maternally toxic dosages.

Lack of selective developmental neurotoxicity in rat pups from dams treated by gavage with chlorpyrifos.

Pregnant Sprague-Dawley rats were given chlorpyrifos (O:, O-diethyl-O:-[3,5,6-trichloro-2-pyridinyl] phosphorothioate; CPF) in corn oil by gavage from gestation day 6 (GD 6) through lactation day 10 (LD 10) at dosages of 0, 0.3, 1, or 5 mg/kg/day in a developmental neurotoxicity study that conformed to U.S. Environmental Protection Agency 1991 guidelines. GD 0 was the day when evidence of mating was observed and postnatal day 0 (PND 0) was the day of birth. Toxicity was limited to the highest dosage level (5 mg/kg/day) and, in the dams, consisted of muscle fasciculation, hyperpnea, and hyperreactivity. A nonsignificant overall trend toward weight gain and feed consumption was also observed in the high-dosage dams, with a statistically significant Group x Time interaction for reduced weight gain in the 5-mg/kg/day group near the end of gestation. Although many developmental indices were normal, pups from high-dosage dams had increased mortality soon after birth, gained weight more slowly than controls, and had several indications of slightly delayed maturation. The early deaths and delayed maturation were attributed to maternal toxicity, though a possible contributing role of direct pup toxicity in delayed development cannot be eliminated. In spite of the apparent delay in physical development, high-dosage pups tested just after weaning had normal learning and memory as tested on a T-maze spatial delayed-alternation task. Habituation, a primitive form of learning, was tested in 2 tasks (motor activity and auditory startle) and was not affected. No overt effects were noted in either dams or pups at 1 or 0.3 mg/kg/day. Based on these data, chlorpyrifos produced maternal and developmental toxicity in the 5-mg/kg/day-dosage group. There was no evidence of selective developmental neurotoxicity following exposure to chlorpyrifos.

Lack of effects of nose-only inhalation exposure on testicular toxicity in male rats.

Reductions in testicular mass, sperm motility, and mating frequency have been attributed to the stresses caused by confinement of Sprague-Dawley male rats in nose-only inhalation exposure tubes. Testicular changes, including an increase in testicular atrophy, have been detected at an increased incidence in male rats used in inhalation studies as compared with rats of the same age and strain used in oral toxicity studies. This study was designed to determine whether nose-only exposure of male rats caused testicular toxicity under conditions of cooling of the exposure room and appropriate acclimation to the exposure tubes. In order to acclimate the rats to the nose-only inhalation exposure apparatus, all male rats were placed in the exposure tubes for at least four successively increasing time intervals (15, 30, 45, and 60 min) on 4 separate days, with a rest period of approximately 48 h between the first and second acclimation. Twenty male rats were exposed nose-only to filtered air for approximately 2 h per day for 28 days before cohabitation and continuing throughout a 14-day cohabitation period. To reduce thermal stress, the exposure room temperature was maintained at 64 to 70 degrees F. Twenty control rats were housed in the same room as the exposed rats but were not placed in exposure tubes. End points monitored were body weight, testicular weight, sperm count, sperm motility, and histopathology of the testes, epididymides, prostate, and seminal vesicles. The control rats gained weight more rapidly than the exposed rats. All the rats in both groups mated successfully, and testicular weights, normalized to body weight, were similar for both groups. More importantly, there were no microscopic changes that could be considered an adverse effect on the reproductive tissues in the male rats placed in exposure tubes. Thus, nose-only exposure for up to 2 h per day for a total of 42 days did not cause adverse effects on the reproductive organs, fertility, or reproductive performance of male rats under the conditions of this study.

Treatment of urinary tract infections.

Treatment of UTI with oral antibiotics alone is generally effective, even in young children with pyelonephritis. Cefixime has a broad spectrum of activity and is suitable as an empiric agent in most cases. In patients who are unlikely to tolerate oral medications because of vomiting or who appear toxic on examination, hospitalization and initial treatment with i.v. therapy is indicated. In general, radiographic studies can be performed prior to completion of the primary course of antibiotics, and prophylactic treatment is unnecessary. Patients should receive instruction about the risk of recurrent infection and should be advised to seek medical attention when symptoms of UTI develop.

Oral versus initial intravenous therapy for urinary tract infections in young febrile children.

BACKGROUND: The standard recommendation for treatment of young, febrile children with urinary tract infection has been hospitalization for intravenous antimicrobials. The availability of potent, oral, third-generation cephalosporins as well as interest in cost containment and avoidance of nosocomial risks prompted evaluation of the safety and efficacy of outpatient therapy. METHODS: In a multicenter, randomized clinical trial, we evaluated the efficacy of oral versus initial intravenous therapy in 306 children 1 to 24 months old with fever and urinary tract infection, in terms of short-term clinical outcomes (sterilization of the urine and defervescence) and long-term morbidity (incidence of reinfection and incidence and extent of renal scarring documented at 6 months by 99mTc-dimercaptosuccinic acid renal scans). Children received either oral cefixime for 14 days (double dose on day 1) or initial intravenous cefotaxime for 3 days followed by oral cefixime for 11 days. RESULTS: Treatment groups were comparable regarding demographic, clinical, and laboratory characteristics. Bacteremia was present in 3.4% of children treated orally and 5.3% of children treated intravenously. Of the short-term outcomes, 1) repeat urine cultures were sterile within 24 hours in all children, and 2) mean time to defervescence was 25 and 24 hours for children treated orally and intravenously, respectively. Of the long-term outcomes, 1) symptomatic reinfections occurred in 4.6% of children treated orally and 7.2% of children treated intravenously, 2) renal scarring at 6 months was noted in 9.8% children treated orally versus 7.2% of children treated intravenously, and 3) mean extent of scarring was approximately 8% in both treatment groups. Mean costs were at least twofold higher for children treated intravenously ($3577 vs $1473) compared with those treated orally. CONCLUSIONS: Oral cefixime can be recommended as a safe and effective treatment for children with fever and urinary tract infection. Use of cefixime will result in substantial reductions of health care expenditures.

Lack of developmental neurotoxicity of MN rgp 120/HIV-1 administered subcutaneously to neonatal rats.

The potential for neurotoxic effects was evaluated in rat off-spring after exposure in utero and/or during the neonatal period to a recombinant subunit vaccine of gp120 prepared from the MN strain of HIV-1 (MN rgp 120/HIV-1). Thirty pregnant female rats were given MN rgp120/HIV-1 with alum adjuvant, and 30 rats were given vehicle, once every 3 days from Day 1 of presumed gestation until parturition. One pup/sex/litter from treated and control group dams were given a daily subcutaneous injection, from Day 1 through Day 22 postpartum (PP) of vehicle, MN rgp120/HIV-1, MN rgp120/HIV-1 with alum, or MN rgp120/HIV-1 with QS-21 adjuvant. Neurobehavioral and physical development were evaluated (preweaning reflex and development, sexual maturation, motor activity, acoustic startle, passive avoidance, functional observational battery, and water M-maze testing), and tissues were processed for anatomical examination (whole and regional brain weights, and neuropathology). Administration of MN rgp120/HIV-1, with or without adjuvant, to pups did not cause any persistent effect on any parameter evaluated. Neurohistological examination did not reveal any pathological effects related to treatment. Thus, MN rgp120/HIV-1 alone or formulated as a vaccine does not cause neurotoxicity or developmental toxicity in neonatal rats after exposure in utero and/or during the neonatal period.

Developmental toxicity studies of four fragrances in rats.

Four fragrances, 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (AHTN), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-ben zopyran (HHCB), musk ketone and musk xylene were tested for developmental toxicity in Sprague-Dawley rats (25/group, 3 groups/fragrance, 2 fragrances/corn oil control). Dosages tested were HHCB: 50, 150, 500 mg/kg per day; AHTN: 5, 15, 50 mg/kg per day; musk ketone: 15, 45, 150 mg/kg per day; musk xylene: 20, 60, 200 mg/kg per day. All dosages tested exceeded multiples of the estimated maximal daily human dermal exposure. Treatment (gavage, 5 ml/kg) occurred on GDs 7-17 and Caesarean-sectioning on GD 20. Based on the results of these studies, none of the four fragrances tested were more toxic in the conceptuses than in the dams. Maternal NOAELs were 50, 5, 15 and 20 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively (150, 50, 45 and 60 mg/kg per day caused clinical signs and reduced weight gain and feed consumption). Developmental NOAELs were 150, 50, 45 and 200 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively. No adverse effects on embryo-fetal viability, growth or morphology occurred at the highest dosages of AHTN (50 mg/kg per day) or musk xylene (200 mg/kg per day). Developmental toxicity occurred at the high-dosages of HHCB (axial skeletal malformations at 500 mg/kg per day) and musk ketone (increased postimplantation loss and reduced fetal body weight at 150 mg/kg per day). The results of this study indicate that under conditions of normal use, the tested fragrances do not pose a risk to human conceptuses.