Next Article in Journal
A Comparison of Virulence of Three Porcine Circovirus Type 2 (PCV2) Genotypes (a, b, and d) in Pigs Singularly Inoculated with PCV2 and Dually Inoculated with PCV2 and Porcine Reproductive and Respiratory Syndrome Virus
Previous Article in Journal
Zoonotic Malaria: Non-Laverania Plasmodium Biology and Invasion Mechanisms
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Brief Report

Treatment with Micafungin in a Preterm Neonate with an Invasive Candida parapsilosis Infection after a Severe Terlipressin-Induced Skin Necrosis

by
Domenico Umberto De Rose
1,
Fiammetta Piersigilli
2,
Bianca Maria Goffredo
3,
Olivier Danhaive
2,4,
Andrea Dotta
1 and
Cinzia Auriti
1,*
1
Neonatal Intensive Care Unit, Medical and Surgical Department of Fetus, Newborn and Infant—“Bambino Gesù” Children’s Hospital IRCCS, 00165 Rome, Italy
2
Division of Neonatology, Cliniques Saint-Luc, Catholic University of Louvain, 1200 Brussels, Belgium
3
Biochemistry Laboratory, Department of Specialist Pediatrics, “Bambino Gesù” Children’s Hospital IRCCS, 00165 Rome, Italy
4
Division of Neonatology, San Francisco Benioff Children’s Hospital, University of California, San Francisco, CA 94158, USA
*
Author to whom correspondence should be addressed.
Pathogens 2021, 10(7), 890; https://doi.org/10.3390/pathogens10070890
Submission received: 16 June 2021 / Revised: 3 July 2021 / Accepted: 8 July 2021 / Published: 13 July 2021
(This article belongs to the Section Fungal Pathogens)

Abstract

:
Candida parapsilosis infections are increasingly reported in preterm neonates, but the optimal treatment remains uncertain. We report the clinical history of an extremely preterm neonate, who developed a devastating skin necrosis due to terlipressin administration, with subsequent superinfection by Candida parapsilosis. The infant underwent multiple curettages and skin grafts to resolve skin lesions and was treated with systemic micafungin administration at a high dose (8 mg/kg/day), with resolution of the fungal infection.

1. Introduction

Invasive Candida infections (ICIs) are a major cause of morbidity and mortality among very preterm infants [1]; Candida albicans is the most frequently occurring species [2], although Candida parapsilosis infections are increasingly reported in preterm neonates [3]. Despite the high minimum inhibitory concentration (MIC) necessary for Candida parapsilosis eradication, echinocandins have a prominent role when an ICI occurs in very preterm infants. These patients often carry a central vascular catheter in which Candida parapsilosis forms a biofilm, due to its adherence properties that favor attachment to skin and catheters [4]. Echinocandins allow infection resolution despite the presence of the biofilm, and also have very little effect on the immature renal function of these babies. Micafungin is the only echinocandin approved for neonates and young infants. Therapy with 8 mg/kg/day achieved a high response in a phase two study on 35 neonates with confirmed or suspected ICIs and medical and surgical underlying diseases [5]. Herein, we report the successful treatment of an invasive Candida parapsilosis infection in a seriously ill, very preterm infant with a wide devasting skin necrosis, achieved thanks to systemic micafungin administration, combined with multiple curettages and skin grafts.

2. Case Description

An extremely preterm neonate (gestational age, 24 weeks; body weight, 500 g) was born by vaginal delivery in a 2nd level hospital. She was intubated at birth and required surfactant administration and mechanical ventilation. Patent ductus arteriosus was closed with the administration of ibuprofen. Moreover the baby suffered from cholestasis, hypothyroidism treated with L-thyroxine (2 μg/kg/day), thrombosis of the inferior vena cava, requiring low-molecular-weight heparin, Clexane®,( marketed in Italy by Sanofi S.p.A.—Viale L. Bodio, 37/B—20158 Milano Italy) therapy and retinopathy of prematurity treated with photocoagulation. Antifungal prophylaxis with Fluconazole was started at birth, for a period of six weeks, then stopped on day of life 45. On day of life 63 (postmenstrual age: 33 weeks, weight: 1600 g), the neonate was still on mechanical ventilation due to severe bronchopulmonary dysplasia and pulmonary hypertension. An Escherichia coli sepsis occurred, and its condition worsened despite antibiotic treatment with imipenem, netilmicin and vancomycin. She developed persistent hypotension refractory to volume expanders, dopamine, epinephrine, vasopressin and norepinephrine. Therefore, therapy with terlipressin (triglycyl-lysine vasopressin, Glypressin®,( Ferring Pharmaceuticals Ltd.,Drayton Hall, Church Road. West Drayton, UB7 7PS, UK) dose: 20 μg/kg/h, was attempted and was administered through a well-positioned epicutaneo-cava catheter, placed through the right upper arm. After twenty days of continuous infusion, the baby showed indurative perineal edema, with a purple discoloration of the perineum and thigh teguments, quickly evolving into severe necrotic skin lesions (Figure 1). The neonate was, therefore, transferred to our neonatal intensive care unit (NICU) and the antifungal prophylaxis was already suspended.
Cutaneous swab and urine culture both yielded Candida parapsilosis. The fungal load in urine was 1,000,000 CFU/mL. Susceptibility tests were performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines [6,7]. Blood cultures resulted negative, but the child had been on antimicrobial therapy for several days. The isolated Candida strain was susceptible to micafungin (MIC, 0.5 µg/mL), anidulafungin (MIC, 2 µg/mL), fluconazole (MIC, 0.5 µg/mL), itraconazole (MIC, 0.06 µg/mL), voriconazole (MIC, <0.008 µg/mL) and amphotericin B (MIC, 0.5 µg/mL). Among the effective antifungals, we chose micafungin because of the feasibility of plasma concentration monitoring via heel stick capillary samples [8]. After given and obtained informed consent from the parents, both in relation to the high dosage of micafungin to be administered and monitored and to the participation in clinical trials and publications, micafungin was administered intravenously at a dose of 8 mg/kg/day; it was diluted in 0.9% saline solution at a concentration of 2 mg/mL and infused intravenously through epicutaneo-cava catheter in one hour. Plasma micafungin concentrations were measured by high performance liquid chromatography (HPLC) on the third day of the starting of therapy. The lower limit of detection (LLOD) of micafungin was 0.5 mg/L, and the lower limit of quantification (LLOQ) was 1 mg/L. (Table 1).
With an 8 mg/kg/day micafungin dose, we were able to obtain adequate micafungin plasma concentrations pre-administration (on the third day of therapy plasma concentration was 3.73 mg/L), achieving a plasma Cmax/MIC ratio > 10. Although the first typical choice would have been catheter removal, we opted not to do so, because of the infant’s critical condition.
ICI resolved after 15 days of treatment. Concurrently, after surgical debridement of necrotic tissue, hydrocolloid dressing was applied twice weekly to stimulate skin healing (Figure 2).
Subsequently, cutaneous lesions were treated with two skin grafts (Figure 3). In order to allow the rapprochement with her parents, the child was transferred back to the hospital of origin, where she died after 2 months due to respiratory failure related to her severe bronchopulmonary dysplasia.

3. Discussion

We report an invasive Candida parapsilosis infection in an infant, who was born very preterm, with a wide devasting skin necrosis. The fungal infection was successfully treated with high-dose systemic micafungin. The baby required multiple curettages and skin grafts to treat the necrotic skin lesions, provoked by terlipressin infusion. Among non-albicans species, Candida parapsilosis is more frequent in neonates than in older children, given the wide use of intravascular devices in NICUs. Adherence properties of Candida parapsilosis favor adherence to skin and indwelling catheters, followed by biofilm formation [9]. Invasive Candida spp. infections in preterm neonates require a strong and early medical approach, given the high related mortality [10]. The most commonly used primary antifungal therapies for neonatal invasive candidiasis are fluconazole (32%), caspofungin (24%), liposomal amphotericin B (16%) and micafungin (8%), according to a large multicenter network [11].
Since, in our Unit Fluconazole is used as a prophylaxis, it is rarely and only in specific clinical situations administered as therapy to treat systemic fungal infections. Usually, the antifungal prophylaxis with fluconazole prevents the colonization of small patients hospitalized in NICU by the different species of Candida. To date, no resistance to this drug is reported and Fluconazole is the primary means of preventing fungal colonization in preterm infants. Probably in our patient, the fungal colonization occurred after the interruption of prophylaxis, in relation to prolonged antibiotic therapies, the patient’s long hospital stay, the site and extent of skin lesions.
Micafungin is the most studied echinocandin in neonates and the only one approved by both the European Medicine Agency (EMA) and United States Food and Drug Administration (US-FDA) for younger children, although the susceptibility of the Candida parapsilosis complex to echinocandins is not clear yet. In vitro activity of echinocandins seems to be adequate [12], but reduced echinocandin susceptibility has been reported in some strains [13].
Studies published so far still lack clear recommendations on recommendable micafungin dosages in preterm infants. It seems that these fragile patients require higher micafungin doses than older children and adults in order to reach therapeutic effects, due to increased plasma clearance [14]. Several studies demonstrated that high-dose micafungin is effective and safe in very preterm neonates also [15,16,17].
Given the severe clinical conditions of our patient, the epicutaneo-cava catheter was difficult to replace safely. The systemic therapy allowed complete infection control. Despite the baby’s previous cholestasis, therapy with micafungin did not cause side effects. We observed a transient increase in aspartate aminotransaminase and alanine aminotransaminase, which rapidly returned within normal range after discontinuation of therapy. We monitored plasma concentration of micafungin on 0.3 mL heel puncture blood samples, as previously described, in order to avoid excessive blood draws in a patient of low weight and in such severe clinical conditions [8].
Terlipressin is a synthetic long-acting analogue of vasopressin with a vasoconstrictor action. Its effects include significant increase in mean arterial pressure and systemic vascular resistance as well as significant decrease in heart rate, cardiac output, hepatic venous portal pressure gradient, and portal venous blood flow [18]. Although the actual efficacy of terlipressin in the neonatal period is still discussed [18], it can be used for the treatment of severe hypotension refractory to volume expansion, catecholamines, and corticosteroids. Skin necrosis has been described in adults as a rare side effect of terlipressin, presumably secondary to its long-acting vasoconstrictive effect [19,20,21]. To our knowledge, very few data are available to date regarding such severe complication in the neonatal period [22].

4. Conclusions

Micafungin, at a dose of 8 mg/kg/day, was effective and well tolerated in this extremely preterm, seriously ill neonate with an invasive Candida parapsilosis infection.
Although limited data exist about the use of terlipressin in neonates, skin necrosis seems to be an established severe side effect [22]. Given limited experience, its use should always be well weighed and limited only to life-threatening hypotensive shock.

Author Contributions

Conceptualization, C.A., F.P., D.U.D.R. and F.P.; methodology, F.P., B.M.G. and C.A.; investigation, D.U.D.R., F.P., B.M.G. and C.A.; writing—original draft preparation, D.U.D.R. and F.P.; writing—review and editing, O.D., A.D. and C.A. All authors have read and agreed to the published version of the manuscript.

Funding

This manuscript received no external funding. The clinical trial on micafungin in which the girl was enrolled with other patients was funded by Astellas company.

Institutional Review Board Statement

The baby was enrolled and treated in the course of a clinical trial conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy (protocol code 800-OPBG-2014, approved on 12 of November 2014).

Informed Consent Statement

The informed consent was administered to the parents of the patient and obtained, both for the administration of the drug and for the purposes and objectives of the research.

Data Availability Statement

Clinical data are available in the electronic archive of the Bambino Gesù Hospital and upon request to the author. Researchers may request access to anonymized participant-level data, trial-level data, and protocols from Astellas-sponsored clinical trials at www.clinicalstudydatarequest.com (accessed on 8 July 2021). For the Astellas criteria on data sharing, see https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx (accessed on 8 July 2021).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kett, D.H.; Azoulay, E.; Echeverria, P.M.; Vincent, J.L. Extended Prevalence of Infection in ICU Study (EPIC II) Group of Investigators. Candida bloodstream infections in intensive care units: Analysis of the extended prevalence of infection in intensive care unit study. Crit. Care Med. 2011, 39, 665–670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Warris, A.; Pana, Z.D.; Oletto, A.; Lundin, R.; Castagnola, E.; Lehrnbecher, T.; Groll, A.H.; Roilides, E.; EUROCANDY study group. Etiology and Outcome of Candidemia in Neonates and Children in Europe: An 11-year Multinational Retrospective Study. Pediatr. Infect. Dis. J. 2020, 39, 114–120. [Google Scholar] [CrossRef] [PubMed]
  3. Pammi, M.; Holland, L.; Butler, G.; Gacser, A.; Bliss, J.M. Candida parapsilosis is a significant neonatal pathogen: A systematic review and meta-analysis. Pediatr. Infect. Dis. J. 2013, 32, e206–e216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Larkin, E.L.; Dharmaiah, S.; Ghannoum, M.A. Biofilms and beyond: Expanding echinocandin utility. J. Antimicrob. Chemother. 2018, 73, i73–i81. [Google Scholar] [CrossRef] [PubMed]
  5. Auriti, C.; Goffredo, B.M.; Ronchetti, M.P.; Piersigilli, F.; Cairoli, S.; Bersani, I.; Dotta, A.; Bagolan, P.; Pai, M.P. High-dose micafungin in neonates and young infants with invasive candidiasis: Results of a phase 2 study. Antimicrob. Agents Chemother. 2021, 65, e02494–e02520. [Google Scholar] [CrossRef] [PubMed]
  6. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard, 3rd ed.; CLSI Document M27-A3; Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2008. [Google Scholar]
  7. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; 4th Informational Supplement; CLSI Document; M27-S4 Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2012. [Google Scholar]
  8. De Rose, D.U.; Cairoli, S.; Dionisi, M.; Santisi, A.; Massenzi, L.; Goffredo, B.M.; Dionisi-Vici, C.; Dotta, A.; Auriti, C. Therapeutic Drug Monitoring Is a Feasible Tool to Personalize Drug Administration in Neonates Using New Techniques: An Overview on the Pharmacokinetics and Pharmacodynamics in Neonatal Age. Int. J. Mol. Sci. 2020, 21, 5898. [Google Scholar] [CrossRef] [PubMed]
  9. Estivill, D.; Arias, A.; Torres-Lana, A.; Carrillo-Muñoz, A.J.; Arévalo, M.P. Biofilm formation by five species of Candida on three clinical materials. J. Microbiol. Methods. 2011. [Google Scholar] [CrossRef] [PubMed]
  10. Greenberg, R.G.; Benjamin, D.K., Jr.; Gantz, M.G.; Cotten, C.M.; Stoll, B.J.; Walsh, M.C.; Sánchez, P.J.; Shankaran, S.; Das, A.; Higgins, R.D.; et al. Empiric antifungal therapy and outcomes in extremely low birth weight infants with invasive candidiasis. J. Pediatr. 2012, 161, 264–269.e2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Steinbach, W.J.; Roilides, E.; Berman, D.; Hoffman, J.A.; Groll, A.H.; Bin-Hussain, I.; Palazzi, D.L.; Castagnola, E.; Halasa, N.; Velegraki, A.; et al. Results from a prospective, international, epidemiologic study of invasive candidiasis in children and neonates. Pediatr. Infect. Dis. J. 2012, 31, 1252–1257. [Google Scholar] [CrossRef] [PubMed]
  12. Khodavaisy, S.; Badali, H.; Meis, J.F.; Modiri, M.; Mahmoudi, S.; Abtahi, H.; Salehi, M.; Manshadi, S.A.D.; Aala, F.; Afshari, S.A.K.; et al. Comparative in vitro activities of seven antifungal drugs against clinical isolates of Candida parapsilosis complex. J. Mycol. Med. 2020, 30, 100968. [Google Scholar] [CrossRef] [PubMed]
  13. Lindberg, E.; Hammarström, H.; Ataollahy, N.; Kondori, N. Species distribution and antifungal drug susceptibilities of yeasts isolated from the blood samples of patients with candidemia. Sci. Rep. 2019, 9, 3838. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Yanni, S.B.; Smith, P.B.; Benjamin, D.K., Jr.; Augustijns, P.F.; Thakker, D.R.; Annaert, P.P. Higher clearance of micafungin in neonates compared with adults: Role of age-dependent micafungin serum binding. Biopharm. Drug Dispos. 2011, 32, 222–232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Smith, P.B.; Walsh, T.J.; Hope, W.; Arrieta, A.; Takada, A.; Kovanda, L.L.; Kearns, G.L.; Kaufman, D.; Sawamoto, T.; Buell, D.N.; et al. Pharmacokinetics of an elevated dosage of micafungin in premature neonates. Pediatr. Infect. Dis. J. 2009, 28, 412–415. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Benjamin, D.K., Jr.; Smith, P.B.; Arrieta, A.; Castro, L.; Sánchez, P.J.; Kaufman, D.; Arnold, L.J.; Kovanda, L.L.; Sawamoto, T.; Buell, D.N.; et al. Safety and pharmacokinetics of repeat-dose micafungin in young infants. Clin. Pharmacol. Ther. 2010, 87, 93–99. [Google Scholar] [CrossRef] [PubMed]
  17. Auriti, C.; Falcone, M.; Ronchetti, M.P.; Goffredo, B.M.; Cairoli, S.; Crisafulli, R.; Piersigilli, F.; Corsetti, T.; Dotta, A.; Pai, M.P. High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis. Antimicrob. Agents Chemother. 2016, 60, 7333–7339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Shivanna, B.; Rios, D.; Rossano, J.; Fernandes, C.J.; Pammi, M. Vasopressin and its analogues for the treatment of refractory hypotension in neonates. Cochrane Database Syst. Rev. 2013, 3, CD009171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Mégarbané, H.; Barete, S.; Khosrotehrani, K.; Izzedine, H.; Moguelet, P.; Chosidow, O.; Frances, C.; Aractingi, S. Two observations raising questions about risk factors of cutaneous necrosis induced byterlipressin (Glypressin). Dermatology 2009, 218, 334–337. [Google Scholar] [CrossRef] [PubMed]
  20. Yefet, E.; Gershovich, M.; Farber, E.; Soboh, S. Extensive epidermal necrosis due to terlipressin. Isr. Med. Assoc. J. 2011, 13, 180–181. [Google Scholar] [PubMed]
  21. Coskun, B.D.O.; Karaman, A.; Gorkem, H.; Buğday, I.; Poyrazoğlu, O.K.; Senel, F. Terlipressin-induced ischemic skin necrosis: A rare association. Am. J. Case Rep. 2014, 15, 476–479. [Google Scholar] [CrossRef] [Green Version]
  22. Rodríguez-Núñez, A.; Oulego-Erroz, I.; Gil-Antón, J.; Pérez-Caballero, C.; López-Herce, J.; Gaboli, M.; Milano, G.; RETSPED-II Working Group of the Spanish Society of Pediatric Intensive Care. Continuous terlipressin infusion as rescue treatment in a case series of children with refractory septic shock. Ann. Pharmacother. 2010, 44, 1545–1553. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Indurative edema with violet stained skin of both thighs and perineal region (A) and severe necrotic skin lesions (B).
Figure 1. Indurative edema with violet stained skin of both thighs and perineal region (A) and severe necrotic skin lesions (B).
Pathogens 10 00890 g001
Figure 2. After surgical debridement of necrotic tissue (A), hydrocolloid dressing was applied twice weekly to stimulate skin healing (B).
Figure 2. After surgical debridement of necrotic tissue (A), hydrocolloid dressing was applied twice weekly to stimulate skin healing (B).
Pathogens 10 00890 g002
Figure 3. Gradual resolution of skin wounds after skin grafts.
Figure 3. Gradual resolution of skin wounds after skin grafts.
Pathogens 10 00890 g003
Table 1. Plasma micafungin concentrations (mg/L) evaluated using HPLC. Pre-administration value corresponds to the minimum plasma concentration (C min) of the time/concentration curve. The value one hour after infusion corresponds to the maximum plasma concentration (C max) of the time/concentration curve.
Table 1. Plasma micafungin concentrations (mg/L) evaluated using HPLC. Pre-administration value corresponds to the minimum plasma concentration (C min) of the time/concentration curve. The value one hour after infusion corresponds to the maximum plasma concentration (C max) of the time/concentration curve.
Dose (Over 24 h)Site30 min before Infusion1 h after Infusion2 h after Infusion8 h after Infusion
8 mg/kgPlasma3.7311.799.707.9
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

De Rose, D.U.; Piersigilli, F.; Goffredo, B.M.; Danhaive, O.; Dotta, A.; Auriti, C. Treatment with Micafungin in a Preterm Neonate with an Invasive Candida parapsilosis Infection after a Severe Terlipressin-Induced Skin Necrosis. Pathogens 2021, 10, 890. https://doi.org/10.3390/pathogens10070890

AMA Style

De Rose DU, Piersigilli F, Goffredo BM, Danhaive O, Dotta A, Auriti C. Treatment with Micafungin in a Preterm Neonate with an Invasive Candida parapsilosis Infection after a Severe Terlipressin-Induced Skin Necrosis. Pathogens. 2021; 10(7):890. https://doi.org/10.3390/pathogens10070890

Chicago/Turabian Style

De Rose, Domenico Umberto, Fiammetta Piersigilli, Bianca Maria Goffredo, Olivier Danhaive, Andrea Dotta, and Cinzia Auriti. 2021. "Treatment with Micafungin in a Preterm Neonate with an Invasive Candida parapsilosis Infection after a Severe Terlipressin-Induced Skin Necrosis" Pathogens 10, no. 7: 890. https://doi.org/10.3390/pathogens10070890

APA Style

De Rose, D. U., Piersigilli, F., Goffredo, B. M., Danhaive, O., Dotta, A., & Auriti, C. (2021). Treatment with Micafungin in a Preterm Neonate with an Invasive Candida parapsilosis Infection after a Severe Terlipressin-Induced Skin Necrosis. Pathogens, 10(7), 890. https://doi.org/10.3390/pathogens10070890

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop