Invasive Candida infection: epidemiology, clinical and therapeutic aspects of an evolving disease and the role of rezafungin

Figures & data

Figure 1. Pathogenesis and hematogenous routes of Candida species bloodstream dissemination with possible secondary infections as endocarditis (A), retinitis (B), skin fungal vasculitis (C) with macular/papular lesion (D) and multifocal hepatitis (E). CVC: central venous catheter; PICC: peripherally inserted central catheter.

Table 1. Exogenous versus endogenous route of invasive Candida infection: differences in etiologies, epidemiology, and antifungal resistance.

Feature	Endogenous route	Exogenous route
Involved Candida species	C. albicans, C. glabrata (Nakaseomyces glabrata), Candida lusitaniae (Clavispora lusitaniae), C. tropicalis, C. parapsilosis, C krusei	C. auris, C. haemulonii, C. parapsilosis, Candida lusitaniae (Clavispora lusitaniae)
Antifungal resistance	Uncommon*	Common
Habitat	Commensal of the gastrointestinal tract	Commensal of the skin
Healthcare-associated infection	Uncommon	Common
Environmental contamination	Uncommon	Common

Note: *C. glabrata is the species more frequently associated to azole and echinocandin resistance.

Table 2. Underlying diseases and conditions, main Candida species involved, therapy options and management of different ICIs.

Type of infection	Reference	Underlying diseases/conditions	Main Candida spp. involved	Clinical onset	Initial therapy^ (§ indicates surgery)	Maintenance therapy^ (or long term/CS therapy) [total course: wks]^^^
Primary peritonitis	[135,136]	ESLD, nephrotic syndrome, peritoneal dialysis	C. albicans>C. krusei (Pichia kudriavzeveii) >C. glabrata (Nakaseomyces glabrata)	Acute	echino+fluco or L ampho B	fluco [total course: 2–4 wks]
Secondary peritonitis	[135–137]	abdominal trauma or surgery, abnormal biliary tract	C. albicans>C. glabrata (N. glabrata)>C. tropicalis	Acute	echino+fluco, fluco or L ampho B §	fluco [total course: 2–4 wks]
Intrabdominal abscess	[135–137]	abnormalities of bile and pancreas ducts	C. albicans>C. glabrata (N. glabrata)>C. tropicalis	acute/subacute	fluco, L-ampho B, echino±azole §	fluco [total course: 2–4 wks]
Infected pancreas necrosis	[135–137]	chronic pancreatitis, abnormal biliary tract	C. albicans>C. glabrata (N. glabrata)	Acute	echino± fluco, L ampho B§	fluco [total course: 2–4 wks]
Ascending pyelonephritis	[138]	older age, female, DM, antibiotic use, urinary tract obstruction & surgery, drainage devices, steroids us	C. albicans>C. glabrata (N. glabrata)>C. tropicalis	Acute	fluco or D ampho B, L ampho B or echino in selected cases	fluco [total course: 2 wks]
Renal fungus ball	[139]	same as ascending pyelonephritis	C. albicans>C. glabrata (N. glabrata)>C. tropicalis	acute & recurrent	same as ascending pyelonephritis §	fluco [total course: 2 wks]
Emphysematous pyelonephritis	[140]	same as ascending pyelonephritis	C. albicans>C. glabrata (N. glabrata)>C. tropicalis	acute/fulminant	same as ascending pyelonephritis §	fluco [total course: 2 wks]
Right sided NVE	[131,132,141,142]	abdominal surgery, IVDA, CIED	C. albicans>C. parapsilosis>C. glabrata (N. glabrata)	acute/subacute	echino, L ampho B, fluco	fluco [total course: 6 wks]*
Left sided NVE	[131,132,141,142]	previous NVE, abdominal surgery, IVDA, malignancy	C. albicans>C. parapsilosis>C. glabrata (N. glabrata)	acute/subacute	echino±L ampho B §	fluco [total course: 6 months or CS therapy]*
PVE	[131,132,141,143]	post valve replacement candidemia	C. albicans>C. parapsilosis>C. glabrata (N. glabrata)	subacute/chronic	L ampho B±echino. §	fluco [total course: 6 months or CS therapy]^*#
PV-thrombophlebitis	[144,145]	long term vein cannulation, IVDA	C. albicans>C. parapsilosis>C. tropicalis	Acute	echino, L ampho B §	fluco [total course: 2 wks after first negative FUBC]
CV-septic thrombosis	[146]	Long term CVC; abdominal surgery, polytrauma	C. albicans>C. parapsilosis>C. glabrata (N. glabrata)	Acute	echino, L ampho B, & anticoagulation §°	fluco [total course: 2 wks after first negative FUBC]
meningitis	[133,147,148]	previous candidemia, SOT, ESLD, IVAD	C. dubliniensis>C. albicans> other spp.	chronic	vorico or fluco, L ampho B	vorico or fluco [total course: 4–6 wks]
Brain abscess	[149]	previous candidemia, SOT, ESLD, IVAD	C. albicans> other spp.	subacute/chronic	L amphoB ± 5FC, vorico or fluco, B	vorico or fluco [total course: 6–12 months]
shunt related meningitis	[150]	previous pneumonia or brain infection, steroid use	C. albicans>C. parapsilosis>C. glabrata (N. glabrata)	subacute/chronic	vorico or fluco; L ampho B ± 5FC §	vorico or fluco [total course: 2-4wks]
Endophthalmitis	[128,129,131]	usual risk factor of candidemia (CVC, TPN, etc), IVDA	C. albicans>C. dubliniensis>C. tropicalis	subacute/chronic	fluco^or vorico, L ampho B	vorico or fluco^[total course: at least 2-4wks]^°°
Esophagitis	[151,152]	HIV, chronic steroid therapy, alcohol consumption, chronic renal disease	C. albicans>C. glabrata (N. glabrata)>C. tropicalis & C. dubliniensis	acute/subacute	fluco, posaco & vorico, echino, L ampho B	fluco, vorico or posaco [total course: at least 2-4wks]^°°° *
Hepatosplenic infection	[21,22,153]	prolonged chemotherapy induced granulocytopenia for hematologic malignancy	C. albicans>C. glabrata (N. glabrata)>C. tropicalis, C. krusei (P. kudriavzeveii)	Acute/subacute	Fluco, vorico, echino, L ampho B	fluco, vorico[total course: 3–12 months]
Osteomyelitis	[154,155]	spinal, abdominal & cardio-thoracic surgery, IVDA	C. albicans>C. tropicalis>C. glabrata (N. glabrata)	subacute/chronic	L ampho B, fluco or vorico, echino §°°°°	fluco [total course: 3–12 months]*
Arthritis (usually disk space infection and bursitis)	[156]	disk space infection: previous candidemia, IVDA. Bursitis: previous candidemia, trauma	C. albicans> C. tropicalis>C. glabrata (N. glabrata)	subacute/chronic	L ampho B, fluco or vorico, echino §°°°°	fluco [total course: 2–12 months]*
Trauma-related fracture	[134]	open fracture	C. parapsilosis> C. albicans>C. glabrata (N. glabrata)	chronic	L ampho B, fluco or vorico, echino §	fluco [total course: 3–12 months]*
Prosthetic joint infection (PJI)	[157]	implant	C. albicans>C. parapsilosis> C. glabrata (N. glabrata)	chronic	L ampho B, fluco or vorico, echino §	fluco [total course: 3–12 months]*

Note: Legend: § indicates surgery or percutaneous drainage for source control (i.e. for secondary peritonitis or abscess) and/or device removal/replacement (i.e. for PVE, shunt-related meningitis or osteosynthesis-related fracture infection).

CS therapy= chronic suppressive therapy; ESLD= end-stage liver disease; DM= diabetes mellitus; IVDA= intravenous drug addiction; CIED= cardiovascular implantable electronic device; NVE= native valve endocarditis; PVE= prosthetic valve endocarditis; SOT= solid organ transplantation; PV= peripheral vein; CV= central vein; 5FC = 5 fluorocytosine; ^ increased exposure to doses of fluco (800 mg, or 12 mg/kg, once daily i.v./oral) may be required for C glabrata or to achieve adequate concentrations at the infection site (e.g. meninges and eye); ^{^^}total course of therapy includes initial+maintenance course of therapy; echino=echinocandins; fluco=fluconazole; vorico=voriconazole; posaco=posaconazole; L ampho B=liposomal amphotericin B; D ampho B=desossicholate amphotericin B; *in cases of fluconazole/azole resistance, once weekly dose regimen with rezafungin may be a reasonable option; ^#= CS therapy may be required in cases where surgical valve replacement cannot be performed; FUBC= follow-up blood culture; surgical debridement is required in a minority of cases;°final therapy duration may depend on lesion resolution as determined by repeated ophthalmological examinations, and vitrectomy may be required in some cases; ^°°°CS-therapy might be required in cases of recurrent esophagitis; ^°°°°surgery is required in a minority of cases, usually when a foreign body must be removed.

Figure 2. Chemical structure of rezafungin.

Table 3. Pharmacokinetic parameters of rezafungin vs. older echinocandins.

	Rezafungin	Anidulafungin	Caspofungin	Micafungin
Dose (mg)	400 LD/200 OW	200 LD/100 OD	70 LD/50 OD	100 OD
Cmax (mg/L)	22.7	7.2	12.1	7.2
Plasma protein binding (%)	99	99	97	99
Vd (L)	35.9	35.2	9.7	25.6
CL (L/h)	0.2	1.0	0.6	1.3
Elimination t1/2 (h)	129–133	24–26	9–11	11–17
Excretion in feces (%)	38	30	35	40
Excretion in urine (%)	14	1	41	15

Note: LD: loading dose; OW: once weekly; OD: once daily; Vd: Volume of distribution; CL: clearance.

Majeed A, Ullah W, Zahid U, et al. Persistent spontaneous fungal peritonitis secondary to Candida albicans in a patient with alcoholic cirrhosis and review of the literature. BMJ Case Rep. 2016;2016:bcr2016216979. doi: 10.1136/bcr-2016-216979

 PubMedGoogle Scholar

Hwang SY, Yu SJ, Lee JH, et al. Spontaneous fungal peritonitis: a severe complication in patients with advanced liver cirrhosis. Eur J Clin Microbiol Infect Dis. 2014;33(2):259–264. doi: 10.1007/s10096-013-1953-2

 PubMed Web of Science ®Google Scholar

Kauffman CA. Diagnosis and management of fungal urinary tract infection. Infect Dis Clin North Am. 2014;28(1):61–74. doi: 10.1016/j.idc.2013.09.004

 PubMed Web of Science ®Google Scholar

Tan WP, Turba UC, Deane LA. Renal fungus ball: a challenging clinical problem. Urologia. 2017;84(2):113–115. doi: 10.5301/uro.5000201

 PubMed Web of Science ®Google Scholar

Ideguchi S, Yamamoto K, Ikeda A, et al. A case of bilateral emphysematous pyelonephritis caused by Candida albicans. J Infect Chemother. 2019;25(4):302–306. doi: 10.1016/j.jiac.2018.10.011

 PubMed Web of Science ®Google Scholar

Venditti M, De Bernardis F, Micozzi A, et al. Fluconazole treatment of catheter-related right-sided endocarditis caused by Candida albicans and associated with endophthalmitis and folliculitis. Clin Infect Dis. 1992;14(2):422–426. doi: 10.1093/clinids/14.2.422

 PubMed Web of Science ®Google Scholar

Giuliano S, Guastalegname M, Russo A, et al. Candida endocarditis: systematic literature review from 1997 to 2014 and analysis of 29 cases from the Italian Study of Endocarditis. Expert Rev Anti Infect Ther. 2017;15(9):807–818. doi: 10.1080/14787210.2017.1372749

 PubMed Web of Science ®Google Scholar

Rivoisy C, Vena A, et al; French Mycoses Study Group and Grupo de Apoyo al Manejo de las Endocarditis en España (GAMES). Prosthetic Valve Candida spp. Endocarditis: New Insights into Long-term Prognosis-The ESCAPE Study. Clin Infect Dis. 2018;66(6):825–832. doi:10.1093/cid/cix913

 PubMed Web of Science ®Google Scholar

Falcone M, Barzaghi N, Carosi G, et al. Candida infective endocarditis: report of 15 cases from a prospective multicenter study. Medicine (Baltimore). 2009;88(3):160–168. Italian Study on Endocarditis (SEI). doi: 10.1097/MD.0b013e3181a693f8

 PubMed Web of Science ®Google Scholar

Russo A, Falcone M, Picciarella A, et al. Candidaemia after heart valve replacement surgery: recurrence as prosthetic valve endocarditis is an expected over one-year complication. Clin Microbiol Infect. 2016;22(5):466–467. doi: 10.1016/j.cmi.2016.01.019

 PubMed Web of Science ®Google Scholar

Torres-Rojas JR, Stratton CW, Sanders CV, et al. Candidal suppurative peripheral thrombophlebitis. Ann Intern Med. 1982;96(4):431–435. doi: 10.7326/0003-4819-96-4-431

 PubMed Web of Science ®Google Scholar

Caccese R, Carfagna P, Pistilli N, et al. Candidal thrombophlebitis of central veins: case report and review. Med Mycol. 2012;50(3):299–304. doi: 10.3109/13693786.2011.604046

 PubMed Web of Science ®Google Scholar

Strinden WD, Helgerson RB, Maki DG. Candida septic thrombosis of the great central veins associated with central catheters Clinical Features And Management. Ann Surg. 1985;202(5):653–658. doi: 10.1097/00000658-198511000-00019

 PubMed Web of Science ®Google Scholar

van Hal SJ, Stark D, Harkness J, et al. Candida dubliniensis meningitis as delayed sequela of treated C. dubliniensis fungemia. Emerg Infect Dis. 2008;14(2):327–329. doi: 10.3201/eid1402.070985

 PubMed Web of Science ®Google Scholar

Tahir M, Peseski AM, SJ J. Case Report: Candida dubliniensis as a Cause of Chronic Meningitis. Front Neurol. 2020;11:601242. doi: 10.3389/fneur.2020.601242

 PubMed Web of Science ®Google Scholar

Yamahiro A, Lau KH, Peaper DR, et al. Meningitis Caused by Candida Dubliniensis in a Patient with Cirrhosis: A Case Report and Review of the Literature. Mycopathologia. 2016;181(7–8):589–593. doi: 10.1007/s11046-016-0006-7

 PubMed Web of Science ®Google Scholar

Fennelly AM, Slenker AK, Murphy LC, et al. Candida cerebral abscesses: a case report and review of the literature. Med Mycol. 2013;51(7):779–784. doi: 10.3109/13693786.2013.789566

 PubMed Web of Science ®Google Scholar

Kelly L, Walsh J, Skally M, et al. Candida meningitis/ventriculitis over a decade. Increased morbidity and length of stay a concern. Br J Neurosurg. 2023;37(2):227–230. doi: 10.1080/02688697.2022.2054947

 PubMed Web of Science ®Google Scholar

Tirpack AR, Duker JS, Baumal CR. An Outbreak of Endogenous Fungal Endophthalmitis Among Intravenous Drug Abusers in New England. JAMA Ophthalmol. 2017;135(6):534–540. doi: 10.1001/jamaophthalmol.2017.0650

 PubMed Web of Science ®Google Scholar

Haseeb AA, Elhusseiny AM, Siddiqui MZ, et al. Fungal Endophthalmitis: A Comprehensive Review. J Fungi (Basel). 2021;7(11):996. doi: 10.3390/jof7110996

 PubMedGoogle Scholar

López-Dupla M, Mora Sanz P, Pintado García V, et al. Clinical, endoscopic, immunologic, and therapeutic aspects of oropharyngeal and esophageal candidiasis in HIV-infected patients: a survey of 114 cases. Am J Gastroenterol. 1992;87(12):1771–1776.

 PubMed Web of Science ®Google Scholar

Chen YH, Jao TM, Shiue YL, et al. Prevalence and risk factors for Candida esophagitis among human immunodeficiency virus-negative individuals. World J Clin Cases. 2022;10(30):10896–10905. doi: 10.12998/wjcc.v10.i30.10896

 PubMed Web of Science ®Google Scholar

Pagano L, Mele L, Fianchi L, et al. Chronic disseminated candidiasis in patients with hematologic malignancies. Clinical features and outcome of 29 episodes. Haematologica. 2002;87(5):535–541.

 PubMed Web of Science ®Google Scholar

Cornely OA, Bangard C, Jaspers NI. Hepatosplenic candidiasis. Clin Liver Dis. 2015;6(2):47–50. doi: 10.1002/cld.491

 Google Scholar

Candon S, Rammaert B, Foray AP, et al. Chronic Disseminated Candidiasis During Hematological Malignancies: An Immune Reconstitution Inflammatory Syndrome with Expansion of Pathogen-Specific T Helper Type 1 Cells. J Infect Dis. 2020;221(11):1907–1916. doi: 10.1093/infdis/jiz688

 PubMed Web of Science ®Google Scholar

McLeod N, Fisher M, Lasala PR. Vertebral osteomyelitis due to Candida species. Infection. 2019;47(3):475–478. doi: 10.1007/s15010-019-01294-6

 PubMed Web of Science ®Google Scholar

Slenker AK, Keith SW, Horn DL. Two hundred and eleven cases of Candida osteomyelitis: 17 case reports and a review of the literature. Diagn Microbiol Infect Dis. 2012;73(1):89–93. doi: 10.1016/j.diagmicrobio.2012.02.004

 PubMed Web of Science ®Google Scholar

Gamaletsou MN, Rammaert B, Brause B, et al. International Consortium for Osteoarticular Mycoses Osteoarticular Mycoses. Clin Microbiol Rev. 2022 Dec 21;35(4):e0008619. doi: 10.1128/cmr.00086-19

 PubMedGoogle Scholar

De Meo D, Cera G, Ceccarelli G, et al. Candida fracture-related infection: a systematic review. J Bone Jt Infect. 2021;6(7):321–328. doi: 10.5194/jbji-6-321-2021

 PubMedGoogle Scholar

Koutserimpas C, Zervakis SG, Maraki S, et al. Non-albicans Candida prosthetic joint infections: A systematic review of treatment. World J Clin Cases. 2019;7(12):1430–1443. doi: 10.12998/wjcc.v7.i12.1430

 PubMed Web of Science ®Google Scholar