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.
Candida infections are a significant cause of mortality (10 to 54%) and morbidity (25%) in the neonatal intensive care unit (NICU).1, 2 Prematurity, a history of exposure to antibiotics, presence of central vascular catheters, endotracheal intubation, prior colonization with Candida species, lack of enteral feeds and concomitant drug use such as H2 blockers and steroids are some of the reported risk factors for candidal infections in neonates.3, 4, 5, 6, 7 Amphotericin B deoxycholate (fungizone®) is the traditional drug of choice for children with candidemia.6 The lipid formulations of amphotericin B, flucytosine and fluconazole are other therapeutic options. The disadvantages of these drugs are that they are not always efficacious and are associated with adverse effects, especially on the kidneys and liver.
Caspofungin is an antifungal agent in the echinocandin class, which acts by inhibiting the synthesis of β-1,3 D-glucan, a component of the fungal cell wall.8 The drug has a concentration-dependent fungicidal activity against multiple Candida species.9, 10 It is effective as primary treatment of esophageal, oropharyngeal and invasive candidiasis as well as for candidal infections not responding to fluconazole and amphotericin B in adults.11, 12, 13 Randomized controlled trials in adults have shown that the efficacy of caspofungin is similar to that of amphotericin B deoxycholate in invasive candidiasis and the adverse effects are significantly fewer.11, 14 It is as effective as and better tolerated than liposomal amphotericin B as empiric therapy in adults with fever and neutropenia.7
Caspofungin is not a substrate for the cytochrome p450 system or the intestinal glycopeptides, thereby reducing drug interactions.8, 15 This is an important advantage for infants in the NICU where multiple concomitant drug use is common. In adult studies, the primary adverse effects are fever, headache, vomiting, diarrhea, signs of histamine release and irritation at the injection site.16, 17, 18 Caspofungin has been approved in adults for the treatment of esophageal and invasive candidiasis and invasive aspergillosis not responding or intolerant to other antifungal therapies. However, the data on its use in children are limited and practically nonexistent in neonates in whom it may be a valuable therapeutic addition, given the increasing frequency and importance of invasive fungal infections in the NICU.
We therefore report our experience of the addition of caspofungin in 13 critically ill infants with documented candidemia who failed to respond to conventional antifungal therapy.
MATERIALS AND METHODS
This is a retrospective descriptive chart review in which the pharmacy database was used to identify infants who had received at least two doses of caspofungin in the NICUs at Children's Hospital of Michigan and Hutzel Women's Hospital, between July 2001 and March 2004. Clinical and laboratory profiles, details of therapy and clinical and microbiological outcomes were reviewed. Data on birth weight, gestational ages, underlying diagnoses, episodes of bacterial infections and the use of antibiotics, steroids and ranitidine prior to candidemia were collected. Caspofungin was added in each case at the discretion of the treating physician for proven candidemia that persisted in spite of conventional antifungal therapy. After an initial positive peripheral blood culture for Candida species, blood cultures from a peripheral vein and through an intravascular catheter, if present, were routinely obtained in all infants at least every other day until a minimum of three consecutive blood cultures were sterile. As part of our standard care, renal ultrasonography, an ophthalmologic examination by a pediatric ophthalmologist, echocardiography and cerebrospinal fluid analysis were performed on all infants at the time of the initial positive blood culture. Weekly renal ultrasonography and echocardiography were performed while the blood cultures remained positive for Candida and if a focal complication was found, these studies were continued until resolution or death. All the patients underwent liver and renal function tests at least once a week and more frequently, if abnormal, while on antifungal therapy. Electrolytes, calcium, magnesium and phosphorus were monitored at least twice a week and platelets were followed daily until blood cultures turned negative. The complete blood count was performed at least once a week.
A brief database review of 13 other neonates with candidal infection in our NICU who were not treated with caspofungin was also performed. Data obtained included birth weight, gestational age, duration and type of antifungal treatment and clinical and microbiological outcomes. The Human Investigational Committee of Wayne State University School of Medicine approved the study.
A total of 13 infants (seven female infants and six male infants) who received at least two doses of caspofungin in the NICU were identified (Table 1). In total, 12 were premature with a median gestational age of 27 weeks (range, 24 to 28 weeks) and a median birth weight of 727 g (range, 530 to 1000 g). All 12 infants had moderate to severe hyaline membrane disease, required prolonged ventilator support and had hemodynamically significant patent ductus arteriosus. Seven also had necrotizing enterocolitis. The single-term infant (case 6) weighed 5600 g at birth. His underlying medical problems included a 47, XYY karyotype, congenital hydrocephalus requiring a ventriculoperitoneal shunt placement, long-segment Hirschsprung disease requiring colostomy and ventilator-dependent bronchopulmonary dysplasia. He had multiple episodes of bacterial sepsis and underwent a gastrostomy tube placement for feeding.
Prior to candidemia, 11 infants received systemic antibiotic treatment for a duration of 1 week or longer, nine of whom had documented bacteremia (methicillin-resistant Staphylococcus aureus in four, S. epidermidis in three, group B Streptococcus in one and polymicrobial bacteremia in one). Among the third-generation cephalosporins, five infants had received cefotaxime for 1 week or longer and one infant had received cefepime for 10 days. Ampicillin and cefotaxime were the empiric antibiotics used in the NICU while awaiting cultures to which all 13 infants had been exposed for at least 48 hours. Only one infant received an antifungal agent (fluconazole) for a fungal urinary tract infection before the candidemia. Three infants received ranitidine and two were given steroids prior to the fungal infection (hydrocortisone for blood pressure support in one case and dexamethasone for airway edema in the other).
Details of Candidemia
All patients were diagnosed with candidemia by a peripheral blood culture. Six patients had C. parapsilosis bloodstream infections, five had C. albicans, one had C. tropicalis and in one patient, both C. albicans and C. parapsilosis were isolated from the blood. The median age at initial diagnosis of candidemia was 24 days (range, 10 to 158 days). Two infants had candidemia alone whereas 11 infants had evidence of deep-seated invasive disease. Renal fungal balls were identified in eight infants, five of whom had positive urine cultures. Three infants developed intravascular thrombosis while two infants had candidal meningitis. Concomitant pneumonia diagnosed by positive endotracheal tube cultures and consistent radiographic changes was noted in three patients. One patient in whom Candida species was also isolated from stool culture had diarrhea, which resolved after antifungal therapy. None had the findings of endophthalmitis on examination.
Conventional antifungal therapy was started immediately after a positive blood culture. Four infants were started on a lipid formulation of amphotericin B while eight were started on amphotericin B deoxycholate and were subsequently switched to the lipid formulation when they failed to respond to the deoxycholate formulation or their renal function deteriorated. Prior to caspofungin use, seven infants were receiving the liposomal formulation (AmBisome®) and five were receiving the lipid complex formulation (Abelcet®). The doses of the lipid formulations ranged from 5 to 10 mg/kg/day in all cases. One infant (case 13) received fluconazole alone for candidal urinary tract infection that later evolved into a bloodstream infection. At that time, caspofungin was preferred as the additional drug because of the patient's oliguria.
All except three infants (cases 3, 6 and 13) had had the intravascular catheter removed prior to initiation of caspofungin therapy (Table 1). The decision to remove the catheter was made by the treating physician. The median duration of catheter removal was 4.5 days (range 1 to 7 days). Three patients (cases 3, 6 and 13) had a central line through most of their fungemic episode, the details of which are described (Table 1). Patient 3 had severe i.v. access problems and had multiple lines placed during the course of his infection. His central line was initially removed on day 2 of candidemia but he had a new central PICC placed on day 8 of the infection, which was subsequently removed on day 13 and then reinserted on day 36 of the infection. Patient 6 during his first episode of candidemia had his central line removed on day 2 of the infection and reinserted on day 9 after blood cultures turned negative. During his second episode, however, he had bilateral iliac vein and superior venacaval thrombosis and a ventriculoatrial shunt, which made him a very difficult i.v.access. His central line was removed on day 1 of the second episode but a new one was placed on day 4, removed on day 11 and reinserted on day 27 of the fungal infection. Patient 13 had a single PICC line through his candidemia, because of his critical condition and severe hypotension requiring three pressors for treatment. He was on the oscillator and had ascites with a peritoneal drain and generalized anasarca.
Candidemia persisted in all patients despite treatment with amphotericin B. A second antifungal drug was added in nine patients (fluconazole in eight and flucytosine in one) at a median duration of 7 days (range 0 to 15 days) after initiation of amphotericin B. The duration of conventional antifungal therapy, either monotherapy or combination therapy, before caspofungin was initiated varied according to the discretion of the treating physician; the median duration of amphotericin B was 14.5 days (range 6 to 30 days) and of combination with fluconazole/flucytosine was 9 days (range 2 to 23 days). All patients received caspofungin in combination with at least one other conventional antifungal (lipid formulation of amphotericin B, fluconazole and/or flucytosine) that the patients were receiving. The dose of caspofungin used was 1 mg/kg i.v. once daily; five infants also received an initial loading dose of 1.5 mg/kg. The total duration of antifungal therapy after negative blood cultures is described (Table 1). When prolonged therapy was required for deep-seated fungal foci, this consisted of amphotericin B in most cases while caspofungin was not continued for the entire duration, probably because of lack of data on a safe cumulative dose in preterm neonates.
Microbiologic sterilization of blood cultures was achieved in 11 of the 13 patients after adding caspofungin. The two patients who did not clear the candidal infection had C. albicans. The median time to sterilization after initiation of caspofungin was 3 days (range, 1 to 21 days). Three patients (cases 3, 6 and 10) developed recurrent candidal infections with the same species 2, 35 and 60 days after completion of the initial caspofungin course. Two of these patients again achieved microbiological clearance with caspofungin and one (case 10) was treated with liposomal amphotericin B (AmBisome®) and fluconazole. Antifungal susceptibilities were available on a single infant (case 4) for C. albicans who had MICs of 0.125 μg/ml at 24 hours and 0.25 μg/ml at 48 hours for amphotericin B and <0.125 μg/ml for fluconazole and caspofungin.
Six of 13 patients survived. Of the seven patients who died, two received only two doses of caspofungin before their death and continued to have persistent albicans candidemia at the time of death. Autopsy on one of these (case 4) confirmed candida pneumonia with intravascular thrombosis and microabscess formation. The other five deaths occurred after clearance of candidal infection from the blood (three negative consecutive blood cultures at least 17 days before death). Of note, three of these patients had recurrent candidemia and were on antifungals at the time of death. Autopsy data on one of them (case 6) showed no tissue or blood evidence of fungal infection. The presumed causes of death are listed (Table 2).
Safety Profile of Caspofungin
The median duration of caspofungin therapy in our cohort was 18 days (range, 2 to 43 days). The longest duration of caspofungin received by a single patient was 47 days, which included two separate treatment courses of 10 and 37 days. Two patients died within 2 days of starting caspofungin. In the remaining 11 patients, no serious adverse events were directly related to caspofungin treatment. One patient developed severe thrombophlebitis after the initial dose. He tolerated the subsequent dose at a greater dilution infused over an extended period. Two patients had hypokalemia while on caspofungin, with serum potassium levels as low as 1.7 mg/dl. Hypokalemia improved with potassium supplementation in spite of the continuation of caspofungin therapy. Renal function, as reflected by blood urea nitrogen and serum creatinine remained stable during the duration of caspofungin administration (Table 2). A greater than three-fold elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in four patients (cases 8, 9, 11 and 13); these patients received the drug for 23 to 43 days. Liver enzymes subsequently improved in three patients whereas one continued to have elevated levels after completion of therapy. Isolated direct hyperbilirubinemia (more than three-fold elevation during treatment) occurred in one patient (case 6).
A database review was performed on 13 control infants in the NICU with candidal infections, who did not receive treatment with caspofungin. The median birth weight was 860 g (range, 400 to 1405 g) and median gestational age was 25 weeks (range, 24 to 30 weeks). C. albicans was isolated in seven patients, C. parapsilosis in five and C. glabrata in one. Two infants had amniotic fluid cultures positive for Candida along with placental pathological evidence of fungal infection but had negative blood cultures. The remaining 11 infants had candidemia; four also had renal fungal balls, two had pneumonia and one infant each had venous thrombosis and subcutaneous abscesses. The median age at diagnosis was 17 days (range, 1 to 137 days). The median age at catheter removal was 3 days after the onset of infection (range, 1 to 6 days) in seven infants. Six infants, however, had central access through most of their fungemic episode. Eight infants were treated with amphotericin B and its lipid formulation (four patients) alone while five received combination therapy with fluconazole (four cases) or flucytosine (one patient). Microbiological clearance of candidemia was achieved in five of the 11 infants (the other two were treated for congenital candidiasis); the median time for sterilization was 5 days (range, 3 to 7 days). Six infants died. Hypokalemia was noted in a single infant while four infants had elevated blood urea nitrogen and creatinine levels during antifungal therapy.
Candida is increasingly being identified as a major cause of sepsis in neonates and is associated with high mortality and morbidity. 2 Several investigators have described a predominance of C. albicans and C. parapsilosis as the etiologic species in neonates, accounting for 40 to 50% of neonatal candidemia each.19, 20, 21, 22 Conventional antifungal regimens include amphotericin B and its lipid formulations and fluconazole. Although in vitro resistance to these drugs, especially for C. albicans and C. parapsilosis; is extremely low, recent studies and newer techniques of testing report resistance rates of 2 to 7%.23 In contrast, clinical treatment failure or persistence of the infection despite treatment with an appropriate dose is well recognized. Persistent infections could occur because an agent fails to reach an infected site in sufficient quantity, because the patient's immune status is unable to eliminate the fungus even though its growth has been inhibited and, rarely, because of true drug resistance.23, 24 In some cases, the fungal burden may be so large that conventional doses and plasma or tissue concentrations of antifungal agents may be ineffective or incompletely effective. In neonates, persistent candidal bloodstream infections (defined in various studies as greater than 2 to 5 days in spite of adequate dosing of conventional antifungals) are reported in about 60% of patients and are associated with poor outcomes including focal ophthalmologic, renal and cardiac complications and death.5, 25 In total, 10% of extremely low birth weight (ELBW) infants have persistent candidemia for longer than 14 days.26 Therefore, neonates with persistent candidal infections present a major challenge.
Current treatments for refractory invasive fungal infection remain inadequate even in adults, though newer drugs such as the echinocandins and voriconazole have shown encouraging results.27, 28 There have been isolated case reports on the efficacy of caspofungin in fungal infections in the pediatric age group.29, 30, 31 A recent report on the use of caspofungin in 25 immunocompromised pediatric patients showed that it was well tolerated with adverse effects noted in only three patients.31 The adverse effects included hypokalemia, hyperbilirubinemia and elevation of serum ALT. No assessment of efficacy was possible in that study however, because the drug was used for both documented and suspected fungal infections.
The present study is the first published case series from the United States on the use of caspofungin in combination with other antifungals as salvage treatment of persistent candidemia in infants. Our entire cohort was critically ill with multiple underlying medical problems and developed candidemia refractory to conventional antifungals, which included combination therapy in the majority of subjects. The need for multiple medications and pressors and poor i.v. access precluded early catheter removal in some of them. Caspofungin, when added as a last resort rescue therapy in this group was efficacious in sterilizing blood cultures in 11 of the 13 infants. This is in contrast to the control group, where microbiological clearance of candidemia was achieved in only five of 11 infants with conventional therapy. The only published neonatal case series to date involved 10 neonates (median gestation of 33 weeks and median birth weight of 1340 g) from Costa Rica, in whom persistent candidemia unresponsive to amphotericin B was successfully treated by caspofungin monotherapy.22 Although the microbiologic outcome in the present study is similar to that in the Costa Rican study, the infants in the present study were more premature and had lower birth weights, and caspofungin was used in combination with other antifungal drugs. We chose the microbiologic clearance of candidemia as our primary outcome for two reasons. One, the clinical outcome in ELBW infants is determined by multiple confounding factors such as race, gender, gestation, birth weight, respiratory and intracranial complications. Also, the presence and duration of candidemia itself is associated with higher mortality and worse outcomes; therefore, clearance of the bloodstream infection would, in itself, be a clinically meaningful end point.26
It can be argued that clearance of fungemia was related to the natural history of the infection or a delayed effect of the conventional antifungals. However, in the majority of the cases, caspofungin was added after prolonged conventional antifungal therapy was ineffective. Caspofungin seems contributory, rather than coincidental, to the microbiologic response in these refractory cases. The mechanism of action of the conventional antifungals differs from caspofungin, and combination therapy may be needed to clear refractory cases of candidemia. However, it is difficult to determine from the present study whether caspofungin was efficacious alone or in combination with other antifungals.
The limitations of this retrospective review are that resistance testing was not performed on the fungal isolates in most cases and there are no pharmacokinetic data. The dose of caspofungin used in the present study was 1 mg/kg; a loading dose of 1.5 mg/kg was used in some cases. This was based on a direct extrapolation of the weight-based adult loading dose of 75 mg and maintenance dose of 50 mg daily. There is a preliminary report that suggests that the dose used may have been low and that a dosing of 70 mg/m2 loading followed by 50 mg/m2 daily in children may achieve better peak and trough concentrations and area under the curve (AUC) similar to adults.32 A loading dose is able to achieve a higher trough concentration on day 1 of treatment and appears desirable. However, a BSA dosing in neonates would be three or more times the weight dosing and the lower dose may be safer until specific dose-finding pharmacokinetic data becomes available in neonates and, preferably, preterms. The dose used in our NICUs is the dose that was used in previous pediatric case reports.29, 31 The only other case series in neonates used a dose of 1 mg/k/day for the first 2 days followed by 2 mg/kg/day with excellent microbiological results.22
Both the patients with candidal meningitis responded to addition of caspofungin. In adults, there are previous isolated case reports of successful treatment of intracranial fungal infections with caspofungin.33 There is also a single case report of a pediatric immunodeficient patient with cerebral fungal abscesses treated with a combination of caspofungin and voriconazole, which seemed to alter the natural rapid progression of the disease.34 Presence of end-organ invasive disease in 11 of the 13 patients did not seem to affect response to therapy though the small sample size precluded any formal analysis of the effects of this or other variables on the efficacy of caspofungin.
The overall mortality rate of 53% in our cohort is within the range of the reported mortality at this gestation and comparable to that in the control group. The two patients who received only two doses of the drug died from persistent candidemia. Of the remaining five, three were still on antifungal treatment for recurrent candidemia at the time of their deaths. Autopsy on one did not show any evidence of fungal infection. However, it is certainly possible that some of the others, though culture negative, may have continued to have sequestered tissue infection, which may have contributed to their death.
While caspofungin was not associated with any serious adverse events in a majority of our patients, two infants died within 2 days of starting the drug. Therefore, safety remains to be established in larger trials. The other drug-related adverse effects included thrombophlebitis after the initial dose in a single patient. Transient hypokalemia while on caspofungin was observed in two patients. In our series, the most common adverse effect was an elevation of liver enzymes, though it was asymptomatic in all cases. A longer duration of caspofungin therapy greater than 3 weeks seems to correlate with a three-fold or greater elevation of liver enzymes. It was difficult to distinguish the effects of the sepsis, other concomitant drugs, parenteral nutrition and prematurity from the caspofungin-related effects on the liver function. Previous studies have reported anemia, probably hemolytic in origin, in adults receiving capsofungin. Anemia and thrombocytopenia, however, are common and multifactorial in premature infants with fungal sepsis and could not be specifically related to caspofungin in any patient in our cohort. It is probably prudent to monitor liver enzymes, serum potassium levels and complete blood counts during treatment with caspofungin.
Caspofungin is a promising new addition for the treatment of persistent candidemia in neonates, a population in whom therapeutic options are desperately sought. Our results, though, are limited by the small sample size and presence of many confounders. The appropriate dose of caspofungin in neonates remains to be determined with pharmacokinetic studies conducted specifically in premature infants. The issues of a safe cumulative dose and duration of treatment have not been addressed. Long-term safety data are sparse even in adults and are particularly important in neonates, whose organ systems are at a critical developmental stage. It is also important to elucidate the role of caspofungin as primary versus salvage therapy and in combination with other antifungals in this population.
In conclusion, caspofungin may be an efficacious addition to the therapeutic armamentarium for candidemia refractory to conventional antifungals in neonates. As invasive fungal infections are on the rise in neonates, further evaluation of the appropriate dosing and efficacy of caspofungin in the form of prospective clinical trials is urgently needed in this population.
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Natarajan, G., Lulic-Botica, M., Rongkavilit, C. et al. Experience with Caspofungin in the Treatment of Persistent Fungemia in Neonates. J Perinatol 25, 770–777 (2005). https://doi.org/10.1038/sj.jp.7211380
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