Drugs used for the treatment of cerebral and disseminated infections caused by free-living amoebae

Abstract

Free-living amoebae (FLAs) are protozoa developing autonomously in diverse natural or artificial environments. The FLAs Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri represent a risk for human health as they can become pathogenic and cause severe cerebral infections, named granulomatous amoebic encephalitis (GAE), Balamuthia amoebic encephalitis (BAE), and primary amoebic meningoencephalitis (PAM), respectively. Additionally, Acanthamoeba sp. can also rarely disseminate to diverse organs, such as the skin, sinuses, or bones, and cause extracerebral disseminated acanthamebiasis (EDA). No consensus treatment has been established for cerebral FLA infections or EDA. The therapy of cerebral and disseminated FLA infections often empirically associates a large diversity of drugs, all exhibiting a high toxicity. Nevertheless, these pathologies lead to a high mortality, above 90% of the cases, even in the presence of a treatment. In the present work, a total of 474 clinical cases of FLA infections gathered from the literature allowed to determine the frequency of usage, as well as the efficacy of the main drugs and drug combinations used in the treatment of these pathologies. The efficacy of drug usage was determined based on the survival rate after drug administration. The most efficient drugs, drug combinations, and their mechanism of action were discussed in regard to the present recommendations for the treatment of GAE, EDA, BAE, and PAM. At the end, this review aims to provide a useful tool for physicians in their choice to optimize the treatment of FLA infections.

FIGURE 1

Frequency and efficiencies of drugs used in GAE therapy. (a) Frequency of drug usage (FDU) = percentage of cases treated by the drug among the total number of cases; (b) efficacy of drug usage (EDU) = percentage of survival cases treated by the drug among the total number of cases treated by the drug. (c) Plot of EDU as a function of FDU. The most relevant drugs used in GAE treatment based on both EDU and FDU criteria are underlined in the legend. The drugs selected were used at least in 5 distinct clinical cases among the 119 total GAE clinical cases gathered. Unspecific treatments include general procedures to decrease intracranial pressure (e.g., mannitol), or inflammation (e.g., corticosteroids), or treatment for differential diagnosis, such as antivirals, cephalosporins, carbapenems, or glycopeptides, for viral or bacterial meningitis. GAE, granulomatous amoebic encephalitis caused by Acanthamoeba

FIGURE 2

Frequency and efficiencies of drugs used in EDA therapy. (a) Frequency of drug usage (FDU) = percentage of cases treated by the drug among the total number of cases; (b) efficacy of drug usage (EDU) = percentage of survival cases treated by the drug among the total number of cases treated by the drug. (c) Plot of EDU as a function of FDU. The most relevant drugs used in EDA treatment based on both EDU and FDU criteria are underlined in the legend. The drugs selected were used at least in 5 distinct clinical cases among the 35 EDA clinical cases gathered. Unspecific treatments include general procedures to decrease intracranial pressure (e.g., mannitol), or inflammation (e.g., corticosteroids), or treatment for differential diagnosis, such as antivirals, cephalosporins, carbapenems, or glycopeptides, for viral or bacterial meningitis. EDA, extracerebral disseminated acanthamoebiasis

FIGURE 3

Frequency and efficiencies of drugs used in BAE therapy. (a) Frequency of drug usage (FDU) = percentage of cases treated by the drug among the total number of cases; (b) efficacy of drug usage (EDU) = percentage of survival cases treated by the drug among the total number of cases treated by the drug. (c) Plot of EDU as a function of FDU. The most relevant drugs used in BAE treatment based on both EDU and FDU criteria are underlined in the legend. The drugs selected were used at least in 5 distinct clinical cases among the 111 BAE clinical cases gathered. Unspecific treatments include general procedures to decrease intracranial pressure (e.g., mannitol), or inflammation (e.g., corticosteroids), or treatment for differential diagnosis, such as antivirals, cephalosporins, carbapenems, or glycopeptides, for viral or bacterial meningitis. BAE, Balamuthia amoebic encephalitis

FIGURE 4

Frequency and efficiencies of drugs used in PAM therapy. (a) Frequency of drug usage (FDU) = percentage of cases treated by the drug among the total number of cases; (b) efficacy of drug usage (EDU) = percentage of survival cases treated by the drug among the total number of cases treated by the drug. (c) Plot of EDU as a function of FDU. The most relevant drugs used in PAM treatment based on both EDU and FDU criteria are underlined in the legend. The drugs selected were used at least in 5 distinct clinical cases among the 209 PAM clinical cases gathered. Unspecific treatments include general procedures to decrease intracranial pressure (e.g., mannitol), or inflammation (e.g., corticosteroids), or treatment for differential diagnosis, such as antivirals, cephalosporins, carbapenems, or glycopeptides, for viral or bacterial meningitis. PAM, primary amoebic meningoencephalitis

FIGURE 5

Cellular pathways disrupted by drugs used for the treatment of FLA infections. Drugs used for the treatment of FLA infection can target ergosterol in the amoebal membrane (amphotericin B), cause membrane disruption (chlorhexidine), inhibit microtubule polymerization (albendazole), induce DNA fragmentation by apoptosis‐like pathways (miltefosine and metronidazole), or affect lipid metabolism and mitochondrial membrane potential (miltefosine). Some other drugs can also affect ergosterol (azoles), DNA (flucytosine, trimethoprim, pentamidine, and sulfamides), RNA (macrolides), or protein (rifampicin) biosynthesis. All drugs represented in the figure are in the top five most frequently or most efficiently used drugs to treat Acanthamoeba spp. (Ac), Balamuthia mandrillaris (Bm), or Naegleria fowleri (Nf) infections. Green arrows and red bar‐headed lines represent an activation/alteration and an inhibition of a pathway, respectively. Full lines and dashed‐lines represent a mechanism of action previously described in FLA and in microorganisms other than FLA, respectively. For this latter groups of drugs, their mechanism of action has been previously described in bacteria for rifampicin and macrolides, Leishmania sp. for miltefosine, or Giardia intestinalis for albendazole and metronidazole. FLA, free‐living amoebae