Population genomic analyses reveal high diversity, recombination and nosocomial transmission among Candida glabrata (Nakaseomyces glabrata) isolates causing invasive infections.

Candida glabrata is a commensal yeast of the gastrointestinal tract and skin of humans. However, it causes opportunistic infections in immunocompromised patients, and is the second most common Candida pathogen causing bloodstream infections. Although there are many studies on the epidemiology of C. glabrata infections, the fine- and large-scale geographical nature of C. glabrata remain incompletely understood. Here we investigated both the fine- and large-scale population structure of C. glabrata through genome sequencing of 80 clinical isolates obtained from six tertiary hospitals in Qatar and by comparing with global collections. Our fine-scale analyses revealed high genetic diversity within the Qatari population of C. glabrata and identified signatures of recombination, inbreeding and clonal expansion within and between hospitals, including evidence for nosocomial transmission among coronavirus disease 2019 (COVID-19) patients. In addition to signatures of recombination at the population level, both MATa and MATα alleles were detected in most hospitals, indicating the potential for sexual reproduction in clinical environments. Comparisons with global samples showed that the Qatari C. glabrata population was very similar to those from other parts of the world, consistent with the significant role of recent anthropogenic activities in shaping its population structure. Genome-wide association studies identified both known and novel genomic variants associated with reduced susceptibilities to fluconazole, 5-flucytosine and echinocandins. Together, our genomic analyses revealed the diversity, transmission patterns and antifungal drug resistance mechanisms of C. glabrata in Qatar as well as the relationships between Qatari isolates and those from other parts of the world.

Switch to oral antibiotics in Gram-negative bacteraemia: a randomized, open-label, clinical trial.

OBJECTIVES: To evaluate the safety and efficacy of switching from intravenous (IV) to oral antimicrobial therapy in patients with Enterobacterales bacteraemia, after completion of 3-5 days of microbiologically active IV therapy. METHODS: A multicentre, open-label, randomized trial of adults with monomicrobial Enterobacterales bacteraemia caused by a strain susceptible to ≥1 oral beta-lactam, quinolone, or trimethoprim/sulfamethoxazole. Inclusion criteria included completion of 3-5 days of microbiologically active IV therapy, being afebrile and haemodynamically stable for ≥48 hours, and absence of an uncontrolled source of infection. Pregnancy, endocarditis, and neurological infections were exclusion criteria. Randomization, stratified by urinary source of bacteraemia, was to continue IV (IV Group) or to switch to oral therapy (Oral Group). Agents and duration of therapy were determined by the treating physicians. The primary endpoint was treatment failure, defined as death, need for additional antimicrobial therapy, microbiological relapse, or infection-related re-admission within 90 days. Non-inferiority threshold was set at 10% in the 95% CI for the difference in the proportion with treatment failure between the Oral and IV Groups in the modified intention-to-treat population. The protocol was registered at ClinicalTrials.gov (NCT04146922). RESULTS: In the modified intention-to-treat population, treatment failure occurred in 21 of 82 (25.6%) in the IV Group, and 18 of 83 (21.7%) in the Oral Group (risk difference -3.7%, 95% CI -16.6% to 9.2%). The proportions of subjects with any adverse events (AE), serious AE, or AE leading to treatment discontinuation were comparable. DISCUSSION: In patients with Enterobacterales bacteraemia, oral switch, after initial IV antimicrobial therapy, clinical stability, and source control, is non-inferior to continuing IV therapy.

Genomic Epidemiology of Carbapenem-Resistant Klebsiella in Qatar: Emergence and Dissemination of Hypervirulent Klebsiella pneumoniae Sequence Type 383 Strains.

The emergence of carbapenem-resistant, hypervirulent Klebsiella pneumoniae is a new threat to health care. We studied the molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae isolates in Qatar using whole-genome sequence data. We also characterized the prevalence and genetic basis of hypervirulent phenotypes and established the virulence potential using a Galleria mellonella model. Of 100 Klebsiella isolates studied, NDM and OXA-48 were the most common carbapenemases. Core genome single-nucleotide polymorphism (SNP) analysis indicated the presence of diverse sequence types and clonal lineages; isolates belonging to Klebsiella quasipneumoniae subsp. quasipneumoniae sequence type 196 (ST196) and ST1416 may be disseminated among several health care centers. Ten K. pneumoniae isolates carried rmpA and/or truncated rmpA2, and 2 isolates belonged to KL2, indicating low prevalence of classical hypervirulent isolates. Isolates carrying both carbapenem resistance and hypervirulence genes were confined mainly to ST231 and ST383 isolates. One ST383 isolate was further investigated by MinION sequencing, and the assembled genome indicated that blaNDM was located on an IncHI1B-type plasmid (pFQ61_ST383_NDM-5) which coharbored several virulence factors, including the regulator of the mucoid phenotype (rmpA), the regulator of mucoid phenotype 2 (rmpA2), and aerobactin (iucABCD and iutA), likely resulting from recombination events. Comparative genomics indicated that this hybrid plasmid may be present in two additional Qatari ST383 isolates. Carbapenem-resistant, hypervirulent K. pneumoniae ST383 isolates pose an emerging threat to global health due to their simultaneous hypervirulence and multidrug resistance.

Molecular characterization of Candida auris outbreak isolates in Qatar from patients with COVID-19 reveals the emergence of isolates resistant to three classes of antifungal drugs.

OBJECTIVES: During the COVID-19 pandemic in Qatar, many patients who were severely ill were colonized and infected by Candida auris, an invasive multidrug-resistant yeast pathogen that spreads through nosocomial transmission within healthcare facilities. Here, we investigated the molecular epidemiology of these C. auris isolates and the mechanisms associated with antifungal drug resistance. METHODS: Whole genomes of 76 clinical C. auris isolates, including 65 from patients with COVID-19 collected from March 2020 to June 2021, from nine major hospitals were sequenced on Illumina NextSeq. Single nucleotide polymorphisms were used to determine their epidemiological patterns and mechanisms for antifungal resistance. The data were compared with those published prior to the COVID-19 pandemic from 2018 to 2020 in Qatar. RESULTS: Genomic analysis revealed low genetic variability among the isolates from patients with and without COVID-19, confirming a clonal outbreak and ongoing dissemination of C. auris among various healthcare facilities. Based on antifungal susceptibility profiles, more than 70% (22/28) of isolates were resistant to both fluconazole and amphotericin B. Variant analysis revealed the presence of multi-antifungal resistant isolates with prominent amino acid substitutions: Y132F in ERG11 and V704L in CDR1 linked to reduced azole susceptibility and the emergence of echinocandin resistance samples bearing mutations in FKS1 in comparison with pre-COVID-19 pandemic samples. One sample (CAS109) was resistant to three classes of antifungal drugs with a unique premature stop codon in ERG3 and novel mutations in CDR2, which may be associated with elevated amphotericin B and azole resistance. DISCUSSION: Candida auris isolates from patients with COVID-19 and from most patient samples without COVID-19 in Qatar were highly clonal. The data demonstrated the emergence of multidrug-resistant strains that carry novel mutations linked to enhanced resistance to azoles, echinocandins, and amphotericin B. Understanding the epidemiology and drug resistance will inform the infection control strategy and drug therapy.

Favipiravir for the treatment of coronavirus disease 2019 pneumonia; a propensity score-matched cohort study.

We retrospectively investigated the clinical outcomes of favipiravir in patients with COVID-19 pneumonia. Patients who between 23 May 2020 and 18 July 2020 received ≥ 24 h of favipiravir were assigned to the favipiravir group, while those who did not formed the non-favipiravir group. The primary outcome was 28-day clinical improvement, defined as two-category improvement from baseline on an 8-point ordinal scale. Propensity scores (PS) for favipiravir therapy were used for 1:1 matching. The unmatched cohort included 1493 patients, of which 51.7% were in the favipiravir group, and 48.3% were not receiving supplemental oxygen at baseline. Significant baseline differences between the two unmatched groups existed, but not between the PS-matched groups (N = 774). After PS-matching, there were no significant differences between the two groups in the proportion with 28-day clinical improvement (93.3% versus 92.8%, P 0.780), or 28-day all-cause mortality (2.1% versus 3.1%, P 0.360). Favipiravir was associated with more viral clearance by day 28 (79.8% versus 64.1%, P < 0.001). Adverse events were common in both groups, but the 93.9% were Grades 1-3. Favipiravir therapy for COVID-19 pneumonia is well tolerated but is not associated with an increased likelihood of clinical improvement or reduced all-cause mortality by 28 days.

Clinical characteristics and risk factors for COVID-19-associated Candidemia.

Patients with COVID-19-associated candidemia (CAC) in an intensive care unit (ICU) were matched 1:2 with those without candidemia, based on ICU admission date and length of stay in ICU being at least equal to that before candidemia in the corresponding case. The incidence rate of CAC was 2.34 per 1000 ICU days. Eighty cases could be matched to appropriate controls. In the multivariate conditional logistic regression analysis, age (P 0.001), and sequential organ failure assessment score (P 0.046) were the only risk factors independently associated with CAC. Tocilizumab and corticosteroids therapy were not independently associated with candidemia. LAY SUMMARY: In COVID-19 patients who need medical care in an intensive care unit, the risk of developing bloodstream Candida infection is higher in older patients and in those who have a more severe critical illness. Treatment with steroids or tocilizumab does not seem to affect the risk of candida bloodstream infection in these patients.

Disseminated life threatening Nocardia otitidiscaviarum infection in a young female with newly diagnosed systemic lupus erythematosus, case report and review of literature.

Infection due to Nocardia is reported mainly in immunocompromised patients. It usually presents as a pulmonary or disseminated disease with a predilection for the brain. Infections are a rare etiology of intracranial vascular aneurysms. Herein we report a case of disseminated Nocardia otitidiscaviarum (N. otitidiscaviarum) in a young female newly diagnosed with systemic lupus erythematosus (SLE) complicated by the development of an infectious intracranial aneurysm. To the best of our knowledge this is the fourth case of nocardial infection-related intracranial aneurysm and the second case of N. otitidiscaviarum infection to be reported in a patient with systemic lupus erythematosus. Features of previously reported N. otitidiscaviarum related intracranial aneurysm are reviewed.

Middle East respiratory syndrome coronavirus infection profile in Qatar: An 8-year experience.

The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012. The objective of the study was to describe the epidemiology, risk factors, clinical characteristics, and outcome of MERS-CoV in Qatar. A total of 28 cases of MERS-CoV were identified, corresponding to an incidence of 1.7 per 1,000,000 population. Most patients had a history of contact with camels 15, travel to Kingdom of Saudi Arabia 7 or known contact with individuals with confirmed MERS-CoV infection 7. Majority of patients had acute kidney injury (AKI) 17 and 9 needed renal replacement therapy. All patients were hospitalized, 14 required critical care support. Overall, total of 10 died. The immediate cause of death was multiorgan failure with acute respiratory syndrome (ARDS) 9. MERS-CoV is a rare infection in the State of Qatar. There was no hospital outbreaks or healthcare worker reported infection. The infection causes severe respiratory failure and acute renal failure. Patients with AKI and on ventilator support carry higher risk of mortality.

Genomic Epidemiology of Candida auris in Qatar Reveals Hospital Transmission Dynamics and a South Asian Origin.

Candida auris is an emerging, multidrug-resistant fungal pathogen that has become a public health threat with an increasing incidence of infections worldwide. Candida auris spreads easily among patients within and between hospitals. Infections and outbreaks caused by C. auris have been reported in the Middle East region including Oman, Kuwait, Saudi Arabia, and Qatar; however, the origin of these isolates is largely unknown. Pathogen whole genome sequencing (WGS) was used to determine the epidemiology and drug resistance mutations of C. auris in Qatar. Forty-four samples isolated from patients in three hospitals and the hospital environment were sequenced by Illumina NextSeq. Core genome single nucleotide polymorphisms (SNPs) revealed that all isolates belonged to the South Asian lineage with genetic heterogeneity that suggests previous acquisition from foreign healthcare. The genetic variability among the outbreak isolates in the two hospitals (A and B) was low. Four environmental isolates clustered with the related clinical isolates, and epidemiologically linked isolates clustered together, suggesting that the ongoing transmission of C. auris could be linked to infected/colonized patients and the hospital environment. Prominent mutations Y132F and K143R in ERG11 linked to increased fluconazole resistance were detected.

Bocavirus Infection in a Young Pregnant Woman: A Case Report and Literature Review.

BACKGROUND Human bocavirus (HBoV) is a parvovirus found primarily in children and was first identified in 2005. It usually causes mild upper- and lower-respiratory tract infections. HBoV infection seems to be rare during adulthood, probably due to high antibody titers resulting from childhood infection and seroconversion. The clinical significance, possible complications, and consequences of an adulthood infection are still unclear. Furthermore, the consequences of HBoV infection during pregnancy are seldom reported in the literature. CASE REPORT We report the case of a 22-year-old pregnant woman in her third trimester who presented with a 1-week history of fever and cough followed by progressive shortness of breath. She was treated initially as a case of severe pneumonia; however, her condition deteriorated rapidly, resulting in hypoxic respiratory failure that required intensive care support. The patient was found to have dilated cardiomyopathy on echocardiography, and her fetal ultrasound showed no fetal heart activity; subsequently, labor induction for stillbirth was performed. An extensive workup for an underlying cause was unrevealing apart from positive respiratory viral PCR assay for human bocavirus, performed twice. A provisional diagnosis of HBoV pneumonia complicated by dilated cardiomyopathy, stillbirth, and multiorgan failure was made. Fortunately, the patient had a good recovery and was discharged home in good clinical condition. CONCLUSIONS In addition to severe pneumonia, HBoV infection may result in other life-threatening complications. Although the infection is rare during adulthood, infection in a pregnant woman should be taken seriously and close monitoring of such patients is advised.

A 23-Year-Old Man with SARS-CoV-2 Infection Who Presented with Auditory Hallucinations and Imaging Findings of Cytotoxic Lesions of the Corpus Callosum (CLOCC).

BACKGROUND Cytotoxic lesions of the corpus callosum (CLOCC) is a rare clinical and radiological syndrome that has been associated with various infectious etiologies. CLOCC are among the recently described neurological associations with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with coronavirus disease 2019 (COVID-19). We report a case of CLOCC in a man with SARS-CoV-2 infection who presented with auditory hallucinations and rapidly developed systemic inflammatory response syndrome (SIRS). CASE REPORT A 23-year-old man with no past medical and psychiatric history presented with auditory hallucinations, restlessness, and suicidal ideations. A nasopharyngeal swab specimen tested using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay was positive for SARS-CoV-2. A brain MRI revealed an isolated oval-shaped lesion in the splenium of the corpus callosum, with hyperintense signal on diffusion-weighted imaging (DWI) and hypointense on apparent diffusion coefficient (ADC) maps, suggestive of CLOCC. After a dramatic hospital course associated with multiple organ dysfunction syndrome (MODS) and severe intra-abdominal and cerebral bleeding, he developed cardiac arrest and died on hospital day 15. CONCLUSIONS This case highlights the need for increased vigilance for the atypical manifestations of SARS-CoV-2 infection. In addition, it suggests that CLOCC can be considered as a differential diagnosis by clinicians in patients with SARS-CoV-2 infection who present with unexplained neurological and neuropsychiatric symptoms, leading to poor outcome.

A case report of TB versus idiopathic granulomatous mastitis with erythema nodosum, reactive arthritis, cough, and headache.

Tuberculous mastitis (TBM) is relatively rare disease with an incidence ranging between 0.1 and 4%. Most of the cases are culture negative and often mistaken with chronic benign idiopathic granulomatous mastitis (IGM). It is very crucial to distinguish culture negative TBM from other causes of mastitis as the treatment differs tremendously. We describe here in a young woman originally from India and residing in Qatar; a non endemic area of tuberculosis; for more then fifteen years. She presented with 2 months history of right breast mass, followed by low grade fever, dry cough, headache, erythema nodosum, arthritis, and arthralgia. In view of the origin of the patient, positive family history for tuberculosis and positive quantiferon, the patient was started empirically on anti-tuberculous treatment (ATT). One week later she developed paradoxical reaction to ATT. This case illustrates unusual and rare manifestations of primary TBM and highlights the importance of differentiating and treating culture negative TBM from IGM.

Fatal renal mucormycosis with Apophysomyces elegans in an apparently healthy male.

Mucor is an angioinvasive fungus that was reported mainly in immunocompromised patients. It usually presents as rhino-orbital, pulmonary, gastrointestinal, and disseminated disease. Isolated renal mucormycosis is an extremely rare infection in immunocompetent patients and is associated with high fatality rate. Early diagnosis, prompt antifungal treatment, and surgery give the patient the best chance for cure and survival. We describe herein a case of renal zygomycosis caused by Apophysomyces elegans (A. elegans) in an immunocompetent host. To the best of our knowledge, this is the first case of renal A. elegans to be reported from Qatar and the Middle East.

Incidence and clinical outcome of Cryptococcosis in a nation with advanced HIV surveillance program.

BACKGROUND: Cryptococcosis is a major opportunistic invasive mycosis that mostly affects immunocompromised patients. METHODS: This was an observational study of all culture-confirmed cases of cryptococcosis conducted in the State of Qatar from January 2005 to December 2016. Cryptococcus fungi were identified using Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS). RESULTS: Fourteen culture-confirmed cases of cryptococcosis were identified during the study period. Four patients had a Human Immunodeficiency Virus (HIV) infection with low CD4 count and five were receiving immunosuppressant medications. The rest of the patients were apparently immuno-competent. The central nervous system was the most common site of infection (57%) followed by bloodstream infection (36%) and pneumonia (14%). One patient had a cryptococcal scrotal infection. Twelve isolates were Cryptococcus neoformans and 2 were Cryptococcus laurentii. All isolates were within the wild type ECV values to amphotericin B and fluconazole. Only 2 patients with bloodstream infection (HIV negative) died. The rest were cured of the infection. CONCLUSION: Cryptococcosis is a rare fungal disease in the State of Qatar, mostly diagnosed in Asian immigrants. The central nervous system is the most common site of infection. The presence of the fungus in the blood carries a high mortality.

Epidemiology and clinical outcomes of viral central nervous system infections.

BACKGROUND: Central nervous system (CNS) viral infections are an important cause of morbidity and mortality. No data are available regarding their epidemiology in Qatar. DESIGN: We retrospectively evaluated all cerebrospinal fluid findings from January 2011-March 2015 at Hamad Medical Corporation. Those with abnormal CSF finding were included in our study. We excluded those with missing medical records, no clinical evidence of viral CNS infection, or proven bacterial, fungal or tuberculosis CNS infection. CNS clinical findings were classified as meningitis, encephalitis or myelitis. RESULTS: Among 7690 patients with available CSF results, 550 cases met the inclusion criteria (meningitis 74.7%; encephalitis 25%; myelitis 0.4%). Two-thirds (65%) were male and 50% were between 16-60 years old. Viral etiology was confirmed in 38% (enterovirus, 44.3%; Epstein-Barr virus, 31%; varicella zoster virus, 12.4%). The estimated incidence was 6.4 per 100,000 population. Two persons died and the rest were discharged to home. Among those with confirmed viral etiology, 83.8% received ceftriaxone (mean duration 7.3±5.2 days), 38% received vancomycin (mean duration 2.7±5.4 days) and 38% received at least one other antibiotic. Intravenous acyclovir was continued for more than 48h in patients with confirmed negative viral etiology (mean duration 5±5.6 days). CONCLUSION: Viral etiology is not uncommon among those evaluated for CNS infection in Qatar. Clinical outcomes are excellent in this group of patients. Antibiotics and acyclovir are overly used even when a viral etiology is confirmed. There is a need for clinician education regarding etiology and treatment of viral CNS infections.

Viral infections of the central nervous system in Qatar: epidemiology, pathogenesis and clinical outcomes.

INTRODUCTION: Virus-induced diseases of the central nervous system (CNS) represent a significant burden to human health worldwide. They are common causes of morbidities and mortality. There are no previous epidiomologic studies about viral CNS infections done in Qatar or in the Gulf region. We conducted this study to determine the etiology, clinical and epidimiological characteristics, and outcome of viral central nerveous system infection in patients across a larger national healthcare system. METHODOLOGY: We retrospectively evaluated all cerebrospinal fluid findings from January 2011 - March 2015 at any of the 7 hospitals in the Hamad Medical Corporation healthcare system. We included those with an abnormal CSF finding in our study. We excluded those with missing medical records, those with no clinical evidence of CNS infection or proven bacterial CNS infection. Based on pre-defined clinical and CSF (lab, culture, PCR) criteria, persons with abnormal CSF and CNS clinical findings were classified as having meningitis, meningoencephalitis, encephalitis or myelitis. We reviewed the laboratory results to determine the proportion of persons with confirmed viral etiology. RESULTS: Among 7690 patients with available CSF results, 550 cases met the case definition criteria for viral CNS infection (meningitis 75%; meningoencephalitis 16%; encephalitis 9%; myelitis 0.4%). Two-thirds (65%) were male and 50% were between 16-60 years old. Persons from Southeast Asia (India, Pakistan, Bangladesh, Nepal, and Sri Lanka) accounted for 39.6 of all infections.  A definitive virologic etiologic agent was found in 38%, among whom enterovirus was the most common (44.3%) followed by Epstein-Barr virus (31%) and varicella zoster virus (12.4%). The clinical outcome was overall good, only 2 cases died and the rest discharged to home. Ninety-eight per cent were admitted to medical ward (mean stay 7.8±6.4 days) and 2 % to an intensive care unit. (mean stay 2.7±5.4 days). Among those with confirmed viral etiology, 83.8% received ceftriaxone, 38% received vancomycin and 38% received at least one other antibiotic. CONCLUSION: Viral etiology is not uncommon among those evaluated for CNS infection in Qatar, and is most commonly seen in Southeast Asian immigrants. Clinical outcomes are generally excellent in this group of patients. Antibiotics are overly used even when a viral etiology is confirmed. There is a need for clinician education regarding etiology and treatment of CNS infections.

Delayed Pacemaker Generator Pocket and Lead Primary Infection Due to Burkholderia Cepacia.

BACKGROUND Recently, the use of cardiac implantable electrophysiological devices (CIEDs) has increased. Advances in medical technology, an increasingly aging population, increases in clinical indications, and expanded medical insurance coverage for these devices have all contributed to this trend. Infection is considered to be one of the most serious complications of CIEDs and carries a significant risk of morbidity and mortality. Although infection with Staphylococcus sp. accounts for the majority of cases, other bacteria have been implicated as causative agents of infection of CIEDs. CASE REPORT We report the first case of primary pacemaker generator pocket and lead infection due to Burkholderia cepacia (B. cepacia) in the state of Qatar. To our knowledge, there have been few cases of CIED infection due to B. cepacia previously reported in the literature. CONCLUSIONS This case raises awareness of B. cepacia as a potential opportunistic pathogen in CIED infection. The more rare bacteria require culture on special media to provide an early diagnosis to enable proper antimicrobial therapy to commence. Adherence to infection control standards during CIED insertion would reduce infection from B. cepacia.

Primary Pituitary Tuberculosis Revisited.

BACKGROUND Primary pituitary tuberculosis (in absence of other organ involvement and constitutional symptoms) is an extremely rare disease with total reported cases in the literature fewer than a hundred. Misdiagnosis as pituitary adenoma is common and late diagnosis can result in a permanent endocrine dysfunction and/or long-term neurologic sequelae. CASE REPORT We report on the case of a middle-aged woman who presented with severe headache and left third cranial nerve palsy. Magnetic resonance imaging (MRI) revealed a large pituitary tumor invading the left cavernous sinus. The case was initially misdiagnosed as pituitary adenoma. A pituitary biopsy was performed and was suggestive of pituitary tuberculosis. Extensive radiologic investigations did not reveal any evidence of other organ involvement by tuberculosis. She was successfully treated with anti-tuberculous medications. CONCLUSIONS In areas with a high pre-test probability of tuberculosis, pituitary tuberculosis should be included in the differential diagnosis of pituitary tumors in order to avoid unnecessary surgical interventions. Besides being the first histologically-proven primary pituitary tuberculosis case reported from Qatar, the current case is unique in that extensive radiologic investigations did not reveal any evidence of other systemic or pulmonary tuberculosis.