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Others
Chapter 27
Others Chapter outline Chlamydia Estrella lausannensis Parachlamydia acanthamoebae Bacteroides fragilis
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Aspergillus fumigatus Cryptococcus neoformans Scedosporium spp. References
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Chlamydia Chlamydiae are Gram-negative, obligate intracellular bacteria with a complex developmental cycle consisting of two stages such as elementary body (infectious) and reticulate body (RB). During exposure to antibiotics or other stress factors, growth of Chlamydia is arrested and it is known as aberrant RB/aberrant bodies (AB). Chlamydial infection is common in human and animals. Human-associated pathogenic species such as Chlamydia trachomatis and Chlamydia pneumoniae cause urethritis, epididymitis in men, cervicitis, infertility, ectopic pregnancy in women and atypical pneumonia, respectively (Eick et al., 2011; Marrazzo and Suchland, 2014). Chlamydia suis causes respiratory distress, conjunctivitis, diarrhoea and reproductive disorders in farmed pigs and wild boars (Schautteet and Vanrompay, 2011). Direct zoonotic transmission of C. suis is not confirmed. Genetic material of C. suis is although detected in human clinical samples (Dean et al., 2013; De Puysseleyr et al., 2014). Tetracyclines are recommended for treatment of chlamydiosis in human and livestock. Tetracycline-resistant Chlamydia were started to be reported from pigs in the United States since 1998 and later from European countries such as Italy, Belgium and Switzerland (Andersen and Rogers, 1998; Di Francesco et al., 2008; Schautteet and Vanrompay, 2011; Borel et al., 2012). Tetracycline resistance gene (tetC) present in a genomic island (TetR) was found to be associated with resistance, which encodes a tetracycline efflux pump (Dugan et al., 2004). The genomic island (TetR) of C. suis is the first identified acquired resistance factor in a bacterium through horizontal gene transfer. Majority of C. suis genomic island (TetR) also carries IScs605 originated from Laribacter hongkongensis, a fish pathogen (Sandoz and Rockey, 2010). Use of fish meal was correlated with the origin of IScs605 in C. suis although not confirmed. In human, treatment failure (5%e23%) due to infection with azithromycin- and doxycycline-resistant C. trachomatis and C. pneumoniae was reported from several countries (Horner, 2012). Heterotypic resistance was detected in clinical isolates of Chlamydia associated with phenotypic changes in a stressed bacterial population (AB) (Bhengraj et al., 2010).
Estrella lausannensis Estrella lausannensis belongs to the family Criblamydiaceae under the order Chlamydiales (Lienard et al., 2011). It can infect amoeba, fish cell lines and is associated with tubal pathology in women. Quinolone resistance in E. lausannensis was associated with amino acid substitutions in the quinolone resistance-determining region (QRDR) of GyrA (Ser83Gln and Val70Ser) and ParC (Ser80Ala and Glu84Asp) (de Barsy et al., 2014).
Parachlamydia acanthamoebae Parachlamydia acanthamoebae, a kind of Chlamydia, is found to be associated with varieties of respiratory tract infections in human such as community-acquired pneumonia, ventilator-associated pneumonia, nosocomial pneumonia, lower
Antimicrobial Resistance in Agriculture. https://doi.org/10.1016/B978-0-12-815770-1.00027-4 Copyright © 2020 Elsevier Inc. All rights reserved.
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TABLE 27.1 Antimicrobial resistance genes detected in Bacteroides fragilis. Genes
Resistance
cfiA (metallo-b-lactamase)
Carbapenem
nimA-H, nimJ (nitroimidazole)
Metronidazole
ermB, ermF, ermG
Clindamycin
msrSA, mefA
Macrolide, lincosamide
linAn2
Lincomycin, erythromycin
tetQ, tetX, tetX1
Tetracycline, tigecycline
bexA, bexB
Fluoroquinolone
respiratory tract infections and bronchitis (Greub et al., 2003; Lamoth et al., 2011). Resistance to quinolones was detected in Parachlamydia due to a mutation (position 70 and 83) in the QRDR of gyrA (Casson et al., 2006).
Bacteroides fragilis Bacteroides fragilis are common cause of blood stream infections in human, neonatal diarrhoea in calves, lambs and mastitis in cattle. Resistance to penicillins, cephalosporins (except cefoxitin) and cefoxitin is associated with possession of cepA and cfxA, respectively (Eitel et al., 2013). Other antimicrobial resistance genes detected in B. fragilis are described in Table 27.1.
Aspergillus fumigatus Aspergillus fumigatus causes a spectrum of human and animal infections including invasive aspergillosis (IA) with an estimated mortality rate of 28.5% in human (Bitar et al., 2014). The studies indicated about more than 1.2 million patients suffer with chronic pulmonary aspergillosis and another 4.8 million people are infected with allergic bronchopulmonary aspergillosis throughout the world annually (Denning et al., 2013). Recent emergence of IA is associated with tuberculosis, asthma, chronic obstructive pulmonary disease, therapy in malignancy, organ transplantation and autoimmune diseases (Brown et al., 2012). Different azole compounds such as itraconazole, voriconazole, posaconazole and isavuconazole are common in therapy and prophylaxis of aspergillosis. The azoles act by inhibiting lanosterol 14-alpha-demethylase (cyp51A in A. fumigatus) required for synthesis of ergosterol (Bossche et al., 1995). Resistance to azole in A. fumigatus was restricted earlier to individual patients receiving azoles for prolonged period (Camps et al., 2012). A global emergence of azole resistance in A. fumigatus is current concern even in patients who did not receive azole therapy (azole-naïve) with a mortality rate as high as 88% in culture-positive patients (Van Der Linden et al., 2013; Steinmann et al., 2015). The resistance mechanisms such as presence of a 34 bp tandem repeat (TR) along with leucine to histidine substitution in codon 98 in cyp51A gene (TR34/L98H associated with itraconazole resistance) and a 46 bp tandem repeat associated with tyrosine to phenylalanine substitution in codon 121 and threonine to alanine substitution in codon 289 in cyp51A gene (TR46/Y121F/T289A causing voriconazole and other azole resistance) are described (Snelders et al., 2008; Van Der Linden et al., 2013). Recent study revealed the role of TR46/Y121F in destabilization of CYP51A protein, which produces high azole resistance in A. fumigatus (Snelders et al., 2015). In European countries such as Denmark, TR34/L98H was found as the predominant mechanism of azole resistance in clinical isolates of A. fumigatus (Jensen et al., 2016). The TR34/L98H-mediated azole resistance in A. fumigatus is although spreading into other non-European countries such as China, India, Middle East, Africa and Australia probably through dispersal of fungal spores (Chowdhary et al., 2013).
Cryptococcus neoformans Cryptococcus neoformans causes more than 600,000 deaths annually throughout the world associated with meningitis (Park et al., 2009). The infection is common in HIV patients and currently non-HIV patients are also infected who receive transplanted organs or prolonged anticancer therapy. Amphotericin B (polyene) and fluconazole are the
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antifungals of choice to treat cryptococcosis. Fluconazole is also recommended as a prophylactic drug to avoid cryptococcosis (Gullo et al., 2013). Mutation in ERG11 (encoding lanosterol 14-alpha-demethylase) and active efflux of the drug through ABC transporter (encoded by AFR1) in C. neoformans are associated with azole resistance (Rodero et al., 2003; Sanguinetti et al., 2006). The resistance genes (ERG11 and AFR1) are encoded by chromosome 1 (Chr1). Aneuploidies increasing the numbers of chromosome (Chr1) may cause overexpression of the resistance genes and transcription factors (Cn Yap1) with enhanced fluconazole resistance (‘heteroresistance’) (Sionov et al., 2010; Paul et al., 2015). Cation transporters (Ena1 and Nha1) of C. neoformans regulate membrane stability and cation homeostasis, and it plays a redundant role in resistance against polyene and azoles (Jung et al., 2012).
Scedosporium spp. Scedosporium apiospermum complex, S. apiospermum and S. minutisporum are ubiquitous saprophytic fungi commonly found in sewage, brackish water, salt water, swaps, coastal tidelands, soil, manure of poultry, cattle and bat guano (Samanta, 2015). Scedosporium is associated with cutaneous infection (mycetoma) in healthy human infected through inhalation or direct contact. In immunocompromised patients with malignancy/HIV/solid organ transplant, Scedosporium apiospermum complex causes disseminated infection throughout the body including central nervous system (Nesky et al., 2000; Balandin et al., 2016). Voriconazole is recommended for treatment of Scedosporium, although Scedosporium are increasingly become resistant against azoles and echinocandins (Tortorano et al., 2014).
References Andersen, A.A., Rogers, D.G., 1998. Resistance to tetracycline and sulfadiazine in swine C. trachomatis isolates. In: Chlamydial Infections. Proceedings of the Ninth International Symposium on Human Chlamydial Infection. International Chlamydia Symposium, San Francisco, CA, pp. 313e316. Balandin, B., Aguilar, M., Sánchez, I., Monzón, A., Rivera, I., Salas, C., Valdivia, M., Alcántara, S., Pérez, A., Ussetti, P., 2016. Scedosporium apiospermum and S. prolificans mixed disseminated infection in a lung transplant recipient: an unusual case of long-term survival with combined systemic and local antifungal therapy in intensive care unit. Medical Mycology Case Reports 11, 53e56. Bhengraj, A.R., Vardhan, H., Srivastava, P., Salhan, S., Mittal, A., 2010. Decreased susceptibility to azithromycin and doxycycline in clinical isolates of Chlamydia trachomatis obtained from recurrently infected female patients in India. Chemotherapy 56 (5), 371e377. Bitar, D., Lortholary, O., Le Strat, Y., Nicolau, J., Coignard, B., Tattevin, P., Che, D., Dromer, F., 2014. Population-based analysis of invasive fungal infections, France, 2001e2010. Emerging Infectious Diseases 20 (7), 1149. Borel, N., Regenscheit, N., Di Francesco, A., Donati, M., Markov, J., Masserey, Y., Pospischil, A., 2012. Selection for tetracycline-resistant Chlamydia suis in treated pigs. Veterinary Microbiology 156 (1e2), 143e146. Bossche, H.V., Koymans, L., Moereels, H., 1995. P450 inhibitors of use in medical treatment: focus on mechanisms of action. Pharmacology & Therapeutics 67 (1), 79e100. Brown, G.D., Denning, D.W., Gow, N.A., Levitz, S.M., Netea, M.G., White, T.C., 2012. Hidden killers: human fungal infections. Science Translational Medicine 4, 165rv13. Camps, S.M., van der Linden, J.W., Li, Y., Kuijper, E.J., van Dissel, J.T., Verweij, P.E., Melchers, W.J., 2012. Rapid induction of multiple resistance mechanisms in Aspergillus fumigatus during azole therapy: a case study and review of the literature. Antimicrobial Agents and Chemotherapy 56 (1), 10e16. Casson, N., Greub, G., 2006. Resistance of different Chlamydia-like organisms to quinolones and mutations in the quinoline resistance-determining region of the DNA gyrase A-and topoisomerase-encoding genes. International Journal of Antimicrobial Agents 27 (6), 541e544. Chowdhary, A., Kathuria, S., Xu, J., Meis, J.F., 2013. Emergence of azole-resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health. PLoS Pathogens 9 (10), e1003633. de Barsy, M., Bottinelli, L., Greub, G., 2014. Antibiotic susceptibility of Estrella lausannensis, a potential emerging pathogen. Microbes and Infection 16 (9), 746e754. De Puysseleyr, K., De Puysseleyr, L., Dhondt, H., Geens, T., Braeckman, L., Morré, S.A., Cox, E., Vanrompay, D., 2014. Evaluation of the presence and zoonotic transmission of Chlamydia suis in a pig slaughterhouse. BMC Infectious Diseases 14 (1), 560. Dean, D., Rothschild, J., Ruettger, A., Kandel, R.P., Sachse, K., 2013. Zoonotic Chlamydiaceae species associated with trachoma, Nepal. Emerging Infectious Diseases 19 (12), 1948. Denning, D.W., Pleuvry, A., Cole, D.C., 2013. Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults. Medical Mycology 51 (4), 361e370. Di Francesco, A., Donati, M., Rossi, M., Pignanelli, S., Shurdhi, A., Baldelli, R., Cevenini, R., 2008. Tetracycline-resistant Chlamydia suis isolates in Italy. The Veterinary Record 163, 251e252. Dugan, J., Rockey, D.D., Jones, L., Andersen, A.A., 2004. Tetracycline resistance in Chlamydia suis mediated by genomic islands inserted into the chlamydial inv-like gene. Antimicrobial Agents and Chemotherapy 48 (10), 3989e3995.
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Eick, A.A., Faix, D.J., Tobler, S.K., Nevin, R.L., Lindler, L.E., Hu, Z., Sanchez, J.L., MacIntosh, V.H., Russell, K.L., Gaydos, J.C., 2011. Serosurvey of bacterial and viral respiratory pathogens among deployed US service members. American Journal of Preventive Medicine 41 (6), 573e580. Eitel, Z., Sóki, J., Urbán, E., Nagy, E., 2013. The prevalence of antibiotic resistance genes in Bacteroides fragilis group strains isolated in different European countries. Anaerobe 21, 43e49. Greub, G., Berger, P., Papazian, L., Raoult, D., 2003. Parachlamydiaceae as rare agents of pneumonia. Emerging Infectious Diseases 9 (6), 755. Gullo, F.P., Rossi, S.A., de CO Sardi, J., Teodoro, V.L.I., Mendes-Giannini, M.J.S., Fusco-Almeida, A.M., 2013. Cryptococcosis: epidemiology, fungal resistance, and new alternatives for treatment. European Journal of Clinical Microbiology & Infectious Diseases 32 (11), 1377e1391. Horner, P.J., 2012. Azithromycin antimicrobial resistance and genital Chlamydia trachomatis infection: duration of therapy may be the key to improving efficacy. Sexually Transmitted Infections 88, 154e156. Jensen, R.H., Hagen, F., Astvad, K.M.T., Tyron, A., Meis, J.F., Arendrup, M.C., 2016. Azole-resistant Aspergillus fumigatus in Denmark: a laboratorybased study on resistance mechanisms and genotypes. Clinical Microbiology and Infections 22 (6), 570-e1. Jung, K.W., Strain, A.K., Nielsen, K., Jung, K.H., Bahn, Y.S., 2012. Two cation transporters Ena1 and Nha1 cooperatively modulate ion homeostasis, antifungal drug resistance, and virulence of Cryptococcus neoformans via the HOG pathway. Fungal Genetics and Biology 49 (4), 332e345. Lamoth, F., Jaton, K., Vaudaux, B., Greub, G., 2011. Parachlamydia and Rhabdochlamydia: emerging agents of community-acquired respiratory infections in children. Clinical Infectious Diseases 53 (5), 500e501. Lienard, J., Croxatto, A., Prod’hom, G., Greub, G., 2011. Estrella lausannensis, a new star in the Chlamydiales order. Microbes and Infection 13 (14e15), 1232e1241. Marrazzo, J., Suchland, R., 2014. Recent advances in understanding and managing Chlamydia trachomatis infections. F1000prime Reports 6. Nesky, M.A., McDougal, E.C., Peacock Jr., J.E., 2000. Scedosporium apiospermum complex brain abscess successfully treated with voriconazole and surgical drainage: case report and literature review of central nervous system pseudallescheriasis. Clinical Infectious Diseases 31 (3), 673e677. Park, B.J., Wannemuehler, K.A., Marston, B.J., Govender, N., Pappas, P.G., Chiller, T.M., 2009. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 23 (4), 525e530. Paul, S., Doering, T.L., Moye-Rowley, W.S., 2015. Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance. Fungal Genetics and Biology 74, 1e9. Rodero, L., Mellado, E., Rodriguez, A.C., Salve, A., Guelfand, L., Cahn, P., Cuenca-Estrella, M., Davel, G., Rodriguez-Tudela, J.L., 2003. G484S amino acid substitution in lanosterol 14-a demethylase (ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate. Antimicrobial Agents and Chemotherapy 47 (11), 3653e3656. Samanta, I., 2015. Veterinary Mycology. Springer. Sandoz, K.M., Rockey, D.D., 2010. Antibiotic resistance in chlamydiae. Future Microbiology 5 (9), 1427e1442. Sanguinetti, M., Posteraro, B., La Sorda, M., Torelli, R., Fiori, B., Santangelo, R., Delogu, G., Fadda, G., 2006. Role of AFR1, an ABC transporterencoding gene, in the in vivo response to fluconazole and virulence of Cryptococcus neoformans. Infection and Immunity 74 (2), 1352e1359. Schautteet, K., Vanrompay, D., 2011. Chlamydiaceae infections in pig. Veterinary Research 42 (1), 29. Sionov, E., Lee, H., Chang, Y.C., Kwon-Chung, K.J., 2010. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathogens 6 (4), e1000848. Snelders, E., Van Der Lee, H.A., Kuijpers, J., Rijs, A.J.M., Varga, J., Samson, R.A., Mellado, E., Donders, A.R.T., Melchers, W.J., Verweij, P.E., 2008. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Medicine 5 (11), e219. Snelders, E., Camps, S.M., Karawajczyk, A., Rijs, A.J., Zoll, J., Verweij, P.E., Melchers, W.J., 2015. Genotypeephenotype complexity of the TR46/ Y121F/T289A cyp51A azole resistance mechanism in Aspergillus fumigatus. Fungal Genetics and Biology 82, 129e135. Steinmann, J., Hamprecht, A., Vehreschild, M.J.G.T., Cornely, O.A., Buchheidt, D., Spiess, B., Koldehoff, M., Buer, J., Meis, J.F., Rath, P.M., 2015. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. Journal of Antimicrobial Chemotherapy 70 (5), 1522e1526. Tortorano, A.M., Richardson, M., Roilides, E., van Diepeningen, A., Caira, M., Munoz, P., Johnson, E., Meletiadis, J., Pana, Z.D., Lackner, M., Verweij, P., 2014. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others. Clinical Microbiology and Infections 20, 27e46. Van Der Linden, J.W., Camps, S.M., Kampinga, G.A., Arends, J.P., Debets-Ossenkopp, Y.J., Haas, P.J., Rijnders, B.J., Kuijper, E.J., Van Tiel, F.H., Varga, J., Karawajczyk, A., 2013. Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. Clinical Infectious Diseases 57 (4), 513e520.
Others Chapter outline Chlamydia Estrella lausannensis Parachlamydia acanthamoebae Bacteroides fragilis
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Aspergillus fumigatus Cryptococcus neoformans Scedosporium spp. References
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Chlamydia Chlamydiae are Gram-negative, obligate intracellular bacteria with a complex developmental cycle consisting of two stages such as elementary body (infectious) and reticulate body (RB). During exposure to antibiotics or other stress factors, growth of Chlamydia is arrested and it is known as aberrant RB/aberrant bodies (AB). Chlamydial infection is common in human and animals. Human-associated pathogenic species such as Chlamydia trachomatis and Chlamydia pneumoniae cause urethritis, epididymitis in men, cervicitis, infertility, ectopic pregnancy in women and atypical pneumonia, respectively (Eick et al., 2011; Marrazzo and Suchland, 2014). Chlamydia suis causes respiratory distress, conjunctivitis, diarrhoea and reproductive disorders in farmed pigs and wild boars (Schautteet and Vanrompay, 2011). Direct zoonotic transmission of C. suis is not confirmed. Genetic material of C. suis is although detected in human clinical samples (Dean et al., 2013; De Puysseleyr et al., 2014). Tetracyclines are recommended for treatment of chlamydiosis in human and livestock. Tetracycline-resistant Chlamydia were started to be reported from pigs in the United States since 1998 and later from European countries such as Italy, Belgium and Switzerland (Andersen and Rogers, 1998; Di Francesco et al., 2008; Schautteet and Vanrompay, 2011; Borel et al., 2012). Tetracycline resistance gene (tetC) present in a genomic island (TetR) was found to be associated with resistance, which encodes a tetracycline efflux pump (Dugan et al., 2004). The genomic island (TetR) of C. suis is the first identified acquired resistance factor in a bacterium through horizontal gene transfer. Majority of C. suis genomic island (TetR) also carries IScs605 originated from Laribacter hongkongensis, a fish pathogen (Sandoz and Rockey, 2010). Use of fish meal was correlated with the origin of IScs605 in C. suis although not confirmed. In human, treatment failure (5%e23%) due to infection with azithromycin- and doxycycline-resistant C. trachomatis and C. pneumoniae was reported from several countries (Horner, 2012). Heterotypic resistance was detected in clinical isolates of Chlamydia associated with phenotypic changes in a stressed bacterial population (AB) (Bhengraj et al., 2010).
Estrella lausannensis Estrella lausannensis belongs to the family Criblamydiaceae under the order Chlamydiales (Lienard et al., 2011). It can infect amoeba, fish cell lines and is associated with tubal pathology in women. Quinolone resistance in E. lausannensis was associated with amino acid substitutions in the quinolone resistance-determining region (QRDR) of GyrA (Ser83Gln and Val70Ser) and ParC (Ser80Ala and Glu84Asp) (de Barsy et al., 2014).
Parachlamydia acanthamoebae Parachlamydia acanthamoebae, a kind of Chlamydia, is found to be associated with varieties of respiratory tract infections in human such as community-acquired pneumonia, ventilator-associated pneumonia, nosocomial pneumonia, lower
Antimicrobial Resistance in Agriculture. https://doi.org/10.1016/B978-0-12-815770-1.00027-4 Copyright © 2020 Elsevier Inc. All rights reserved.
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TABLE 27.1 Antimicrobial resistance genes detected in Bacteroides fragilis. Genes
Resistance
cfiA (metallo-b-lactamase)
Carbapenem
nimA-H, nimJ (nitroimidazole)
Metronidazole
ermB, ermF, ermG
Clindamycin
msrSA, mefA
Macrolide, lincosamide
linAn2
Lincomycin, erythromycin
tetQ, tetX, tetX1
Tetracycline, tigecycline
bexA, bexB
Fluoroquinolone
respiratory tract infections and bronchitis (Greub et al., 2003; Lamoth et al., 2011). Resistance to quinolones was detected in Parachlamydia due to a mutation (position 70 and 83) in the QRDR of gyrA (Casson et al., 2006).
Bacteroides fragilis Bacteroides fragilis are common cause of blood stream infections in human, neonatal diarrhoea in calves, lambs and mastitis in cattle. Resistance to penicillins, cephalosporins (except cefoxitin) and cefoxitin is associated with possession of cepA and cfxA, respectively (Eitel et al., 2013). Other antimicrobial resistance genes detected in B. fragilis are described in Table 27.1.
Aspergillus fumigatus Aspergillus fumigatus causes a spectrum of human and animal infections including invasive aspergillosis (IA) with an estimated mortality rate of 28.5% in human (Bitar et al., 2014). The studies indicated about more than 1.2 million patients suffer with chronic pulmonary aspergillosis and another 4.8 million people are infected with allergic bronchopulmonary aspergillosis throughout the world annually (Denning et al., 2013). Recent emergence of IA is associated with tuberculosis, asthma, chronic obstructive pulmonary disease, therapy in malignancy, organ transplantation and autoimmune diseases (Brown et al., 2012). Different azole compounds such as itraconazole, voriconazole, posaconazole and isavuconazole are common in therapy and prophylaxis of aspergillosis. The azoles act by inhibiting lanosterol 14-alpha-demethylase (cyp51A in A. fumigatus) required for synthesis of ergosterol (Bossche et al., 1995). Resistance to azole in A. fumigatus was restricted earlier to individual patients receiving azoles for prolonged period (Camps et al., 2012). A global emergence of azole resistance in A. fumigatus is current concern even in patients who did not receive azole therapy (azole-naïve) with a mortality rate as high as 88% in culture-positive patients (Van Der Linden et al., 2013; Steinmann et al., 2015). The resistance mechanisms such as presence of a 34 bp tandem repeat (TR) along with leucine to histidine substitution in codon 98 in cyp51A gene (TR34/L98H associated with itraconazole resistance) and a 46 bp tandem repeat associated with tyrosine to phenylalanine substitution in codon 121 and threonine to alanine substitution in codon 289 in cyp51A gene (TR46/Y121F/T289A causing voriconazole and other azole resistance) are described (Snelders et al., 2008; Van Der Linden et al., 2013). Recent study revealed the role of TR46/Y121F in destabilization of CYP51A protein, which produces high azole resistance in A. fumigatus (Snelders et al., 2015). In European countries such as Denmark, TR34/L98H was found as the predominant mechanism of azole resistance in clinical isolates of A. fumigatus (Jensen et al., 2016). The TR34/L98H-mediated azole resistance in A. fumigatus is although spreading into other non-European countries such as China, India, Middle East, Africa and Australia probably through dispersal of fungal spores (Chowdhary et al., 2013).
Cryptococcus neoformans Cryptococcus neoformans causes more than 600,000 deaths annually throughout the world associated with meningitis (Park et al., 2009). The infection is common in HIV patients and currently non-HIV patients are also infected who receive transplanted organs or prolonged anticancer therapy. Amphotericin B (polyene) and fluconazole are the
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antifungals of choice to treat cryptococcosis. Fluconazole is also recommended as a prophylactic drug to avoid cryptococcosis (Gullo et al., 2013). Mutation in ERG11 (encoding lanosterol 14-alpha-demethylase) and active efflux of the drug through ABC transporter (encoded by AFR1) in C. neoformans are associated with azole resistance (Rodero et al., 2003; Sanguinetti et al., 2006). The resistance genes (ERG11 and AFR1) are encoded by chromosome 1 (Chr1). Aneuploidies increasing the numbers of chromosome (Chr1) may cause overexpression of the resistance genes and transcription factors (Cn Yap1) with enhanced fluconazole resistance (‘heteroresistance’) (Sionov et al., 2010; Paul et al., 2015). Cation transporters (Ena1 and Nha1) of C. neoformans regulate membrane stability and cation homeostasis, and it plays a redundant role in resistance against polyene and azoles (Jung et al., 2012).
Scedosporium spp. Scedosporium apiospermum complex, S. apiospermum and S. minutisporum are ubiquitous saprophytic fungi commonly found in sewage, brackish water, salt water, swaps, coastal tidelands, soil, manure of poultry, cattle and bat guano (Samanta, 2015). Scedosporium is associated with cutaneous infection (mycetoma) in healthy human infected through inhalation or direct contact. In immunocompromised patients with malignancy/HIV/solid organ transplant, Scedosporium apiospermum complex causes disseminated infection throughout the body including central nervous system (Nesky et al., 2000; Balandin et al., 2016). Voriconazole is recommended for treatment of Scedosporium, although Scedosporium are increasingly become resistant against azoles and echinocandins (Tortorano et al., 2014).
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