amphotericin-b and Infant--Premature--Diseases

Fungemia is a serious problem within neonatal intensive care units around the world. Premature infants are at high risk for this complication, which is often fatal. Prophylaxis for invasive fungal infection has been practiced worldwide in different settings and with various patient groups. Both oral and intravenous drugs have been used with some success. In the population of preterm infants, oral nystatin, intravenous fluconazole, and intravenous amphotericin B have all been cited as possible drugs for prophylactic use. Intravenous fluconazole has emerged as the best choice for chemoprophylaxis in premature infants.

Topics: Administration, Intravenous; Administration, Oral; Amphotericin B; Antifungal Agents; Aspergillosis; Candidemia; Fluconazole; Fungemia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Malassezia; Nystatin; Zygomycosis

A variety of antifungal drugs, drug preparations and drug combinations are available to treat newborn infants with suspected or confirmed invasive fungal infection. There is a need to assess their relative merits.. To assess the effect of treatment with different antifungal drugs, drug preparations or drug combinations on mortality and morbidity in newborn infants with suspected or confirmed invasive fungal infection.. We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2012, Issue 2), MEDLINE, EMBASE, CINAHL (to March 2012), conference proceedings and previous reviews.. Randomised and quasi-randomised control trials comparing one antifungal agent or combination of agents with another in newborn infants with suspected or confirmed invasive fungal infection.. We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using risk ratio and risk difference.. We identified only one small trial in which 24 newborn infants participated. This trial compared the use of fluconazole versus amphotericin B (plus 5-fluorocytosine if fungal meningitis present). The trial did not detect a statistically significant effect on mortality (risk ratio 0.73; 95% confidence interval 0.26 to 2.05).. There are insufficient data to inform practice. Large randomised controlled trials are required to compare antifungal drugs, drug preparations or drug combinations for treating newborn infants with invasive fungal infection.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Flucytosine; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Mycoses; Randomized Controlled Trials as Topic

Rhodotorula is emerging as an important cause of nosocomial and opportunistic infections. We present two cases of Rhodotorula mucilaginosa fungemia diagnosed over a period of 3 months at our hospital. The first case was of a pre-term neonate in the neonatal ICU who presented with respiratory failure and sepsis. The second involved an adult female who had been injured in a road traffic accident requiring an operation for a hematoma and was later shifted to the medical ICU. For a new hospital like ours, finding two cases of Rhodotorula fungemia within a span of 3 months prompted us to describe them in this report. These cases emphasize the emerging importance of Rhodotorula mucilaginosa as a pathogen and the importance of identification and MIC testing for all fungal isolates recovered from the blood stream.

Topics: Amphotericin B; Antifungal Agents; Catheterization, Central Venous; Female; Fungemia; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Microbial Sensitivity Tests; Middle Aged; Opportunistic Infections; Pyrimidines; Rhodotorula; Treatment Outcome; Triazoles; Voriconazole; Wounds and Injuries

In neonatal intensive care units, deep fungal disease due to Candida spp. are an important clinical problem, partly due to the increasing prevalence of Candida disease and also to the high associated and constant morbimortality; both factors are independently maintained though there has been a significant improvement in the management of neonatal patients.. To define the therapeutic use of micafungin for the treatment of neonatal invasive candidiasis.. We use a review of biomedic data bases namely Medline and EMBASE.. Micafungin is the latest introduced echinocandin. It has a wide spectrum of activity and covers Candida albicans and non-albicans Candida species. It has scarce drugs interactions and is devoid of toxicity, being an attractive approach for the treatment of invasive candidiasis (without meningitis, endocarditis and endophthalmitis). Althought the European Medicines Agency approved in 2008 the use of Micafungin for the treatment of invasive candidiasis in children, the available clinical experience is limited and currently more clinical studies are warranted to define its efficacy and safety in neonates.

Topics: Adolescent; Adult; Age Factors; Amphotericin B; Antifungal Agents; Candidiasis; Child; Child, Preschool; Clinical Trials as Topic; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lipopeptides; Male; Meta-Analysis as Topic; Micafungin; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies

Invasive fungal infection is an increasingly common cause of mortality and morbidity in preterm infants. In addition to amphotericin B, a variety of newer antifungal drugs and drug preparations are available for treatment. There is a need to assess their relative merits.. In preterm infants with suspected or confirmed invasive fungal infection, does treatment with newer systemic antifungal drugs or drug preparations, versus conventional amphotericin B alone, reduce mortality and adverse neurodevelopmental outcomes?. 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, Issue 3, 2003), MEDLINE (1966 - August 2003), EMBASE (1980 - August 2003), conference proceedings, and previous reviews.. Randomised and quasi-randomised control trials comparing one antifungal agent or combination of agents with another in preterm infants with suspected or confirmed invasive fungal infection.. We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using relative risk and risk difference. The pre-specified outcomes were death prior to hospital discharge, longer term neurodevelopment, and adverse drug reactions resulting in discontinuation of therapy.. We identified only one small trial. This study compared the use of fluconazole with amphotericin B (5-Fluorocytosine added if fungal meningitis present). Three of 11 infants who were treated with fluconazole died and four of 10 infants who were treated with amphotericin B died : Relative risk: 0.68 (95% confidence interval 0.20, 2.33), Risk Difference -0.13 (95% confidence interval -0.53, 0.27) There were not any data on longer term outcomes.. From this one small study there are insufficient data to favour one antifungal agent or combination to reduce mortality and adverse neurodevelopmental outcomes in preterm infants with suspected or confirmed invasive fungal infection. A large randomised controlled trial is required to compare the newer antifungal preparations with conventional amphotericin B. Further research may also determine the relative convenience and cost effectiveness of the available drugs.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Mycoses; Randomized Controlled Trials as Topic

Mucormycosis (zygomycosis) normally occurs among individuals with predisposing factors such as prematurity, use of broad spectrum antibiotics, metabolic acidosis or advanced stages of immunosuppression. There have been reports of sporadic cases of cutaneous mucormycosis related to predisposing skin lesions and contact with contaminated material such as adhesive bandages and tongue depressors placed close to intravenous catheter insertion sites. We report successful treatment of a case of Absidia corymbifera infection with the combination of amphotericin B and surgical debridement of the affected area.

Topics: Absidia; Amphotericin B; Antifungal Agents; Debridement; Dermatomycoses; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Mucormycosis; Treatment Outcome

Mucormycosis is an uncommon infection caused by fungi of the order Mucorales, family Mucoraceae, and almost always occurs in individuals with predisposing factors such as diabetes mellitus, metabolic acidosis, or immunodeficiency states. Although mucormycosis is a rare infection in childhood, sporadic cases of skin infections have been described in young infants and older children; primary skin infection has been associated with multiple nosocomial outbreaks caused by contaminated elastic bandages. In all reported cases involving premature infants, the elimination of the infection involved surgical debridement. We report for the first time successful conservative treatment with intravenous amphotericin B in a premature infant with primary cutaneous infection caused by Rhizopus oryzae.

Topics: Amphotericin B; Antifungal Agents; Biopsy; Dermatomycoses; Dexamethasone; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Mucormycosis; Necrosis; Respiratory Distress Syndrome, Newborn; Rhizopus

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases

Topics: Amphotericin B; Candidiasis; Drug Therapy, Combination; Endocarditis; Female; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Male

Very low birth weight infants often have multiple predisposing conditions for the development of invasive candidiasis. In patients with systemic candidiasis, the kidney is vulnerable to the formation of cortical abscesses or obstructive intrarenal masses ("fungus balls"), usually at the ureteropelvic junction. Ureteropelvic junction obstructive fungal uropathy necessitates invasive debridement to restore renal function. A very low birth weight infant, infected with Candida, was first seen with hypertension, renal insufficiency, and urine cultures positive for fungus; obstructive bladder fungus ball was diagnosed by ultrasonography. Mechanical disruption with amphotericin B bladder irrigation was accomplished via ultrasonographic guidance, relieving renal obstruction and insufficiency. Systemic antifungal therapy was completed with amphotericin B and flucytosine. The first reported case of bladder obstructive fungal uropathy in a neonate is added to a review of 16 cases of neonatal renal obstructive uropathy.

Topics: Administration, Intravesical; Amphotericin B; Candidiasis; Humans; Hydronephrosis; Hypertension, Renal; Infant, Newborn; Infant, Premature, Diseases; Male; Ultrasonography; Urinary Bladder Diseases

Topics: Amphotericin B; Candida; Candidiasis; Catheters, Indwelling; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Meningitis

Disseminated fungal infections are a major problem in high risk neonates. Conventional antifungal agents are often unsatisfactory and have a high incidence of severe adverse effects.. We administered liposomal encapsulated amphotericin B (AmBisome), which is an alternative to conventional amphotericin B, to 40 preterm (mean birth weight, 1090 +/- 313.6 g; mean gestational age, 28.35 +/- 2.13 weeks) and 4 full term (mean birth weight, 3080 +/- 118 g; mean gestational age, 39 +/- 0.7 weeks) newborn infants with a severe fungal infection.. Candida albicans was the most frequent fungus isolated (70%). The duration of intravenous AmBisome therapy ranged from 7 to 49 days; the cumulative dose ranged from 7 to 138.8 mg/kg (median, 45.2 mg/kg). Administration of AmBisome was effective in 72.7% of patients; 5 of 6 cases of meningitis also recovered; 63.6% of 33 very low birth weight infants survived. No side effects were observed.. To our knowledge this is the largest study of the treatment of neonates with liposomal amphotericin B, and the results confirm its effectiveness and safety. However, randomized clinical trials are required to establish the most effective administration protocol for AmBisome, i.e. the starting dosage, the maximum effective dosage and the cumulative dosage, and to verify whether the preparation should be associated with another antifungal agent.

Topics: Amphotericin B; Antifungal Agents; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Liposomes; Mycoses

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Dermatomycoses; Edema; Erythema; Humans; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Male; Twins

Fungemia due to uncommon/rare Candida species is an emerging problem of global clinical significance. Here, we describe a case of Candida conglobata bloodstream infection in a preterm neonate. The diagnosis was established by repeated isolation of C. conglobata in blood cultures and by detection of rDNA of the fungus in serum samples. The identity of the isolate as C. conglobata was confirmed by sequencing of ITS region and D1/D2 domains of rDNA. Despite initial treatment with a liposomal amphotericin B (AmBisome) for 7 days, the blood culture remained positive. The neonate was successfully treated by combination therapy with caspofungin for 25 days. To the best of our knowledge, this is the first proven report unequivocally proving the etiologic role of C. conglobata in bloodstream infection.

Topics: Amphotericin B; Antifungal Agents; Candidemia; Candidiasis; Caspofungin; Catheter-Related Infections; Drug Therapy, Combination; Echinocandins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lipopeptides; Male; Treatment Outcome

Fluconazole prophylaxis of invasive fungal infections is a cornerstone of neonatal care, but in vitro studies have shown that it inhibits corticosteroid production. This study assessed whether preterm infants demonstrated an association between fluconazole administration, and its duration, and symptoms of adrenocortical insufficiency.. We compared two groups who were treated before and after we introduced the use of fluconazole to our neonatal intensive care unit. Infants with a gestational age of ≤27 weeks or with a birth weight of ≤750 g were considered for the retrospective analysis. In order to assess whether the duration of prophylaxis was related to adrenocortical insufficiency, regression models were performed in all preterm infants in the fluconazole group.. The fluconazole group (n = 37) and nonfluconazole group (n = 41) were compared. No differences were found in the percentage of infants with symptoms of adrenocortical insufficiency, such as hypotension or need of vasopressor therapy. The incidence of hypotension and the use of vasopressor therapy were not related to duration of fluconazole prophylaxis.. Fluconazole and it duration were not associated with the incidence of symptoms related to adrenocortical insufficiency. Further prospective trials are needed to better define the relationship between fluconazole and adrenocortical insufficiency.

Topics: Amphotericin B; Antifungal Agents; Antigens, Fungal; Apgar Score; Bronchoalveolar Lavage Fluid; Candida; Chemoprevention; Female; Fluconazole; Humans; Hypoaldosteronism; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Logistic Models; Male; Mycoses; Outcome Assessment, Health Care; Retrospective Studies

Primary cutaneous aspergillosis (PCA) is a rare fungal infection in premature infants. Extreme prematurity, immature immune system, therapy with broad-spectrum antibiotics and systemic steroids, as well as hyperglycaemia and a vulnerable and very thin epidermal layer are considered risk factors in this patient population. We present a premature male infant born at 24(+3) weeks of gestation with PCA, successfully treated with amphotericin and surgical curettage of the ulcerating skin lesions. Complete resolution of the lesions was achieved and scarring was barely visible at later follow-up.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Biopsy; Dermatologic Surgical Procedures; Dermatomycoses; Diagnosis, Differential; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Skin

The effect of delayed antifungal therapy in critically ill infants with invasive candidiasis has not been studied. Our objective was to evaluate the effect of time to initiation of antifungal therapy (TIA) on mortality, disseminated disease, and postinfection hospital stay. We conducted a cohort study of critically ill infants with cultures positive for Candida from 1990 to 2008. TIA was defined as the number of hours from the collection of the first positive culture until the start of antifungal therapy. Of 96 infants, 57% were male, the median gestational age was 27 weeks (range, 23 to 41 weeks), and the median birth weight was 956 g (range, 415 to 6,191 g). Most subjects received amphotericin B deoxycholate. TIA was ≤ 24 h for 35% of infants, between 25 and 48 h for 42%, and >48 h for 23%. Eleven subjects died during hospitalization, and 22% had disseminated candidiasis. The median duration of hospital stay postinfection was 53 days (range, 6 to 217 days). Both univariate and multivariate analyses demonstrated that TIA was not associated with mortality, disseminated disease, or hospital stay postinfection. However, ventilator use for >60 days significantly increased the risk of death (odds ratio [OR], 9.5; 95% confidence interval [CI], 2.2 to 66.7; P = 0.002). Prolonged candidemia increased the risk of disseminated disease by 10% per day of positive culture (OR, 1.1; 95% CI, 1.08 to 1.2; P = 0.007), and low gestational age was associated with increased neonatal intensive care unit (NICU) stay after the first positive Candida culture by 0.94 weeks (95% CI, 0.70 to 0.98; P < 0.001). The TIA was not associated with all-cause mortality, disseminated candidiasis, and postinfection length of hospital stay.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis, Invasive; Cohort Studies; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Length of Stay; Male; Time Factors; Time-to-Treatment; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Humans; Infant, Premature, Diseases; Kidney Diseases; Mycoses

Topics: Amphotericin B; Antifungal Agents; Humans; Infant, Premature, Diseases; Kidney Diseases; Mycoses

Invasive disseminated neonatal aspergillosis is an uncommon disease, with only scattered reports in literature in the last few years. Here we report on a 25-week gestational age, 730 g at birth preterm female infant who developed on day-of-life 10 multiple cutaneous exhulcerative lesions in her right arm, trunk and abdomen. Early recognition and diagnosis of these lesions as a due to cutaneous initial symptom of cutaneous disseminated aspergillosis, as well as prompt treatment with Liposomal amphotericin B + Itraconazole, secured successful recovery from the systemic infection. Skin lesions healed without any surgical treatment. The infant was discharged in good health. Long-term follow-up at three years of age revealed normality of all neurodevelopmental and cognitive parameters. To our knowledge, this is one of the very few cases of survival, free from sequelae, for a preterm infant affected by neonatal cutaneous disseminated aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Dermatomycoses; Female; Follow-Up Studies; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Itraconazole; Treatment Outcome

Liposomal amphotericin B (LAMB) is frequently administered in NICU to preterm infants <1500 g at birth (VLBW) for treatment of systemic fungal infections (SFI). Concerns exist on safety and tolerability of such drug in patients who are at risk for renal function impairment due to their prematurity.. To assess the occurrence of renal function impairment related to LAMB in a 10-year cohort of VLBW neonates treated with this drug.. Through database search of clinical charts, all VLBW neonates admitted to a 3(rd) level NICU in the years 1998-2007 and undergoing treatment with LAMB were identified. The occurrence of LAMB-attributable renal toxicity was investigated; infants withdrawn from treatment for development of adverse effects or toxicity were identified.. In the study period, 71 of 792 admitted VLBW neonates (8.9%) underwent antifungal treatment with LAMB administered at the recommended dosages (3-to-5 mg/kg/day). Mean duration of treatment was 14 (±9) days, mean cumulative dose given was 58 (±25) mg/kg per infant. Renal compromise, defined as hypokalaemia, and/or elevated creatinine serum levels, and/or decreased urine output, occurred in 2 of 71 (2.8%) treated patients, by 5 (±3) mean days after treatment initiation. In both patients LAMB was withdrawn; renal function impairment was only mild and transient, and normal renal function was restored at discharge. No other significant adverse effects were recorded in any treated neonate.. LAMB is generally safe and well tolerated in VLBW neonates. The occurrence of LAMB-related nephrotoxicity appears to be uncommon, mild and transient.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Cohort Studies; Creatinine; Fluconazole; Humans; Hypokalemia; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Kidney; Kidney Diseases; Kidney Function Tests; Mycoses; Premature Birth; Retrospective Studies; Sepsis

In the USA, the incidence of invasive candidiasis in neonates is respectively 0.3% of infants over 2500 g and up to 20% of infants less than 1000 g. Their incidence is increasing. Two populations of newborn infants are particularly vulnerable: the premature infants and newborn infants with severe neonatal digestive diseases. Fifty percent of infants hospitalized in NICU are colonized with Candida at the end of the first week of hospitalization; a direct relationship exists between the importance of colonization and the invasive infection risk. C. albicans is the species most often responsible for invasive candidiasis in the newborn. These infections represent the third cause of related-catheter infection in the USA. Mortality rate in neonates linked to this disease is 20 to 50%; morbidity primarily concerns brain and lungs. Neonatal invasive candidiasis risk factors are known and a primary prevention is possible. The diagnosis of neonatal invasive candidiasis is difficult and often delayed because of a polymorphic clinical expression. Empiric and preemptive treatment are based on the use of amphotericin B. Prophylactic treatment using fluconazole of newborns with birth weight ≤ 1000 grams and/or gestational age ≤ 27 weeks gestation is recommended by the American Academy of Paediatrics and the Infectious Diseases Society of America. A better knowledge of French epidemiological data in this area would improve both the diagnosis and therapeutic management of this disease.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Catheters; Fluconazole; France; Humans; Incidence; Infant; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Intensive Care, Neonatal; Risk Factors; Treatment Outcome

The occurrence of Candida spp. was investigated during a three-year period in two neonatal intensive care units, Budapest, Hungary. The species distribution among the 41 analysed cases was the following: C. albicans (30/41, 73%), C. parapsilosis (10/41, 24%) and C. glabrata (1/41, 3%). All of the isolates were susceptible to the tested drugs. There was a significant difference in the birth weight, the gestational age <30 weeks and the occurrence of caesarean section between the C. albicans and the C. parapsilosis groups of the cases. Respiratory tract colonization was the same (76-77%) in the extremely low birth weight (ELBW) and the very low birth weight (VLBW) groups. Comparing the ELBW, VLBW, and >1500 g birth weight groups, significant difference was found in the parenteral nutrition, the gestation weeks <36 or <30, the polymicrobial infection and the transfusion. The ratio of C. albicans, C. parapsilosis and C. glabrata was 9:7:1 in ELBW group; 6:3:0 in VLBW group and 15:1:0 in >1500 g group. The mortality rate for C. parapsilosis was higher than for C. albicans.

Topics: Amphotericin B; Candida; Candida albicans; Candida glabrata; Candidiasis; Cesarean Section; Female; Fluconazole; Gestational Age; Humans; Hungary; Infant, Extremely Low Birth Weight; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Male; Parenteral Nutrition

Micafungin is an echinocandin-class antifungal agent licensed for treatment of invasive disease in adults. The optimal dosing regimens have not been established for infants. We describe a premature infant who developed hepatitis and cholestasis during micafungin therapy initiated for protracted candidemia. Practitioners should be aware of this potential adverse effect if using micafungin in young patients.

Topics: AIDS-Related Opportunistic Infections; Alanine Transaminase; Amphotericin B; Antifungal Agents; Aspartate Aminotransferases; Candidiasis; Chemical and Drug Induced Liver Injury; Cholestasis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Lipopeptides; Liver Function Tests; Micafungin

Topics: Amphotericin B; Antifungal Agents; Brain; Brain Abscess; Candidiasis; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Echoencephalography; Female; Flucytosine; Follow-Up Studies; Fungemia; Humans; Infant; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Magnetic Resonance Imaging

Treatment options for primary cutaneous aspergillosis in neonates are limited by the lack of pharmacokinetic and safety data of newer antifungal agents that are effective against Aspergillus spp. We report the successful treatment of cutaneous aspergillosis in an extremely low-birth-weight preterm infant with liposomal amphotericin B, voriconazole and micafungin, and provide pharmacokinetic profiles for voriconazole and micafungin.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Dermatomycoses; Echinocandins; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lipopeptides; Lipoproteins; Micafungin; Peptides, Cyclic; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

The first outbreak of Candida haemulonii fungemia is described. The seven isolates from the blood of four neonates were identified by DNA sequencing of the ribosomal DNA. They were all resistant to amphotericin B, fluconazole, and itraconazole. This report highlights the emergence of C. haemulonii as an opportunistic pathogen in immunocompromised patients.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Disease Outbreaks; Drug Resistance, Fungal; Female; Fluconazole; Fungemia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Itraconazole; Male; Microbial Sensitivity Tests; Molecular Sequence Data; Sequence Analysis, DNA

Reported here are the features of a Rhodotorula mucilaginosa outbreak that occurred in a neonatal intensive care unit. Over a period of 19 days, clinical and laboratory signs of sepsis appeared in four premature infants carrying indwelling vascular catheters. After bloodstream infection with R. mucilaginosa was ascertained, the patients underwent amphotericin B therapy and recovered completely. In a retrospective case-control study, the variables displaying a statistical difference between case and control-group neonates were birth weight, gestational age, duration of parenteral nutrition, duration of antibiotic therapy and prophylactic administration of fluconazole. To our knowledge, this is the first reported outbreak caused by yeasts of the Rhodotorula genus.

Topics: Amphotericin B; Antifungal Agents; Bacteremia; Case-Control Studies; Catheterization, Central Venous; Catheters, Indwelling; Disease Outbreaks; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Male; Mycoses; Rhodotorula

Primary cutaneous aspergillosis is a rare, life-threatening, infectious complication in premature infants that may result in fulminant sepsis and subsequent multi-organ failure. In the past decade, the incidence of primary aspergillosis has increased significantly, whereas the high morbidity and mortality of invasive aspergillosis remains unaltered. In vitro studies reveal that more and more Aspergillus species seem to be refractory to the classical treatment with fluconazole or amphotericin B. This case report presents two extremely low birth weight infants (ELBW) with primary cutaneous aspergillosis, which was refractory to amphotericin B. Both patients were successfully treated with systemic voriconazole, an extended-spectrum triazole antifungal, supported by topical care. This paper provides the clinical manifestation, diagnostics and pharmacotherapy of primary cutaneous aspergillosis, as well as pharmacokinetic aspects of voriconazole in ELBW infants.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Dermatomycoses; Drug Resistance, Fungal; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Pyrimidines; Triazoles; Voriconazole

Endogenous Candida endophthalmitis is a rare disease with increasing frequency and poor prognosis.. The course of endogenous Candida endophthalmitis in 7 eyes of 5 patients (age 2 months to 76 years) was evaluated. Underlying general diseases were diagnosed as colon cancer, diverticulitis, pancreatic insufficiency (with subclavian catheter), ileus and diabetes mellitus. Diagnosis was based on the very typical ocular feature combined with a positive blood or vitreous culture. Intensive antimycotic drug therapy was initiated and pars plana vitrectomy performed as soon as possible.. The delay between onset of ocular symptoms and diagnosis amounted to one week and 2 months. In 3 eyes of 2 patients no vitrectomy could be done because of the very impaired state of health. These patients died of their general diseases one week and 2 months, respectively, later. During follow-up (4 weeks to 51 months) three eyes reached visual acuity of 5/10, 4/10 and 1/10. One eye reached 1/20 after additional surgery because of retinal detachment. In all vitrectomized eyes the diagnosis was substantiated by a positive culture of vitreous fluid. No recurrence of ocular inflammation was observed.. Early vitrectomy seems to be mandatory in each case which is suspected of Candida endophthalmitis. Only with this option it is possible to fix the diagnosis and initiate adequate therapy in due time in order to improve the original poor prognosis.

Topics: Aged; Amphotericin B; Anterior Chamber; Antifungal Agents; Candidiasis; Endophthalmitis; Female; Fungemia; Gentamicins; Humans; Infant, Newborn; Infant, Premature, Diseases; Injections; Male; Ophthalmic Solutions; Opportunistic Infections; Prednisone; Risk Factors; Treatment Outcome; Vitrectomy; Vitreous Body

Primary cutaneous aspergillosis is a rare diagnosis. Predisposing factors are immunodeficiency and macerated skin. The mortality of infections with Aspergillus species is high, especially in neonatal intensive care units (NICUs). We present a premature (24 wk of gestation) infant with primary cutaneous aspergillosis appearing on the sixth day of life. Predisposing factors in this patient were prematurity, extremely vulnerable skin, treatment with antibiotics and renovation in the radiology department nearby. The patient was treated with amphotericin B intravenously for a total of 40 d. He did not have, nor develop, disseminated aspergillosis, and suffered no side effects from the treatment. The only remaining trace of his infection was scarring in the affected area.. After having treated this patient successfully and having gone through the available literature, we conclude that treating primary cutaneous aspergillosis with intravenous amphotericin B prevents disseminated aspergillosis and is the treatment of choice.

Topics: Amphotericin B; Aspergillosis; Dermatomycoses; Diseases in Twins; Humans; Infant, Newborn; Infant, Premature, Diseases; Male

To review our experience of caspofungin in the treatment of persistent candidemia in the neonatal intensive care unit.. This was a retrospective chart review on 13 infants in whom caspofungin was added to conventional antifungals (amphotericin B and/or fluconazole or flucytosine) for the treatment of refractory candidemia.. A total of 12 infants were preterm (gestational age, 24 to 28 weeks) and one was term; the median birth weight was 800 g (range, 530 to 5600 g). Candidemia (Candida albicans in five, C. parapsilosis in six, C. albicans and C. parapsilosis in one and C. tropicalis in one) persisted despite 6 to 30 days of conventional antifungal therapy. After the addition of caspofungin, sterilization of blood cultures was achieved in 11 infants at the median time of 3 days (range, 1 to 21 days). Adverse events included thrombophlebitis (one patient), hypokalemia (two patients) and elevation of liver enzymes (four patients). Three infants had a second episode of candidemia and seven patients died.. Caspofungin may be an efficacious addition for treatment of candidemia refractory to conventional antifungal therapy. This drug should be further investigated in neonates.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Caspofungin; Drug Therapy, Combination; Echinocandins; Female; Fluconazole; Flucytosine; Fungemia; Gestational Age; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care, Neonatal; Lipopeptides; Male; Peptides, Cyclic; Retrospective Studies

Fungal sepsis is becoming more frequent in neonatal intensive care units (NICU) and has a high mortality rate due to the invasive nature of the disease and to the insufficiency of low doses and high incidence of renal problems with effective doses of amphotericin B. New generation lipid formulated amphotericin B preparations may be more efficient because they are less toxic to be applied in target doses. However, there is limited experience in neonates and preterm infants.. The charts of 917 patients admitted to NICU between 2001 and 2003 were reviewed and the data of 21 patients with systemic Candida infection, requiring different amphotericin B therapy, were analyzed.. Infants with fungal septicemia were treated with amphotericin B lipid complex (Abelcet)(n = 10) and liposomal amphotericin B (AmBisome)(n = 9) for a mean duration of 21 and 18 days. The mean gestational age of the patients was 30.9 +/- 4.2 weeks and mean birth weight was 1536 +/- 714 g. Two patients in the Abelcet group and one patient in the AmBisome group died during therapy. Fungal eradication was achieved in 16 surviving infants and mean eradication time was 8.1 +/- 2.6 days and mean duration of therapy was 19.2 +/- 4.1 days. Mortality rates related to treatment failure were similar being 20% in the Abelcet group and 11% in the AmBisome group. No patient showed severe side-effects from the antifungal therapy; the incidence of minimal side-effects were similar in both groups and they were elevated serum transaminase levels in six patients, increased serum creatinine in one patient and hypokalemia in one patient.. Both preparations have the same benefits for the treatment of neonatal fungal sepsis and they can be used safely in neonates including very low birth weight infants. However, the clinician must keep in mind the cost of treatment.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Drug Combinations; Fungemia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Phosphatidylcholines; Phosphatidylglycerols; Retrospective Studies; Treatment Outcome

Systemic fungal infections are being recognized with increasing frequency in extremely premature neonates. We report two such infants with late-onset mixed infection with Staphylococcal species and unusual fungi. These cases are of interest in view of recent reports on the interaction of Staphylococcal cell wall components and neutrophils, as damaged skin sites could form a nidus and portal of entry for saprophytic fungal pathogens. It is also important to consider fungal infection as a possibility in sick premature infants with necrotic skin lesions even when the systemic signs have an alternative explanation with ongoing bacteremia.

Topics: Amphotericin B; Antifungal Agents; Dermatomycoses; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Male; Staphylococcal Infections; Trichosporon

Greater use of invasive procedures and aggressive antimicrobial therapy predispose extremely low birth weight (ELBW) infants to systemic fungal sepsis. Despite its adverse effects (including renal and electrolyte disturbances), amphotericin B (amphoB) remains the preferred drug for fungal therapy. Multiple studies have indicated that sodium loading may prevent renal toxicity among animals and human adults. The effects of fluid and electrolyte management on amphoB-induced nephrotoxicity among ELBW infants have not been evaluated extensively. The purpose of this study was to examine the effects of fluid and electrolyte management on amphoB-induced nephrotoxicity among ELBW infants.. The medical records were reviewed for all ELBW infants (birth weights of < or =1250 g) who developed systemic fungal sepsis, requiring amphoB therapy, between January 1992 and December 2000. Demographic, clinical, and laboratory data were collected from the medical records for each patient.. Fungal sepsis requiring amphoB treatment developed for 4.4% of ELBW infants (25 of 573 infants), with a gestational age of 25 +/- 1 weeks and a birth weight of 738 +/- 37 g, at a postnatal age of 16 +/- 2 days. Renal compromise, as manifested by low urine output and high creatinine levels, occurred for 44% of those infants (11 of 25 infants). There was no difference between the infants who developed renal compromise (renal compromise group [RCG], n = 11) and those who did not (no-renal-compromise group [NCG], n = 14) with respect to birth weight, gestational age, and risk factors predisposing the infants to fungal sepsis. The RCG demonstrated a decrease in urine output by 3.4 +/- 2 days and an increase in serum creatinine levels by 3.9 +/- 2 days after the initiation of amphoB therapy. Infants in the RCG had a significantly higher incidence of hyponatremia, compared with infants in the NCG (7 of 11 infants vs 0 of 14 infants), with no significant difference in the incidences of hypokalemia (2 of 11 infants vs 0 of 14 infants). Infants in the RCG, compared with infants in the NCG, had significantly lower mean daily sodium intakes in the 4 days before the initiation of amphoB therapy (2.6-2.9 mEq/kg per day vs 4.2-4.7 mEq/kg per day) and in the first 4 days of amphoB treatment (2.7-3.1 mEq/kg per day vs 4.5-5.6 mEq/kg per day). Mean daily sodium intakes were not statistically significantly different between the 2 groups between day 5 and day 10 of amphoB therapy. Infants in the RCG tended to have lower mean daily potassium intakes in the 4 days before the initiation of amphoB therapy and during the first 4 days of amphoB therapy. Subsequently, the mean daily potassium intakes remained not statistically significantly different between the groups. Mean daily fluid intakes were not different between the groups.. Conventional amphoB combined with adequate hydration and higher sodium intakes of >4 mEq/kg per day may provide effective protection against amphoB-induced nephrotoxicity among ELBW infants. Our data confirm the published results of animal and human adult studies and suggest that higher sodium intakes may prevent renal compromise during amphoB therapy among ELBW infants.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Creatinine; Female; Fluid Therapy; Fungemia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Kidney Diseases; Male; Potassium; Retrospective Studies; Risk Factors; Sodium; Water-Electrolyte Balance

We report a preterm infant with 30 weeks of gestation, that received broad spectrum antimicrobials during the first days of life. At nine days of life, the infant appeared with abdominal distension and hematochezia. A systolic murmur with changing auscultatory features also appeared. An echocardiography showed an atrial vegetation. A yeast, that was identified as the emergent pathogen Saccharomyces cerevisiae appeared in two blood cultures. Treatment with amphotericin B was started, the dose was adjusted calculating the minimal inhibitory concentration of amphotericin B, and measuring plasma levels of the antimicrobial. Therefore the minimal effective dose was prescribed, avoiding its deleterious effects. After 14 days of antifungal therapy, a new echocardiography showed a reduction in the size of the atrial vegetation. At 35 days, it disappeared and amphotericin B was discontinued. On the outpatient follow up, the infant has shown a normal growth and a normal cardiac auscultation.

Topics: Amphotericin B; Antifungal Agents; Endocarditis; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Mycoses; Saccharomyces cerevisiae

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lung; Male; Placenta; Pregnancy; Pregnancy Complications, Infectious; Radiography; Respiratory Distress Syndrome, Newborn; Umbilical Cord

Candida parapsilosis is an increasingly important bloodstream pathogen in neonatal intensive care units (NICU). We investigated a cluster of bloodstream infections in a NICU to determine whether nosocomial transmission occurred. During a 3-day period, 3 premature infants hospitalized in the same unit presented with sepsis caused by C. parapsilosis. Electrophoretic karyotype of the organisms was performed by using pulsed field gel electrophoresis in a countour-clamped homogeneous electric field system. The isolate from 1 newborn could not be typed, and the isolates from the remaining 2 infants had identical patterns. All 3 cases are described. We conclude that nosocomial transmission of C. parapsilosis occurred and that neonates under intensive care may represent a risk group for this pathogen.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Cross Infection; Diseases in Twins; Electrophoresis, Gel, Pulsed-Field; Fungemia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Karyotyping; Risk Factors

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Female; Heart Atria; Heart Diseases; Humans; Infant, Newborn; Infant, Premature, Diseases; Uveitis

Topics: Amphotericin B; Antifungal Agents; Arthritis, Infectious; Candida albicans; Candidiasis; Diseases in Twins; Hip Joint; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Knee Joint; Male; Osteomyelitis; Risk Factors

To determine the epidemiology of candidemia in our neonatal intensive care unit; to compare risk factors, clinical presentation, and outcomes for neonates infected with Candida albicans, Candida parapsilosis, and coagulase-negative staphylococcus (CoNS); and to suggest a rational approach to empiric antifungal therapy of neonates at risk for nosocomial infection.. Retrospective chart review of all neonatal intensive care unit patients with systemic candidiasis or CoNS infection between January 1, 1995 and July 31, 1998 at Duke University Medical Center.. Fifty-one patients were reviewed. Nine of 19 patients infected with C parapsilosis and 5 of 15 patients infected with C albicans died of fungemia. Seventeen neonates had >2 positive cultures for CoNS obtained within 96 hours and 1 died. There was no statistically significant difference in birth weight, gestational age, or age at diagnosis between patient groups; however, candidemic patients had a sevenfold higher mortality rate. Before diagnosis, candidemic patients had greater exposure to systemic steroids, antibiotics, and catecholamine infusions. Of the 51 patients, 32 received third-generation cephalosporins in the 2 weeks before diagnosis and 19 did not. Twenty-nine of the 32 who were treated with third-generation cephalosporins subsequently developed candidemia, while candidemia occurred in only 5 of 19 patients who were not treated with cephalosporins. At the time of diagnosis, candidemic patients were more likely to have required mechanical ventilation and were less likely to be tolerating enteral feeding. Multivariate clustered logistic regression analysis revealed that candidemic patients had more exposure to third-generation cephalosporins. Once the clinician was notified of a positive blood culture for Candida, patients infected with C parapsilosis retained their central catheters longer than patients infected with C albicans.. In this retrospective review, we were able to identify aspects of the clinical presentation and medication history that may be helpful in differentiating between candidemia and CoNS bacteremia. Those key features may be used by clinicians to initiate empiric amphotericin B therapy in premature neonates at risk for nosocomial infections. Prolonged use of third-generation cephalosporins was strongly associated with candidemia. There was no statistically significant difference in the morbidity and mortality between patients infected with C parapsilosis and those infected with C albicans. Observed delays in removal of the central venous catheter may have contributed to finding a mortality rate from C parapsilosis that was higher than was previously reported.

Topics: Amphotericin B; Analysis of Variance; Anti-Bacterial Agents; Antifungal Agents; Bacteremia; Candida; Candida albicans; Candidiasis; Catheterization, Central Venous; Cephalosporins; Cross Infection; Diagnosis, Differential; Fungemia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Logistic Models; Retrospective Studies; Risk Factors; Staphylococcal Infections

Liposomal amphotericin B (L-Amp B), a novel formulation of amphotericin B, is effective for the treatment of invasive fungal infections in children and adults and is associated with less toxicity than the conventional preparation. Data on the use of Liposomal amphotericin B in neonates is scarce. We describe the clinical course of two premature infants who were treated with Liposomal amphotericin B (one infant had candidemia, and the other had candidemia and meningitis), and provide a summary of previously published experience on this topic. Liposomal amphotericin B may be an option for therapy of invasive candidiasis in neonates who are at high risk of nephrotoxicity and other amphotericin-related reactions, but clinical trials are necessary to document its safety and efficacy in this age group.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Drug Carriers; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Liposomes; Male

Amphotericin B is still the first-line therapy for neonatal fungal infections. With several comparative trials of intralipid-based amphotericin B (IL-AmB) demonstrating its clinical effectiveness and reduced renal toxicity in adults, we examined the renal tolerance and infection outcome in low-birth-weight infants in our 48-bed NICU treated with IL-AmB. Over 2 years, 52 patients (58 courses) received > or = 10 days of IL-AmB. Nineteen charts (23 episodes) were randomly accessed and reviewed. Mean birthweight = 747 grams, gestational age = 25.6 weeks, total IL-AmB dosage = 19.8 +/- 3.3 mg/kg (n = 23); 20 of these episodes were fungal culture positive (9 fungemias). Only one patient (who died during therapy) had a rise in creatinine of > 0.3 mg/dL. Overall, serum creatinine decreased significantly after Day 10 of IL-AmB therapy, from 0.93 +/- 0.42 mg/dL at baseline, to 0.54 +/- 0.24 after 19 days of therapy (p < 0.0001). Serial urine output, serum potassium and potassium supplementation data showed no significant differences from baseline. No interruption of therapy nor infusion reactions occurred. Only one death occurred attributable to fungal infection. Intralipid-amphotericin B may provide an effective alternative in the antifungal therapy of low birthweight neonates, without nephrotoxicity. Further prospective, comparative trials are warranted.

Topics: Amphotericin B; Analysis of Variance; Antifungal Agents; Blood Urea Nitrogen; Candida albicans; Candidiasis; Chi-Square Distribution; Creatinine; Female; Fungemia; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Kidney; Kidney Function Tests; Male; Registries; Retrospective Studies; Treatment Outcome; Urine

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Male; Retrospective Studies

Topics: Amphotericin B; Brain Abscess; Candidiasis; Drug Therapy, Combination; Female; Fluconazole; Flucytosine; Fungemia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Tomography, X-Ray Computed

Topics: Abdominal Muscles; Amphotericin B; Cellulitis; Combined Modality Therapy; Debridement; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Mucormycosis; Necrosis; Rhizopus

Topics: Amphotericin B; Antifungal Agents; Cryptococcosis; Drug Administration Schedule; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Intravenous; Male

We report a case of Candida albicans meningitis in a neonate born after 27 weeks of gestation. To the best of our knowledge this is the first report of a premature infant with Candida-meningitis treated with liposomal amphotericin B (AmBisome(R)). The patient did not respond well to conventional Amphotericin B, but was successfully cured with Ambisome(R). Liposomal amphotericin B was well tolerated and the baby recovered with a postinfectious hydrocephalus which necessitated a permanent ventriculo-peritoneal shunt. Six months after the infection the baby appears to have a near-normal cerebral development.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Meningitis, Fungal

Topics: Amphotericin B; Candidiasis; Fluconazole; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Kidney Diseases; Male; Ultrasonography

Congenital candida infection is a rare disease, although the incidence of candida vaginitis during pregnancy is high. We report on five cases each showing patterns considered typical for candida infection. The infective agent can cause chorioamnionitis even in the presence of intact fetal membranes. An intrauterine device (IUD) has been proved to be a risk factor for a congenital candida infection. The pathogenetic significance of contamination with candida for the fetus appears to depend largely on gestational age. A premature infant with a birth-weight less than 1500 g presented with bilateral candida endophthalmitis which was cured by intravenous Fluconazole therapy. Another premature infant weighing 800 g at birth developed a systemic candida infection. The other three more mature infants had milder symptoms, two of them presented with cutaneous candidiasis.

Topics: Adult; Amniocentesis; Amphotericin B; Candidiasis; Candidiasis, Cutaneous; Candidiasis, Oral; Candidiasis, Vulvovaginal; Chorioamnionitis; Drug Therapy, Combination; Endophthalmitis; Female; Fetal Membranes, Premature Rupture; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Nystatin; Pregnancy

We introduced continuous intravenous infusion of amphotericin-B (AMPH-B) to extremely low birthweight (ELBW) infants (< 1000 g) with or without renal failure as a single agent for treating definite or probable systemic candidiasis. The species of Candida isolated from blood or tracheal aspirate or urine were C. albicans in seven infants, C glabrata in two, C. tropicalis in one and C. parapsilosis in one. The minimal inhibitory concentrations (MIC) of AMPH-B required against these isolates were less than 0.2 micrograms/mL except for that against one strain of C. albicans (0.78 microgram/mL). Serum AMPH-B levels were 0.31-0.78 (0.51 +/- 0.14) micrograms/mL when doses of 0.2-0.55 (0.32 +/- 0.11) mg/kg per day were being administered. The serum level was higher than the MIC of each isolate in all but one infant who died of disseminated intravascular coagulation and Candida pneumonia. Another infant died of congenital heart disease. The other nine infants survived. The serum level showed no correlation with the daily dose. The ratio of the serum level to the daily dose (L/D ratio) showed a significant correlation to serum creatinine (r = 0.787) and the linear regression curve followed the equation: L/D ratio = 0.223 x serum creatinine + 1.11 (P < 0.01). Few adverse effects due to AMPH-B were noted. Our data may give a simple reference to serum AMPH-B levels during continuous intravenous infusion from the dose and the serum creatinine level.

Topics: Acute Kidney Injury; Amphotericin B; Candidiasis; Creatinine; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Infusions, Intravenous; Serum Bactericidal Test; Time Factors

A case of asymptomatic intraamniotic infection with Candida albicans in a woman presenting with preterm premature rupture of membranes is reported. Active prenatal diagnostic procedures and prompt and accurate neonatal treatment (Amphotericin B) improved significantly the usually poor outcome of these pregnancies.

Topics: Adult; Amniotic Fluid; Amphotericin B; Candida albicans; Candidiasis; Chorioamnionitis; Female; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Infant, Premature, Diseases; Ketoconazole; Male; Mediastinal Emphysema; Pneumonia; Pregnancy

A case of primary cutaneous aspergillosis in a very low birthweight infant that responded to medical therapy is reported. Knowledge of the potential pathogenic role of this organism in neonatal skin lesions is important because of resistance to standard empirical antibacterial therapy and the potential for dissemination and deep parenchymal invasion. Surgical excision may be necessary if cutaneous aspergillosis progresses despite systemic antifungal therapy.

Topics: Amphotericin B; Aspergillosis; Aspergillus fumigatus; Dermatomycoses; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care, Neonatal; Male

Topics: Amphotericin B; Candidiasis; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases

Renal candidal bezoar is uncommonly encountered in neonatal intensive care. An affected neonate who improved only after surgical removal of obstructive fungus from the renal pelvis and local irrigation with amphotericin B is described. The need for early consideration of surgical intervention is stressed.

Topics: Amphotericin B; Candidiasis; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Kidney; Kidney Diseases; Male; Ultrasonography

Topics: Amphotericin B; Aspergillosis; Aspergillus fumigatus; Candidiasis; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Liposomes; Male

Unilateral renal obstruction secondary to fungus balls is described in a premature infant. Noninvasive medical management, which included amphotericin B and 5-flucytosine therapy and forced diuresis, resulted in disappearance of fungus balls and resolution of the obstruction.

Topics: Amphotericin B; Candidiasis; Diuresis; Flucytosine; Humans; Hydronephrosis; Infant, Newborn; Infant, Premature, Diseases; Kidney; Male; Ultrasonography; Ureteral Obstruction

We report a case of anuria in a premature neonate secondary to bilateral ureteropelvic junction obstructions related to Candida bezoars. Percutaneous decompression and drainage of both kidneys contributed significantly to the successful management of renal candidiasis in this patient. A review of the literature is presented.

Topics: Amphotericin B; Anuria; Bezoars; Candidiasis; Drainage; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Kidney Diseases; Male; Nephrostomy, Percutaneous

Two very low birth weight infants who developed renal candidiasis with pelvicalyceal fungal concretions were treated medically with Amphotericin B and 5 Fluorocytosine. Two months following cessation of therapy, the fungal concretions decreased in size, became sterile and developed calcification in residual debris. The calcifications was still present at demise in one patient and at 18 months follow up in the other. These calcifications occurred in the absence of simultaneous furosemide therapy.

Topics: Amphotericin B; Candidiasis; Female; Flucytosine; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Kidney Calculi; Kidney Diseases

Endocarditis is an uncommon complication of disseminated candidiasis among premature infants, but has been recently reported to be almost uniformly fatal. The lone previously documented survivor required extensive surgical resection as well as prolonged systemic antifungal therapy. The present report details a premature infant who recovered from Candida endocarditis with medical therapy alone.

Topics: Amphotericin B; Candidiasis; Endocarditis; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Male

We report a case of neonatal infection with rhizopus, one of the Mucoraceae family. Human infection is rare but the mortality is high without prompt, correct treatment. The infant had a simultaneous candida septicaemia secondary to colonisation of a central venous line. Serial C reactive protein estimations are valuable in monitoring treatment.

Topics: Abscess; Amphotericin B; Candidiasis; Drainage; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Mucormycosis; Rhizopus

Twenty-two preterm infants with systemic candidiasis are reported, of which seven cases were presumed to be antenatally acquired and 15 postnatally acquired. All except one were of very low birthweight. Fifteen infants had positive cultures of blood, cerebrospinal fluid or urine and seven had candida pneumonia only. Clinical features included general instability, respiratory deterioration and a necrotizing enterocolitis-like presentation. The incidence of leukocytosis, shift to the left, eosinophilia and thrombocytopenia were not different from those with bacterial infection. The diagnosis was made after death in two infants. In the remaining 20 infants, treatment was initiated between 5 and 97 days of age, with a median delay of 4 days after the first positive cultures were taken. Complications of amphotericin and 5-flucytosine therapy which developed in five infants resolved on cessation of treatment. The mortality rate was 18% and impairment rate among the 17 very low birthweight survivors was 18%. A high index of suspicion is required for systemic candidiasis, especially in infants of less than 1000 g birthweight. If recognized early, effective and safe antifungal therapy is possible with favourable short- and long-term outcome.

Topics: Amphotericin B; Candidiasis; Developmental Disabilities; Drug Administration Schedule; Drug Therapy, Combination; Female; Flucytosine; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Pneumonia; Pregnancy; Pregnancy Complications, Infectious

We report on 5 neonates with obstructive urinary tract candidiasis in whom percutaneous nephrostomy had a major role in management. The advantages of percutaneous nephrostomy in this setting include prompt drainage of the obstructed renal pelvis or ureter, direct access to obtain specimens from the renal pelvis to confirm the diagnosis, direct irrigation of the fungus balls with amphotericin B and an access route for fragmentation of fungus balls by guide wire manipulation. In 3 cases percutaneous placement of the nephrostomy tube was successful in obtaining and maintaining access to the renal pelvis, while in 2 surgical intervention was required because of problems maintaining placement of the percutaneous catheters. Percutaneous nephrostomy with antegrade amphotericin B irrigation, coupled with systemic antifungal therapy, is the mainstay of treatment. The usefulness of ultrasonography in the early diagnosis of renal candidiasis also is emphasized.

Topics: Amphotericin B; Candidiasis; Combined Modality Therapy; Drug Therapy, Combination; Female; Flucytosine; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Male; Nephrostomy, Percutaneous; Urinary Tract Infections

Amphotericin B (Amp-B) serum concentrations were determined in five infants with disseminated candidiasis. All patients had positive blood cultures for Candida and one patient had Candida albicans meningitis. Amp-B sterilized the blood and the cerebrospinal fluid within four to nine days. Total doses of Amp-B varied from 11.6-62.3 mg. There was no laboratory or clinical evidence of renal toxicity. Two infants died of causes unrelated to disseminated candidiasis. Disseminated candidiasis in premature infants was treated successfully with 0.5 mg/kg doses of Amp-B, but further studies with more evaluable cases are needed to confirm the correct dose.

Topics: Amphotericin B; Candida albicans; Candidiasis; Cross Infection; Humans; Infant, Newborn; Infant, Premature, Diseases; Microbial Sensitivity Tests

The pharmacokinetics of amphotericin B (AmB) have not previously been evaluated in children. Five very small, premature infants and five older children received 0.25-1.0 mg of AmB/kg per 24 hr for Candida infections. Serum concentrations of AmB, measured by bioassay, were used to determine various pharmacokinetic parameters of AmB. A one-compartment model of drug distribution was most consistent with the data. The volume of AmB distributed per kilogram of body weight was smaller and the elimination clearance more rapid than those previously reported for adults. Serum levels were approximately one-half those seen in adults given comparable doses. The mean concentrations of AmB after various doses were as follows: at 0.25 mg/kg, 0.08 microgram/ml; at 0.50 mg/kg, 0.20 microgram/ml; at 0.75 mg/kg, 0.42 microgram/ml; and at 1.0 mg/kg, 0.54 microgram/ml. Interpatient variability was, however, marked, especially among the premature infants. AmB pharmacokinetics are different in infants and children than in adults; these differences may have implications for determining optimal pediatric dosing regimens.

Topics: Adolescent; Amphotericin B; Body Fluids; Candidiasis; Child; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Kinetics; Tissue Distribution

Over a 13-month period 52 neonates (10% of those admitted to the Mersey Regional Neonatal Intensive Care Unit) were found to be colonised with the ascosporagenous yeast Hansenula anomala. 8 babies became infected, all but 1 of whom were heavily colonised before infection. 7 of the 8 infected babies were of very low birth-weight (less than 1500 g). All 8 had multiple problems associated with low birth-weight and prematurity and were kept in the intensive care unit. 5 babies had fungaemia, 2 had fungaemia and ventriculitis, and 1 had ventriculitis only. In each case H anomala was the sole pathogen isolated. Anti-Hansenula antibodies developed in 5 babies within 3 months of infection. Infected babies were successfully treated with a combination of 5-flucytosine and amphotericin B. Despite extensive searches the babies appeared to be the only reservoir of the yeast.

Topics: Amphotericin B; Disease Outbreaks; Drug Therapy, Combination; England; Flucytosine; Gestational Age; Humans; Infant, Newborn; Infant, Premature, Diseases; Mycoses; Pichia; Rectum; Saccharomycetales

Systemic candidiasis with renal involvement is a well recognised complication of intensive care in premature newborns. However, the development of reversible obstructive oliguric acute renal failure has not been well documented. We report a premature infant who developed anuria associated with bilateral candidal bezoar formation in the renal collecting system. The sonographic appearance of the renal fungus balls is described. Treatment by surgical removal of the bezoars, open placement of nephrostomy tubes and intravenous antifungal therapy resulted in apparent complete recovery.

Topics: Amphotericin B; Anuria; Bezoars; Candidiasis; Female; Flucytosine; Follow-Up Studies; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Injections, Intravenous; Kidney Diseases; Radiography; Time Factors; Ureteral Diseases

Topics: Amphotericin B; Candidiasis; Combined Modality Therapy; Female; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Ketoconazole; Male; Parenteral Nutrition; Respiration, Artificial

The hospital records of 45 infants and children with one or more blood cultures positive for Candida species were studied retrospectively in an attempt to define the risk of Candida-related complications. Death of eight of the patients (18%) was related to Candida infection, and five additional patients (11%) had metastatic foci of infection but survived. No characteristics were identified that would predict patients who were at high risk for complications of candidemia. Eleven patients were treated with amphotericin B for longer than a week and were examined for evidence of nephrotoxicity. None had persistent abnormalities of blood urea nitrogen or serum creatinine concentrations develop during treatment; two patients had hypokalemia.

Topics: Adolescent; Amphotericin B; Blood; Blood Urea Nitrogen; Candidiasis; Child; Child, Preschool; Creatinine; Drug Therapy, Combination; Female; Flucytosine; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Kidney Diseases; Male; Retrospective Studies

Ten babies who required neonatal intensive care developed systemic candidiasis. Eight were extremely preterm (28 weeks' gestation or less) and all received prolonged ventilation, multiple courses of broad spectrum antibiotics, and intravenous hyperalimentation. Diagnosis was established by culture of yeasts from suprapubic urine specimens; venous blood cultures proved unreliable. Initial treatment with 5-flucytosine alone in eight babies and combined with amphotericin B in two, eradicated the infection in nine babies, the treatment failure arising through diagnostic delay and development of resistance to 5-flucytosine. Prophylactic topical antifungal drugs, regular screening of suprapubic urine specimens, and prompt use of systemic antifungal agents before multifocal infection becomes established may reduce the incidence and improve outcome.

Topics: Amphotericin B; Anti-Bacterial Agents; Candidiasis; Critical Care; Drug Therapy, Combination; Flucytosine; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Respiration, Artificial

Eleven premature infants with systemic candidiasis from 1981 to 1984 have been reported previously. The experience with antifungal drugs is presented. Amphotericin B at lower maintenance dose, together with 5 flucytosine (5FC), are the preferred drugs for treatment of systemic candidiasis at present.

Topics: Amphotericin B; Candidiasis; Cytosine; Drug Therapy, Combination; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Ketoconazole; Miconazole

Two premature neonates with birth weight less than 1,200 g developed systemic candidiasis during treatment with multiple antibiotics and parenteral hyperalimentation. Clinical findings included signs of necrotizing enterocolitis in one patient and multiple fungal renal cortical abscesses in the other. The Candida antigen, mannan, was present in the sera of both patients at the time of clinical deterioration. Multiple blood cultures and urine and stool samples from both patients grew Candida albicans. Systemic antifungal therapy was given for a 6-week period and was associated with prolonged antigenemia despite negative findings on follow-up cultures. Antifungal therapy was stopped soon after antigen was no longer detected. Both patients recovered without evidence of further fungal infection. Candida antigen detection may be useful in the diagnosis and follow-up of premature infants with disseminated candidiasis.

Topics: Amphotericin B; Antigens, Fungal; Candida; Candidiasis; Enterocolitis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Mannans; Parenteral Nutrition, Total; Postoperative Complications

Primary renal candidiasis and hydronephrosis were diagnosed in two premature neonates in whom systemic hypertension developed. The clinical course in these patients and in 16 patients with renal candidiasis described in the literature indicated that prematurity, use of broad-spectrum antibiotics, and use of intravenous (IV) catheters are predisposing factors. Anuria and flank mass were the initial manifestations in the reviewed cases. Only four of the 16 patients survived following either antifungal therapy or nephrectomy. Both of our patients survived after antifungal therapy with amphotericin B and flucytosine for systemic effect as well as topical instillation of amphotericin B solution via a nephrostomy. We believe that a high index of suspicion in infants at risk and early institution of antifungal therapy for systemic as well as topical effect can improve the outcome in infants with renal candidiasis.

Topics: Amphotericin B; Candidiasis; Drug Therapy, Combination; Female; Flucytosine; Humans; Hydronephrosis; Hypertension; Infant; Infant, Newborn; Infant, Premature, Diseases; Kidney Diseases; Kidney Pelvis; Male

Previous reports in the literature have documented that systemic infection with Candida albicans in very premature infants is frequently fatal (54%) or associated with significant morbidity in survivors (25%). Five patients with a mean birth weight of 829 g had a diagnosis of systemic candidiasis during their stay in a newborn intensive care unit. All infants survived with minimal sequelae following aggressive early treatment with amphotericin B and 5-flucytosine. A review of these five extremely premature infants and 26 previously reported patients suggests the following: (1) disseminated candidiasis is common in the absence of positive findings in blood, CSF, and/or urine cultures; (2) transient candidemia rarely resolves without therapy; (3) meningitis and osteoarthritis occur more frequently than in older patients with disseminated disease; and (4) premature infants tolerate amphotericin B and 5-flucytosine well. Infants who are found to have systemic cultures positive for candidiasis should be treated by (1) removing all factors that predispose to systemic candidiasis (eg, indwelling catheters, broad-spectrum antibiotics); (2) early initiation of systemic antifungal therapy with amphotericin B and 5-flucytosine; and (3) searching for additional foci of disease. After the disease is recognized and treatment is prompt and aggressive, outcome can be substantially improved.

Topics: Amphotericin B; Candidiasis; Cytosine; Female; Flucytosine; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases

The improved survival of very low-birth-weight infants, who require prolonged hospitalization and many invasive procedures, increases the risks for nosocomial illnesses, such as disseminated fungal infections. In a 2-year period, systemic fungal infections were clinically diagnosed in ten infants. This necessitated the institution of antifungal therapy in extremely premature infants (mean birth weight 788 g, mean gestational age 28 weeks) despite the paucity of knowledge about the pharmacokinetics and toxicity of these drugs in the very immature patient. Despite the absence of reported toxicity in infants and older children, severe nephrotoxicity was commonly observed with oliguria/anuria, temporally related to the administration of amphotericin B in seven of these infants. Additional evidence of nephrotoxicity included either a rise in creatinine levels (greater than or equal to 1.3 mg/dL), an increase in BUN (greater than or equal to 30 mg/dL), hypokalemia (less than or equal to 2.9 mEq/L), or hyperkalemia (greater than or equal to 6.0 mEq/L). Six of these seven drug-toxic infants died. Interruption of amphotericin B therapy, with reinstitution at a lower dose, was the most successful factor in alleviating the anuria. There is an urgent need for detailed pharmacokinetic and toxicity studies of antifungal agents in immature infants.

Topics: Acute Kidney Injury; Amphotericin B; Cytosine; Flucytosine; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Mycoses; Time Factors

Topics: Amphotericin B; Candidiasis; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Meningitis; Miconazole

A 720-g premature newborn developed disseminated candidiasis during treatment with systemic antibiotics and total parenteral nutrition through an umbilical arterial catheter. Clinical features were typical for candidal skeletal infection at this age and included warmth and fusiform swelling of the lower extremities together with radiographic evidence of osteolysis and cortical bone erosion. Candida albicans was cultured from blood, urine, joint fluid, and a bone aspirate. The infection was cured with a 44-day course of amphotericin B and flucytosine (5-fluorocytosine). Antifungal therapy was monitored closely with serum drug levels and laboratory tests for bone marrow toxicity and renal dysfunction. Serum levels of both drugs were comparable to those achieved in older patients treated with similar doses. Significant concentrations of amphotericin B were detected in serum four and 17 days after completion of therapy, indicating a slow rate of elimination similar to that which occurs in adults. There was no evidence of drug-induced toxicity other than transient elevation in the fractional urinary excretion of sodium. This suggests that antifungal therapy may be effectively and safely administered to infants in dose schedules similar to those used for older patients.

Topics: Amphotericin B; Arthritis, Infectious; Candidiasis; Cytosine; Drug Therapy, Combination; Female; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Osteomyelitis; Outcome and Process Assessment, Health Care

Topics: Amphotericin B; Candidiasis; Drug Therapy, Combination; Flucytosine; Humans; Imidazoles; Infant, Newborn; Infant, Premature, Diseases; Injections, Intravenous; Male; Miconazole

An attempt was made to determine the incidence and natural history of Candida endophthalmitis in the premature infant with systemic candidiasis. Each of eight premature infants were examined by indirect ophthalmoscopy within one week of their diagnosis. At this stage, four infants had multiple fluffy white lesions on both the retina and the vitreous, together with a diffuse vitreous haze. Three of the infants had interlesional and lesional-retinal vitreous strands. Three infants treated with amphotericin B and 5-fluorocytosine showed gradual disappearance of the lesions. The fourth infant died early in the course of antifungal therapy, when the eye lesions were progressing. Candida sepsis was particularly prevalent in the very low-birth-weight infant with a prolonged hospital course and treated with multiple broad-spectrum antibiotics. The course of the eye lesions indicates a good prognosis for Candida endophthalmitis, although further follow-up is necessary.

Topics: Amphotericin B; Candidiasis; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Ophthalmia Neonatorum; Ophthalmoscopy; Prognosis; Prospective Studies

Candida albicans meningitis was diagnosed in a 45-day-old premature infant whose birth weight was 1,616 gm. Symptoms consisted of poor weight gain and poor suckling. The combined use of amphotericin B and 5-fluorocytosine (5-FC) resulted in negative CSF cultures after 12 days of therapy. Amphotericin B was given for 45 days (total 83 mg) and 5-FC for 60 days (total 19 mg). Only one other premature infant has been reported in the literature who had similar treatment. A review of Candida meningitis diagnosed before death in 11 other infants less than 1 year of age is presented.

Topics: Amphotericin B; Candidiasis; Drug Therapy, Combination; Female; Flucytosine; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Male; Meningitis

Meningitis due to Candida albicans was successfully treated in a 1.1 kg premature infant using combined antifungal therapy of amphotericin B for three weeks and 5-fluorocytosine for four months. Hydrocephalus and profound psychomotor retardation were present one year later. Psychomotor retardation, aqueductal stenosis and hydrocephalus were found to be common in a review of 16 previously reported cases of central nervous system (CNS) candidiasis in newborn infants. The diagnosis and institution of therapy were frequently delayed, and the mortality rate was 29% in the 17 patients reviewed here. The subacute course, lack of clinical findings, variable cerebrospinal fluid (CSF) findings, negative CSF cultures due to low concentrations of organisms, slow in vitro growth of C. albicans and misinterpretation of positive cultures as contaminants are factors frequently leading to delayed diagnoses. Using combination therapy, it should be possible to use lower doses and shorter courses of amphotericin B therapy for C. albicans meningitis in the newborn infant.

Topics: Adolescent; Amphotericin B; Candidiasis; Cytosine; Drug Therapy, Combination; Female; Flucytosine; Follow-Up Studies; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Male; Meningitis; Pregnancy; Psychomotor Disorders

A premature neonate developed advanced bilateral endophthalmitis before the significance of underlying Candida sepsis was appreciated. Severe endophthalmitis resulted in corneal thinning, descemetocele formation, and perforation. The infection occurred in the clinical setting of broad-spectrum antibiotic therapy and indwelling intravenous catheters. Cultures of blood and catheter tips had been positive for Candida but were not considered significant until advanced ocular infection was noted. The septic process resulted in the infant's death after systemic amphotericin B therapy was discontinued because of renal toxicity.

Topics: Amphotericin B; Candidiasis; Corneal Diseases; Endophthalmitis; Eye; Humans; Infant, Newborn; Infant, Premature, Diseases; Klebsiella Infections; Male; Nystatin

Topics: Amphotericin B; Antifungal Agents; Arthritis, Infectious; Candidiasis; Cytosine; Drug Resistance, Microbial; Drug Therapy, Combination; Endophthalmitis; Flucytosine; Humans; Infant, Newborn; Infant, Premature, Diseases; Meningitis; Osteomyelitis; Pyelonephritis; Radiography; Recurrence; Sepsis

Topics: Amphotericin B; Candida; Candidiasis, Oral; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Male; Suspensions

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Humans; Imidazoles; Infant, Newborn; Infant, Premature, Diseases; Meningitis

Topics: Amphotericin B; Candidiasis; Craniotomy; Female; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Infusions, Parenteral; Meningitis; Pregnancy

Topics: Amphotericin B; Candidiasis; Exchange Transfusion, Whole Blood; Heart Defects, Congenital; Humans; Infant, Newborn; Infant, Premature, Diseases; Jaundice, Neonatal; Sepsis

Topics: Acute Kidney Injury; Amphotericin B; Bronchopneumonia; Burns; Candida; Candidiasis; Child; Drug Therapy; Erythroblastosis, Fetal; Female; Geriatrics; Heart Failure; Humans; Hyperbilirubinemia; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Postgastrectomy Syndromes; Renal Insufficiency; Sepsis; Toxicology; Uterine Cervical Neoplasms; Wounds, Gunshot