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Between December 2021 and June 2022, 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae (ST8123;â¯nâ¯=â¯8) were detected in the United Kingdom, compared with nine cases during the previous 6 years. Most of these cases were associated with travel from the Asia-Pacific region; all were heterosexual people, with most in their 20s. Although all cases were successfully treated, not all partners of cases could be traced, and there is a risk of further transmission of ceftriaxone-resistant gonococcal infection within the UK.
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Gonorreia , Neisseria gonorrhoeae , Humanos , Neisseria gonorrhoeae/genética , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Testes de Sensibilidade Microbiana , Gonorreia/diagnóstico , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Invasive meningococcal disease (IMD) is endemic to South Africa, where vaccine use is negligible. We describe the epidemiology of IMD in South Africa. METHODS: IMD cases were identified through a national, laboratory-based surveillance program, GERMS-SA, from 2003-2016. Clinical data on outcomes and human immunodeficiency virus (HIV) statuses were available from 26 sentinel hospital sites. We conducted space-time analyses to detect clusters of serogroup-specific IMD cases. RESULTS: Over 14 years, 5249 IMD cases were identified. The incidence was 0.97 cases per 100 000 persons in 2003, peaked at 1.4 cases per 100 000 persons in 2006, and declined to 0.23 cases per 100 000 persons in 2016. Serogroups were confirmed in 3917 (75%) cases: serogroup A was present in 4.7% of cases, B in 23.3%, C in 9.4%; W in 49.5%; Y in 12.3%, X in 0.3%; Z in 0.1% and 0.4% of cases were non-groupable. We identified 8 serogroup-specific, geo-temporal clusters of disease. Isolate susceptibility was 100% to ceftriaxone, 95% to penicillin, and 99.9% to ciprofloxacin. The in-hospital case-fatality rate was 17% (247/1479). Of those tested, 36% (337/947) of IMD cases were HIV-coinfected. The IMD incidence in HIV-infected persons was higher for all age categories, with an age-adjusted relative risk ratio (aRRR) of 2.5 (95% confidence interval [CI] 2.2-2.8; P < .001) from 2012-2016. No patients reported previous meningococcal vaccine exposure. Patients with serogroup W were 3 times more likely to present with severe disease than those with serogroup B (aRRR 2.7, 95% CI 1.1-6.3); HIV coinfection was twice as common with W and Y diseases (aRRR W = 1.8, 95% CI 1.1-2.9; aRRR Y = 1.9, 95% CI 1.0-3.4). CONCLUSIONS: In the absence of significant vaccine use, IMD in South Africa decreased by 76% from 2003-2016. HIV was associated with an increased risk of IMD, especially for serogroup W and Y diseases.
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Coinfecção/epidemiologia , Infecções Meningocócicas/epidemiologia , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Coinfecção/microbiologia , Coinfecção/virologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/microbiologia , Mortalidade Hospitalar , Humanos , Incidência , Masculino , Infecções Meningocócicas/tratamento farmacológico , Infecções Meningocócicas/mortalidade , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Neisseria meningitidis/imunologia , Fatores de Risco , Sorogrupo , África do Sul/epidemiologia , Adulto JovemRESUMO
Zoonotic thermophilic Campylobacter and nontyphoidal Salmonella enterica are a major cause of foodborne human gastroenteritis worldwide. There is little information about reservoirs of these zoonotic agents in Africa. Thus, chicks of kelp gulls (Larus dominicanus, n = 129) and greater crested terns (Thalasseus bergii, n = 100) were studied at five colonies on the Western Cape coast (South Africa) during summer 2013/2014. Campylobacter spp. occurrence was 14.0% (CI95% : 9.9-19.3), with C. jejuni the most frequently isolated species, whilst that of Salmonella was 27.5% (CI95% : 21.9-33.9) overall, with a higher prevalence in gulls (43.0%, CI95% : 34.8-52.4) than terns (7.0%, CI95% : 3.1-14.4). Among the 16 different S. enterica serovars found, Anatum, Enteritidis and Hadar were the most frequent. The same or highly similar pulsed-field gel electrophoresis genotype was found in some Salmonella isolates from seabirds and humans presenting with salmonellosis in Cape Town hospitals. Both Campylobacter and Salmonella isolates exhibited antimicrobial resistance to several agents, including critically important antimicrobials (quinolones, tetracyclines and ß-lactams) and multidrug resistance in Salmonella serovars from kelp gulls. Our results highlight the importance of seabirds as reservoirs of Campylobacter and Salmonella resistant strains and their role in the maintenance and transmission of these bacteria in the environment, with implications for public health.
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Doenças das Aves/epidemiologia , Infecções por Campylobacter/epidemiologia , Campylobacter/isolamento & purificação , Charadriiformes/microbiologia , Infecções por Salmonella/epidemiologia , Salmonella enterica/isolamento & purificação , Animais , Antibacterianos/farmacologia , Doenças das Aves/microbiologia , Campylobacter/classificação , Campylobacter/efeitos dos fármacos , Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/transmissão , Farmacorresistência Bacteriana , Eletroforese em Gel de Campo Pulsado , Humanos , Testes de Sensibilidade Microbiana , Infecções por Salmonella/microbiologia , Infecções por Salmonella/transmissão , Salmonella enterica/classificação , Salmonella enterica/efeitos dos fármacos , África do Sul/epidemiologiaRESUMO
BACKGROUND: The genus emmonsia contains three species that are associated with human disease. Emmonsia crescens and Emmonsia parva are the agents that cause adiaspiromycosis, and one human case of Emmonsia pasteuriana infection has been described. We report a fungal pathogen within the genus emmonsia that is most closely related to E. pasteuriana in human immunodeficiency virus (HIV)-infected adults in South Africa. METHODS: Between July 2008 and July 2011, we conducted enhanced surveillance to identify the cause of systemic, dimorphic fungal infections in patients presenting to Groote Schuur Hospital and other hospitals affiliated with the University of Cape Town, Cape Town, South Africa. DNA sequencing was used to identify pathogenic fungi. RESULTS: A total of 24 cases of dimorphic fungal infection were diagnosed, 13 of which were caused by an emmonsia species. All 13 patients were HIV-infected, with a median CD4+ T-cell count of 16 cells per cubic millimeter (interquartile range, 10 to 44), and all had evidence of disseminated fungal disease. Three patients died soon after presentation, but the others had a good response to a variety of antifungal agents and antiretroviral therapy. Phylogenetic analysis of five genes (LSU, ITS1-2, and the genes encoding actin, ß-tubulin, and intein PRP8) revealed that this fungus belongs in the genus emmonsia and is most closely related to E. pasteuriana. CONCLUSIONS: The findings suggest that these isolates of an emmonsia species represent a new species of dimorphic fungus that is pathogenic to humans. The species appears to be an important cause of infections in Cape Town.
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Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Micoses/microbiologia , Adulto , Chrysosporium/classificação , Chrysosporium/genética , Chrysosporium/isolamento & purificação , Chrysosporium/patogenicidade , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Filogenia , África do SulRESUMO
The contribution of the genetic background of Staphylococcus aureus to biofilm formation is poorly understood. We investigated the association between the genetic background and the biofilm forming ability of clinical invasive S. aureus isolates. Secondary objectives included investigating any correlation with biofilm formation and methicillin resistance or the source of bacteraemia. The study was conducted at a 1300-bed tertiary hospital in Cape Town, South Africa. S. aureus isolates obtained from blood cultures between January 2010 and January 2012 were included. Genotypic characterization was performed by PFGE, spa typing, SCCmec typing and MLST. Thirty genotypically unique strains were assessed for phenotypic biofilm formation with the microtitre plate assay. All isolates were tested in triplicate and an average optical density, measured at a wavelength of 490 nm, was determined. The biofilm forming ability of isolates with A490 ≤ 0.17 were considered non-adherent, A490 > 0.17 'weak positive' and A490 > 0.34 'strong positive'. Fifty seven percent of isolates formed biofilms. Weak biofilm formation occurred in 40% (n = 12) and strong biofilm formation in 17% (n = 5) of isolates. All 5 isolates capable of strong biofilm formation belong to one spa clonal complex (spa-CC 064). Strains from spa-CC 064 were capable of higher biofilm formation than other spa clonal complexes (p = 0.00002). These 5 strains belonged to MLST CC5 and CC8. Biofilm formation correlates with the spa clonal lineage in our population of invasive S. aureus strains. Biofilm formation did not correlate with methicillin resistance and was not related to the source of bacteraemia.
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Biofilmes/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/fisiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Antibacterianos/farmacologia , Bacteriemia/sangue , Bacteriemia/microbiologia , Aderência Bacteriana/genética , Aderência Bacteriana/fisiologia , DNA Bacteriano/genética , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus/métodos , Estudos Prospectivos , Infecções Estafilocócicas/sangue , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificaçãoRESUMO
BACKGROUND: Systemic disease due to shigellae is associated with human immunodeficiency virus (HIV), malnutrition, and other immunosuppressed states. We examined the clinical and microbiologic characteristics of systemic shigellosis in South Africa, where rates of HIV infection are high. METHODS: From 2003 to 2009, 429 cases of invasive shigellosis were identified through national laboratory-based surveillance. At selected sites, additional information was captured on HIV serostatus and outcome. Isolates were serotyped and antimicrobial susceptibility testing performed. RESULTS: Most cases of systemic shigellosis were diagnosed on blood culture (408 of 429 cases; 95%). HIV prevalence was 67% (80 of 120 cases), highest in patients aged 5-54 years, and higher among females (55 of 70 cases; 79%) compared with males (25 of 48 cases; 52%; P = .002). HIV-infected people were 4.1 times more likely to die than HIV-uninfected cases (case-fatality ratio, 29 of 78 HIV-infected people [37%] vs 5 of 40 HIV-uninfected people [13%]; P = .008; 95% confidence interval [CI], 1.5-11.8). The commonest serotype was Shigella flexneri 2a (89 of 292 serotypes [30.5%]). Pentavalent resistance occurred in 120 of 292 isolates (41.1%). There was no difference in multidrug resistance between HIV-infected patients (33 of 71 [46%]) and uninfected patients (12 of 33 [36%]; 95% CI, .65--3.55). CONCLUSIONS: Systemic shigellosis is associated with HIV-infected patients, primarily in older girls and women, potentially due to the burden of caring for sick children in the home; interventions need to be targeted here. Death rates are higher in HIV-infected versus uninfected individuals.
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Bacteriemia/epidemiologia , Disenteria Bacilar/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Bacteriemia/microbiologia , Criança , Pré-Escolar , Disenteria Bacilar/microbiologia , Feminino , Infecções por HIV/complicações , Humanos , Hospedeiro Imunocomprometido , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Shigella/classificação , Shigella/efeitos dos fármacos , Shigella/isolamento & purificação , África do Sul/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: There are few studies describing colonisation with extended spectrum beta-lactamase-producing Enterobacterales (ESBL-PE) and carbapenem-resistant Enterobacterales (CRE) among children in sub-Saharan Africa. Colonisation often precedes infection and multi-drug-resistant Enterobacterales are important causes of invasive infection. METHODS: In this prospective cross-sectional study, conducted between April and June 2017, 200 children in a tertiary academic hospital were screened by rectal swab for EBSL-PE and CRE. The resistance-conferring genes were identified using polymerase chain reaction technology. Risk factors for colonisation were also evaluated. RESULTS: Overall, 48% (96/200) of the children were colonised with at least one ESBL-PE, 8.3% (8/96) of these with 2 ESBL-PE, and one other child was colonised with a CRE (0.5% (1/200)). Common colonising ESBL-PE were Klebsiella pneumoniae (62.5%, 65/104) and Escherichia coli (34.6%, 36/104). The most frequent ESBL-conferring gene was blaCTX-M in 95% (76/80) of the isolates. No resistance- conferring gene was identified in the CRE isolate (Enterobacter cloacae). Most of the Klebsiella pneumoniae isolates were susceptible to piperacillin/tazobactam (86.2%) and amikacin (63.9%). Similarly, 94.4% and 97.2% of the Escherichia coli isolates were susceptible to piperacillin/tazobactam and amikacin, respectively. Hospitalisation for more than 7 days before study enrolment was associated with ESBL-PE colonisation. CONCLUSION: Approximately half of the hospitalised children in this study were colonised with ESBL-PE. This highlights the need for improved infection prevention and control practices to limit the dissemination of these microorganisms.
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Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Infecção Hospitalar/diagnóstico por imagem , Infecções por Enterobacteriaceae/epidemiologia , Enterobacteriaceae/classificação , beta-Lactamases/genética , Proteínas de Bactérias/metabolismo , Criança , Pré-Escolar , Infecção Hospitalar/microbiologia , Estudos Transversais , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Enterobacteriaceae/isolamento & purificação , Feminino , Hospitalização , Hospitais Pediátricos , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Estudos Prospectivos , Fatores de Risco , África do Sul , Centros de Atenção Terciária , beta-Lactamases/metabolismoRESUMO
Background: Residential care facilities (RCFs) act as reservoirs for multidrug-resistant organisms (MDRO). There are scarce data on colonisation with MDROs in Africa. We aimed to determine the prevalence of MDROs and C. difficile and risk factors for carriage amongst residents of RCFs in Cape Town, South Africa. Methods: We performed a cross-sectional surveillance study at three RCFs. Chromogenic agar was used to screen skin swabs for methicillin-resistant S. aureus (MRSA) and stool samples for extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E). Antigen testing and PCR was used to detect Clostridiodes difficile. Risk factors for colonisation were determined with logistic regression. Results: One hundred fifty-four residents were enrolled, providing 119 stool samples and 152 sets of skin swabs. Twenty-seven (22.7%) stool samples were positive for ESBL-E, and 13 (8.6%) residents had at least one skin swab positive for MRSA. Two (1.6%) stool samples tested positive for C. difficile. Poor functional status (OR 1.3 (95% CI, 1.0-1.6)) and incontinence (OR 2.9 (95% CI, 1.2-6.9)) were significant predictors for ESBL-E colonisation. MRSA colonization appeared higher in frail care areas (8/58 v 5/94, p = 0.07). Conclusions: There was a relatively high prevalence of colonisation with MDROs, particularly ESBL-E, but low C. difficile carriage, with implications for antibiotic prescribing and infection control practice.
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Infecções Bacterianas/epidemiologia , Portador Sadio/epidemiologia , Portador Sadio/microbiologia , Clostridioides difficile/isolamento & purificação , Farmacorresistência Bacteriana Múltipla , Instituições Residenciais/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Clostridioides difficile/efeitos dos fármacos , Estudos Transversais , Reservatórios de Doenças/microbiologia , Enterobacteriaceae , Infecções por Enterobacteriaceae/epidemiologia , Fezes/microbiologia , Feminino , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina , Prevalência , Fatores de Risco , Pele/microbiologia , África do Sul/epidemiologia , Infecções Estafilocócicas/epidemiologia , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Antimicrobial resistant bacterial infections are widespread globally and increases in antimicrobial resistance presents a major threat to public health. Pseudomonas aeruginosa is an opportunistic healthcare-associated pathogen with high rates of morbidity and mortality and an extensive range of resistance mechanisms. This study describes the antibiotic susceptibility profiles of P. aeruginosa isolates from patients with bacteraemia submitted by sentinel laboratories in South Africa from 2014 to 2015. METHODOLOGY: Organism identification and antimicrobial susceptibility testing were done using automated systems. Molecular methods were used to detect common resistance genes and mechanisms. RESULTS: Overall the susceptibility was high for all antibiotics tested with a decrease over the two-year period. There was no change in the MIC50 and MIC90 breakpoints for all antibiotics from 2014 to 2015. The MIC50 was within the susceptible breakpoint range for most antibiotics and the MIC90 was within the susceptible breakpoint range for colistin only. Phenotypically carbapenem non-susceptible isolates harboured the following plasmid-mediated genes: blaVIM (n = 81, 12%) and blaGES (n = 6, 0.9%); blaNDM (n = 4, 0.6%) and blaOXA-48 and variants (n = 3, 0.45%). Porin deletions were observed in one meropenem non-susceptible isolate only, and multi-drug resistance efflux pumps were expressed in the majority of the non-susceptible isolates investigated. BlaVEB-1, blaIMP and blaKPC were not detected. CONCLUSION: The prevalence of resistance to commonly used antibacterial agents was low for P. aeruginosa isolates and similarly, tested resistance mechanisms were detected in a relatively small proportion of isolates. Findings in this study represent baseline information for understanding antimicrobial susceptibility patterns in P. aeruginosa isolates from blood. Our surveillance report may assist in contributing to hospital treatment guidelines.
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Antibacterianos/farmacologia , Bacteriemia/microbiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Bactérias/genética , Criança , Pré-Escolar , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Feminino , Humanos , Lactente , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Infecções por Pseudomonas/sangue , Infecções por Pseudomonas/epidemiologia , Pseudomonas aeruginosa/isolamento & purificação , África do Sul/epidemiologia , Adulto Jovem , beta-Lactamases/genéticaRESUMO
Listeria monocytogenesis a Gram-positive bacterium with a ubiquitous presence in the environment. There is growing concern about the increasing prevalence ofL. monocytogenesassociated with food-borne outbreaks. Here we report genome sequences for a cluster of human isolates ofL. monocytogenesidentified in South Africa in 2015.
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Opportunistic fungal infections can cause significant morbidity and mortality in immunocompromised patients. We describe a paediatric case of an unusual disseminated fungal infection. A three-year-old HIV-infected child with severe immunosuppression (CD4+ T-cell count 12 × 106/L) was admitted to hospital with pneumonia, gastroenteritis and herpes gingivostomatitis. Despite antibacterial and antiviral therapy, he experienced high fevers and developed an erythematous maculopapular rash and abdominal tenderness. The child's condition progressively worsened during the admission. A thermally dimorphic fungus was cultured from bone marrow and identified as an Emmonsia species on DNA sequencing. The patient made a good recovery on amphotericin B deoxycholate and antiretroviral therapy. Itraconazole was continued for a minimum of 12 months, allowing for immune reconstitution to occur. This case is the first documented description of disseminated disease caused by a novel Emmonsia species in an HIV-infected child in South Africa.
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BACKGROUND: An association between pneumococcal serotypes and mortality has been suggested. We aimed to investigate this among individuals aged ≥15 years with invasive pneumococcal disease (IPD) in South Africa. METHODS: IPD cases were identified through national laboratory-based surveillance at 25 sites, pre-pneumococcal conjugate vaccine (PCV) introduction, from 2003-2008. We assessed the association between the 20 commonest serotypes and in-hospital mortality using logistic regression with serotype 4 (the third commonest serotype with intermediate case-fatality ratio (CFR)) as referent. RESULTS: Among 3953 IPD cases, CFR was 55% (641/1166) for meningitis and 23% (576/2484) for bacteremia (p<0.001). Serotype 19F had the highest CFR (48%, 100/207), followed by serotype 23F (39%, 99/252) and serotype 1 (38%, 246/651). On multivariable analysis, factors independently associated with mortality included serotype 1 (OR 1.9, 95%CI 1.1-3.5) and 19F (OR 2.9, 95%CI 1.4-6.1) vs. serotype 4; increasing age (25-44 years, OR 1.8, 95%CI 1.0-3.0; 45-64 years, OR 3.6, 95%CI 2.0-6.4; ≥65 years, OR 5.2, 95%CI 1.9-14.1; vs. 15-24 years); meningitis (OR 4.1, 95%CI 3.0-5.6) vs. bacteremic pneumonia; and HIV infection (OR1.7, 95%CI 1.0-2.8). On stratified multivariate analysis, serotype 19F was associated with increased mortality amongst bacteremic pneumococcal pneumonia cases, while no serotype was associated with increased mortality in meningitis cases. CONCLUSION: Mortality was increased in HIV-infected individuals, which may be reduced by increased antiretroviral therapy availability. Serotypes associated with increased mortality are included in the 10-and-13-valent PCV and may become less common in adults due to indirect effects following routine infant immunization.
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Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/mortalidade , Vigilância da População , Estatística como Assunto , Streptococcus pneumoniae/classificação , Adolescente , Adulto , Fatores Etários , Coinfecção/epidemiologia , Coinfecção/microbiologia , Coinfecção/virologia , Demografia , Feminino , Infecções por HIV/epidemiologia , Mortalidade Hospitalar , Humanos , Masculino , Análise Multivariada , Sorotipagem , África do Sul/epidemiologiaRESUMO
The HIV pandemic has resulted in unique clinical presentations in patients, and their diagnosis and management pose challenges to physicians in the developing world. Due to limited resources and difficulties in laboratory diagnosis, most physicians treat according to the most likely etiological agent that might be causing the disease. In South Africa, when acid-fast bacilli are detected, anti-tuberculous treatment is commenced. However, it must be realized that not all acid-fast bacilli are Mycobacterium tuberculosis, and that there are nontuberculous mycobacteria that can cause infections. Clinicians should work closely with the medical microbiologist when unique cases arise to ensure optimal microbial detection, identification, and patient management. This paper describes a very rare case of self-resolving cutaneous Mycobacterium kansasii infection following the initiation of antiretroviral therapy and potentially associated with immune reconstitution inflammatory syndrome.
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Síndrome da Imunodeficiência Adquirida/complicações , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Mycobacterium kansasii/isolamento & purificação , Dermatopatias Bacterianas/diagnóstico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adulto , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Feminino , Humanos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Dermatopatias Bacterianas/microbiologia , África do SulRESUMO
The presence of an opportunistic infection in a patient in sub-Saharan Africa is assumed to be due to underlying immunosuppression from human immunodeficiency virus (HIV) infection. The presence of disseminated cryptococcosis in a non-HIV-infected patient is interesting as it is unique in our setting because the majority of infections are found in HIV-infected individuals. The protean manifestations of the disease and its predilection for immunosuppressed patients make cryptococcosis a challenging and elusive disease to diagnose in HIV-negative patients in our setting, especially due to limited resources. We present a case of disseminated cryptococcosis in an immunocompetent patient and discuss diagnostic and therapeutic features in this subset of patients.