Mixed Aspergillosis and Mucormycosis Infections in Patients with COVID-19: Case Series and Literature Review.

BACKGROUND: Mucormycosis and aspergillosis are angioinvasive infections mainly occurring in immunocompromised patients. However, mixed infection with mucormycosis and aspergillosis in post-COVID-19 patients is rare. In this report, we will report four cases and comprehensively review the published literature on COVID-19 associated mixed infection of aspergillosis and mucormycosis. METHOD: Besides four of our cases, we searched for published articles using PubMed/MEDLINE, Scopus, and Web of Science databases from the beginning of 2020 until October 2023. RESULT: During the COVID-19 pandemic, we analyzed 52 cases (4 from our research and 48 from other studies). The most common underlying disease (59.6%) was diabetes mellitus. However, 19.2% of COVID-19 patients had no underlying condition. Interestingly, rhino-orbital-cerebral mucormycosis featured prominently in India and Iran, while other countries primarily reported a higher prevalence of pulmonary cases. CONCLUSION: In conclusion, this study highlights the presence of mixed aspergillosis and mucormycosis in COVID-19 patients who previously had common underlying diseases or even a healthy immune system. Therefore, managing COVID-19 patients should involve screening serum and respiratory samples using biomarkers to detect superinfections.

Comparing efficacy and safety of high-dose and standard-dose rifampicin in the treatment of brucellosis: a randomized clinical trial.

BACKGROUND: In a few studies, higher doses of rifampicin improved the outcome of patients with TB. There is no information regarding efficacy and safety of higher doses of rifampicin in patients with brucellosis. OBJECTIVES: To compare efficacy and safety of higher and standard doses of rifampicin, each with doxycycline, in the treatment of patients with brucellosis. METHODS: Within a randomized clinical trial, clinical response and adverse events of high-dose rifampicin (900-1200 mg/day) plus doxycycline 100 mg twice daily were compared with standard-dose rifampicin (600 mg/day) plus doxycycline 100 mg twice daily in 120 patients with brucellosis. RESULTS: Clinical response occurred in 57 (95%) of patients in the high-dose group and 49 (81.66%) of patients in the standard-dose group (P = 0.04). The most common adverse events of the treatment were nausea (37.5%), skin rash (13.33%), vomiting (10%) and transaminitis (7.22%). Incidence of these events was comparable between the groups. CONCLUSIONS: The rate of clinical response in patients with brucellosis who were treated with high-dose rifampicin plus standard-dose doxycycline was significantly higher than in the patients who received the standard doses of rifampicin and doxycycline, without further adverse events. The high-dose rifampicin therefore improved clinical response in patients with brucellosis with a similar safety profile to the standard dose. If these findings are confirmed in future studies, higher doses of rifampicin may be recommended for treatment of patients with brucellosis.

In Vitro antibiotic combinations of Colistin, Meropenem, Amikacin, and Amoxicillin/clavulanate against multidrug-resistant Klebsiella pneumonia isolated from patients with ventilator-associated pneumonia.

BACKGROUND: Hospital infections such as ventilator-associated pneumonia (VAP) due to multidrug-resistant Klebsiella pneumoniae (MDR-KP) strains have increased worldwide. In addition, biofilm production by these resistant isolates has confronted clinicians with higher treatment failure and infection recurrence. Given the paucity of new agents and limited data on combination therapy for MDR-KPs, the present study sought to evaluate the in vitro activity of several antibiotic combinations against planktonic and biofilm MDR-KPs isolated from patients with VAP. RESULTS: All 10 carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates demonstrated multidrug resistance against the tested antibiotics. At planktonic mode, combinations of colistin-meropenem and amoxicillin/clavulanate in combination with meropenem, colistin, or amikacin showed synergism against 60-70% isolates. On the other hand, in the biofilm state, colistin-based combinations exhibited synergism against 50-70% isolates and the most effective combination was colistin-amikacin with 70% synergy. CONCLUSIONS: The results revealed that combinations of amoxicillin/clavulanate with colistin, meropenem, or amikacin in the planktonic mode and colistin with amoxicillin/clavulanate, meropenem, or amikacin in the biofilm mode could effectively inhibit CRKP isolates, and thus could be further explored for the treatment of CRKPs.

Occurrence of Acinetobacter baumannii genomic resistance islands (AbGRIs) in Acinetobacter baumannii strains belonging to global clone 2 obtained from COVID-19 patients.

AIM: The Acinetobacter baumannii genomic resistance islands (AbGRIs), which were characterized in the genome of the global clone 2 (GC2) A. baumannii contain resistance genes. Here, we aimed to determine the occurrence of AbGRIs in GC2 A. baumannii obtained from COVID-19 patients in a referral hospital in Tehran, Iran. METHODS: A total of 19 carbapenem-resistant A. baumannii (CRAB) isolates belonging to GC2 and sequence type 2 (ST2), including 17 from COVID-19 patients and two from the devices used in the ICU that the COVID-19 patients were admitted, were examined in this study. Antibiotic susceptibility testing was performed by the disk diffusion method. PCR and PCR mapping, followed by sequencing, were performed to characterize the structure of AbGRI resistance islands in the isolates tested. RESULTS: The AbGRI3 was the most frequent resistance island (RI) detected, present in all the 19 isolates, followed by AbGRI1 (15 isolates; 78.9%) and AbGRI2 (three isolates; 15.8%). Notably, AbGRIs were identified in one of the A. baumannii strains, which was isolated from a medical device used in the ICU where COVID-19 patients were admitted. Furthermore, new structures of AbGRI1 and AbGRI3 resistance islands were found in this study, which was the first report of these structures. CONCLUSIONS: The present study provided evidence for the circulation of the GC2 A. baumannii strains harboring AbGRI resistance islands in a referral hospital in Tehran, Iran. It was found that resistance to several classes of antibiotics in the isolates collected from COVID-19 patients is associated with the resistance genes located within AbGRIs.

Parametric amplification and instability in time-periodic dielectric slabs.

We study the phenomenon of parametric amplification in the context of time-periodic dielectric slabs. These structures show particular promise inasmuch as they are capable of very large amplifications when illuminated by an electromagnetic wave of half the modulation frequency. Successive studies have corroborated this finding but none have yet been able to ascertain the nature of amplification in such devices. On top of that, some studies have raised speculations regarding the instability of a time-periodic slab which are off the mark. The problem lies in the poor understanding (or lack thereof) of the mathematical devices necessary to tackle such problems. We successfully carry out the tasks by tapping into the rich mathematical theory of Hill's equation. Specifically, we make use of the Folquet's theorem in its complete form which brings to light novel physical phenomena that the more prevalent simplified form fails to account for. Also, useful mathematical concepts such as coexistence are employed which to the best of our knowledge have not yet been applied in the field of time-varying optics. Our analytical method proves an effective means of assessing the amplifier's performance, e.g., estimating how long it takes for the device to reach steady state. We further delineate the link between amplification and instability and correct the misconceptions surrounding the subject by presenting a rigorous analysis of the instability problem in such structures.

Clinical epidemiology of pulmonary aspergillosis in hospitalized patients and contribution of Cyp51A, Yap1, and Cdr1B mutations to voriconazole resistance in etiologic Aspergillus species.

Pulmonary aspergillosis is a life-threatening fungal infection with worldwide distribution. In the present study, clinical epidemiology of pulmonary aspergillosis and antifungal susceptibility of etiologic Aspergillus species were evaluated in one-hundred fifty patients with special focus on the frequency of voriconazole resistance. All the cases were confirmed by the clinical pictures, laboratory findings, and isolation of etiologic Aspergillus species which belonged to two major species, i.e., A. flavus and A. fumigatus. Seventeen isolates displayed voriconazole MIC greater than or equal to the epidemiological cutoff value. Expression of cyp51A, Cdr1B, and Yap1 genes was analyzed in voriconazole-intermediate/resistant isolates. In A. flavus, Cyp51A protein sequencing showed the substitutions T335A and D282E. In the Yap1 gene, A78C replacement led to Q26H amino acid substitution that was not reported previously in A. flavus resistant to voriconazole. No mutations associated with voriconazole resistance were found in the three genes of A. fumigatus. The expression of Yap1 was higher than that of two other genes in both A. flavus and A. fumigatus. Overall, voriconazole-resistant strains of both A. fumigatus and A. flavus demonstrated overexpression of Cdr1B, Cyp51A, and Yap1 genes compared to voriconazole-susceptible strains. Although there are still ambiguous points about the mechanisms of azole resistance, our results showed that mutations were not present in majority of resistant and intermediate isolates, while all of these isolates showed overexpression in all three genes studied. As a conclusion, it seems that the main reason of the emergence of mutation in voriconazole-resistant isolates of A. flavus and A. fumigatus is previous or prolonged exposure to azoles.

Percentage of Th1 and Th17 cells and serum level of IL-17 and IFN-γ cytokines in COVID-19-associated mucormycosis.

The considerable number of the 2019 coronavirus disease (COVID-19) patients who developed mucormycosis infections in West and Central Asia urged a need to investigate the underlying causes of this fatal complication. It was hypothesized that an immunocompromised state secondary to the excessive administration of anti-inflammatory drugs was responsible for the outburst of mucormycosis in COVID-19 patients. Therefore, we aimed to study the implication of two major subsets of adaptive immunity T helper (Th)-1 and Th17 cells in disease development. Thirty patients with COVID-19-associated mucormycosis, 38 with COVID-19 without any sign or symptom of mucormycosis, and 26 healthy individuals were included. The percentage of Th1 and Th17 cells in peripheral blood, as well as the serum levels of interleukin (IL)-17 and interferon-gamma (IFN-γ), were evaluated using flow cytometry and ELISA techniques, respectively. Th17 cell percentage in patients with COVID-19-associated mucormycosis was significantly lower than in COVID-19 patients (P-value: <0.001) and healthy subjects (P-value: 0.01). In addition, the serum level of IL-17 in COVID-19 patients was significantly higher than that of healthy individuals (P-value: 0.01). However, neither the frequency of Th1 cells nor the serum level of IFN-γ was different between the study groups. Given the critical role of Th17 cells in the defense against mucosal fungal infections, these findings suggest that low numbers of Th17 and insufficient levels of IL-17 might be a predisposing factor for the development of mucormycosis during or after COVID-19 infection.

Considering the critical role of Th17 cells in defense against mucosal fungal infections, the low numbers of Th17 and insufficient amounts of IL-17 might be a predisposing factor to develop mucormycosis during or after COVID-19 infection.

Characteristics and outcomes of COVID-19 patients during the BA.5 omicron wave in Tehran, Iran: a prospective observational study.

BACKGROUND: Omicron (B.1.1.529) is the fifth variant of concern of SARS-CoV-2, which has several subvariants. Clinical features of BA.1 and BA.2 infections have been described in the literature, but we have limited information about the clinical profile of BA.5, which caused the seventh wave in Iran. METHODS: A prospective observational study was conducted on the BA.5 confirmed patients referred to Imam Khomeini Hospital Complex, Tehran, Iran, from 11th to 31st August 2022. The patients were divided into the two groups of outpatients and hospitalized patients, and their clinical, radiological, and laboratory data and outcomes were recorded and analyzed. RESULTS: We included 193 patients with confirmed BA.5 infection, of whom 48 patients (24·8%) were hospitalized. The mean age of the patients was 45·3 ± 16·5 years, and 113 patients (58·5%) were female. The mean number of days patients had symptoms was 6·8 ± 2·4 days. The most common symptoms were weakness (69·9%), sore throat (67·4%), myalgia (66·3%), hoarseness (63·7%), headache (55·4%), fatigue (54·9%), and dry cough (50·3%). Fever and dyspnea were significantly more observed in the hospitalized patients (p < 0·0001). The COVID-19 vaccination rate was significantly lower in hospitalized patients than in outpatients (35/48-72·9% vs. 140/145 - 96·6%, p < 0·0001). The most common underlying diseases were hypertension (16·1%), diabetes mellitus (9·8%), and cardiovascular diseases (9·8%), all of which were significantly more common in hospitalized patients. Lung opacities were observed in 81·2% of hospitalized patients. By the end of our study, 1·5% of patients died despite receiving critical care services. CONCLUSIONS: Our findings suggested that BA.5 symptoms are more non-respiratory and usually improve within 7 days. Although the proportion of hospitalized patients is still significant, very few patients require intensive care. COVID-19 vaccination is effective in reducing the hospitalization rate. TRIAL REGISTRATION: Not applicable. This study is not a clinical trial.

COVID-19 Associated Rhino-Orbital-Cerebral Mucormycosis: Clinical Features, Antifungal Susceptibility, Management and Outcome in a Tertiary Hospital in Iran.

BACKGROUND: Despite the unprecedented surge in the incidence of mucormycosis in the COVID-19 era, the antifungal susceptibility patterns (ASPs) of COVID-19 associated mucormycosis (CAM) isolates have not been investigated so far and it is unclear if the high mortality rate associated with CAM is driven by decreased susceptibility of Mucorales to antifungal drugs. OBJECTIVES: To describe the clinical, mycological, outcome and in vitro ASPs of CAM cases and their etiologies from Iran. PATIENTS/METHODS: A prospective study from January 2020 to January 2022 at a referral tertiary hospital in Tehran, Iran was conducted for screening mucormycosis through histopathology and mycological methods. The identity of Mucorales isolates was revealed with ITS-panfungal PCR& sequencing and MALDI-TOF. The AS for amphotericin B, itraconazole, isavuconazole and posaconazole was cleared according to the EUCAST antifungal susceptibility testing protocol. RESULT: A total of 150 individuals were diagnosed with CAM. Males constituted 60.7% of the population. The mean age was 54.9 years. Diabetes was the leading risk factor (74.7%). The median interval between diagnosis of COVID-19 and CAM was 31 days. The recovery rate of culture was as low as 41.3% with Rhizopus arrhizus being identified as the dominant (60; 96.7%) agent. Amphotericin B (MIC50 = 0.5 µg/ml) demonstrated the highest potency against Mucorales. CONCLUSION: Majority of the cases had either diabetes, history of corticosteroid therapy or simultaneously both conditions. Accordingly, close monitoring of blood glucose should be considered. The indications for corticosteroids therapy are recommended to be optimized. Also, an anti Mucorales prophylaxis may be necessitated to be administrated in high risk individuals. Although amphotericin B was the most active agent, a higher rate of resistance to this antifungal was noted here in comparison with earlier studies on mucormycetes from non-CAM cases.

Evaluation of the effect of sofosbuvir and daclatasvir in hospitalized COVID-19 patients: a randomized double-blind clinical trial (DISCOVER).

BACKGROUND: The combination of sofosbuvir and daclatasvir has shown preliminary efficacy for hospitalized patients with COVID-19 in four open-label studies with small sample sizes. This larger trial aimed to assess if the addition of sofosbuvir/daclatasvir to standard care improved clinical outcomes in hospitalized patients with COVID-19. METHODS: This was a placebo-controlled, double-blind, randomized clinical trial in adults hospitalized with COVID-19 at 19 hospitals in Iran. Patients were randomized to oral sofosbuvir/daclatasvir 400/60 mg once-daily or placebo in addition to standard of care. Patients were included if they had positive PCR or diagnostic chest CT, O2 saturation <95% and compatible symptoms. The primary outcome was hospital discharge within 10 days of randomization. Secondary outcomes included mortality and time to clinical events. The trial is registered on the Iran Registry of Clinical Trials under IRCT20200624047908N1. RESULTS: Between July and October 2020, 1083 patients were randomized to either the sofosbuvir/daclatasvir arm (n = 541) or the placebo arm (n = 542). No significant difference was observed in the primary outcome of hospital discharge within 10 days, which was achieved by 415/541 (77%) in the sofosbuvir/daclatasvir arm and 411/542 (76%) in the placebo arm [risk ratio (RR) 1.01, 95% CI 0.95-1.08, P = 0.734]. In-hospital mortality was 60/541 (11%) in the sofosbuvir/daclatasvir arm versus 55/542 (10%) in the placebo arm (RR 1.09, 95% CI 0.77-1.54, P = 0.615). No differences were observed in time to hospital discharge or time to in-hospital mortality. CONCLUSIONS: We observed no significant effect of sofosbuvir/daclatasvir versus placebo on hospital discharge or survival in hospitalized COVID-19 patients.

Frequency conversion in time-varying graphene microribbon arrays.

We investigate the possibility of frequency conversion in time-varying metasurfaces, composed of graphene microribbon arrays (GMRAs) with time-periodic modulation of their conductivity. We present a quasi-static model for the interaction of light with a temporally modulated metasurface, as well as an accurate analytical treatment of the problem of time-varying GMRAs. Results coming from numerical simulations are also available. We provide corrections to a previous related proposal for frequency conversion and refute the possibility of attaining frequency shifts not equal to an integral multiple of modulation frequency. Contrary to the preceding results, our findings show that efficient frequency conversion demands more requisites than single-layer GMRAs can supply and that its requirements can be addressed successfully by a multi-layer design.

Antibiotic use during the first 6 months of COVID-19 pandemic in Iran: A large-scale multi-centre study.

WHAT IS KNOWN AND OBJECTIVE: Although antibiotics are ineffective against viral infections, epidemiological studies have revealed that the COVID-19 pandemic resulted in the overuse of antibiotics and disruption of antimicrobial stewardship programmes. We investigated the pattern of antibiotic use during the first 6 months of the COVID-19 pandemic in Iran. METHODS: A multi-centre retrospective study was designed to investigate the use of 16 broad-spectrum antibiotics in 12 medical centres. The rate of antibiotic use was calculated and reported based on the Defined Daily Dose (DDD) per 100 hospital bed-days. The bacterial co-infection rate was also reported. RESULTS AND DISCUSSION: Totally, 43,791 hospitalized COVID-19 patients were recruited in this study. It was found that 121.6 DDD of antibiotics were used per 100 hospital bed-days, which estimated that each patient received approximately 1.21 DDDs of antibiotics every day. However, the bacterial co-infections were detected only in 14.4% of the cases. A direct correlation was observed between the rate of antibiotic use and mortality (r[142] = 0.237, p = 0.004). The rate of antibiotic consumption was not significantly different between the ICU and non-ICU settings (p = 0.15). WHAT IS NEW AND CONCLUSION: In this study, widespread antibiotic use was detected in the absence of the confirmed bacterial coinfection in COVID-19 patients. This over-consumption of broad-spectrum antibiotics may be associated with increased mortality in hospitalized COVID-19 patients, which can be an alarming finding.

Inflawell® improves neutrophil-to-lymphocyte ratio and shortens hospitalization in patients with moderate COVID-19, in a randomized double-blind placebo-controlled clinical trial.

AIMS: COVID-19 is a significant global threat to public health. Despite the availability of vaccines and anti-viral drugs, there is an urgent need for alternative treatments to help prevent and/or manage COVID-19 symptoms and the underlying dysregulated immune response. We hypothesized that administration of Inflawell® syrup, a Boswellia extract formulation enriched for boswellic acids (BAs), can reduce the excessive or persistent inflammation and thereby prevent disease progression. BAs are medicinally activated triterpenoids found in the resins of Boswellia spp., and possess an immense therapeutic potential due to their anti-inflammatory and immunoregulatory activities. We investigated the effect of Inflawell® syrup, on moderate COVID-19 patients along with the current standard of care treatment. METHODS: A randomized placebo-controlled double-blind clinical trial was conducted, following definitive confirmation of COVID-19. Forty-seven hospitalized patients with moderate COVID-19 were enrolled and received either the Inflawell® syrup or placebo. Clinical symptoms and markers of inflammation were evaluated at baseline and completion of the trial. RESULTS: Our clinical trial revealed an increase in the percentage of oxygen saturation level in patients that received the BAs compared to placebo (P < 0.0001). In addition, the average duration of hospitalization was significantly shorter in the BAs group compared with the placebo group (P < 0.04). Concomitantly, some improvement in the clinical symptoms including cough, dyspnea, myalgia, headache, and olfactory and gustatory dysfunction were detected in the BAs group. Hematologic findings showed a significant decrease in the percentage of neutrophils (P < 0.006) and neutrophil-to-lymphocyte ratio (NLR) levels (P < 0.003), associated with a significant increase in the percentage of lymphocytes in the BAs group compared with the placebo (P < 0.002). Additionally, a significant decrease in CRP, LDH, IL - 6 and TNF - α levels was detected in the BAs group. Following the intervention, fewer patients in the BAs group were PCR-positive for COVID-19 compared to placebo, though not statistically significant. CONCLUSION: Overall, the treatment with Inflawell® resulted in shorter hospital stay, alleviation of COVID-19 clinical symptoms and decline in the level of pro-inflammatory cytokines. TRIAL REGISTRATION: The trial has been registered in  https://www.irct.ir  with unique identifier: IRCT20170315033086N10 ( https://en.irct.ir/trial/51631 ). IRCT is a primary registry in the WHO registry network ( https://www.who.int/clinical-trials-registry-platform/network/primary-registries ).

The relationship between biofilm formation and mortality in patients with Candida tropicalis candidemia.

BACKGROUND: Biofilm formation by Candida species is an influential virulence factor in candidemia pathogenesis. We investigated the relationship between biofilm formation of Candida tropicalis isolates with the clinical characteristics and mortality outcomes in patients with candidemia. MATERIALS AND METHODS: Thirty-nine C. tropicalis isolates were recovered from patients with candidemia admitted to two university hospitals in Tehran, Iran. Biofilm mass and metabolic activity of C. tropicalis biofilms were assessed in vitro with two colorimetric methods. The sessile minimum inhibitory concentrations (SMICs) were evaluated in vitro by treating preformed biofilms with diluted concentrations of azoles according to CLSI-M27 A3/S4 protocol, followed by metabolic activity quantification. The expressions of ERG11, UPC2, MDR1, and CDR1 genes were also evaluated. RESULTS: All C. tropicalis isolates produced biofilm. Respectively, higher <7-day and ≥7-day mortality rates were found among cases with high metabolic activity (46.7% vs. 13%, P = 0.03) and high biofilm mass (31.8% vs. 0, P = 0.029). Sessile cells had high resistance to fluconazole, voriconazole, and itraconazole. The azole minimum inhibitory concentrations (MICs) of C. tropicalis sessile were significantly greater than the planktonic minimum inhibitory concentrations (PMICs). In fluconazole-treated biofilms, the expression of ERG11 and UPC2 genes was increased. CONCLUSION: Our findings highlight the importance of C. tropicalis biofilm formation as an important factor in candidemia pathogenesis and the clinical outcome of patients with candidemia.

Predictors of the chest CT score in COVID-19 patients: a cross-sectional study.

BACKGROUND: Since the COVID-19 outbreak, pulmonary involvement was one of the most significant concerns in assessing patients. In the current study, we evaluated patient's signs, symptoms, and laboratory data on the first visit to predict the severity of pulmonary involvement and their outcome regarding their initial findings. METHODS: All referred patients to the COVID-19 clinic of a tertiary referral university hospital were evaluated from April to August 2020. Four hundred seventy-eight COVID-19 patients with positive real-time reverse-transcriptase-polymerase chain reaction (RT-PCR) or highly suggestive symptoms with computed tomography (CT) imaging results with typical findings of COVID-19 were enrolled in the study. The clinical features, initial laboratory, CT findings, and short-term outcomes (ICU admission, mortality, length of hospitalization, and recovery time) were recorded. In addition, the severity of pulmonary involvement was assessed using a semi-quantitative scoring system (0-25). RESULTS: Among 478 participants in this study, 353 (73.6%) were admitted to the hospital, and 42 (8.7%) patients were admitted to the ICU. Myalgia (60.4%), fever (59.4%), and dyspnea (57.9%) were the most common symptoms of participants at the first visit. A review of chest CT scans showed that Ground Glass Opacity (GGO) (58.5%) and consolidation (20.7%) were the most patterns of lung lesions. Among initial clinical and laboratory findings, anosmia (P = 0.01), respiratory rate (RR) with a cut point of 25 (P = 0.001), C-reactive protein (CRP) with a cut point of 90 (P = 0.002), white Blood Cell (WBC) with a cut point of 10,000 (P = 0.009), and SpO2 with a cut point of 93 (P = 0.04) was associated with higher chest CT score. Lung involvement and consolidation lesions on chest CT scans were also associated with a more extended hospitalization and recovery period. CONCLUSIONS: Initial assessment of COVID-19 patients, including symptoms, vital signs, and routine laboratory tests, can predict the severity of lung involvement and unfavorable outcomes.

Co-infection of ST2IP carbapenem-resistant Acinetobacter baumannii with SARS-CoV-2 in the patients admitted to a Tehran tertiary referral hospital.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) is among the most concerning cause of healthcare-associated infections (HAI) due to its high level of antibiotic resistance and high mortality. In the era of the COVID-19 pandemic, the key priority of infection control committees is to contain the dissemination of antibiotic resistant Gram-negative bacteria. Here, we aimed to timely recognize the emergence of CRAB in COVID-19 cases admitted to the wards of a tertiary referral hospital and to identify the genetic relatedness of the isolates. METHODS: From 30 March to 30 May 2020, a total of 242 clinical samples from COVID-19 cases were screened for CRAB isolates using standard microbiologic and antibiotic susceptibility tests. The PCRs targeting oxa23, oxa24, oxa58, blaTEM and blaNDM-1 genes were performed. Two multiplex PCRs for identifying the global clones (GC) of A. baumannii were also performed. The sequence type of CRABs was determined using Institut Pasteur (IP) multilocus sequence typing (MLST) scheme. RESULTS: Eighteen CRAB isolates were recovered from COVID-19 patients with the mean age of 63.94 ± 13.8 years. All but 4 COVID-19 patients co-infected with CRAB were suffering from an underlying disease. Death was recorded as the outcome in ICUs for 9 (50%) COVID-19 patients co-infected with CRAB. The CRAB isolates belong to GC2 and ST2IP and carried the oxa23 carbapenem resistance gene. CONCLUSION: This study demonstrated the co-infection of CRAB isolates and SARS-CoV-2 in the patients admitted to different ICUs at a referral hospital in Tehran. The CRAB isolates were found to belong to ST2IP, share the oxa23 gene and to have caused several outbreaks in the wards admitting COVID-19 patients.

Mucormycosis in patients with COVID-19: A cross-sectional descriptive multicentre study from Iran.

PURPOSE: The aim of the study was to report clinical features, contributing factors and outcome of patients with coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM). METHODS: A cross-sectional descriptive multicentre study was conducted on patients with biopsy-proven mucormycosis with RT-PCR-confirmed COVID-19 from April to September 2020. Demographics, the time interval between COVID-19 and mucormycosis, underlying systemic diseases, clinical features, course of disease and outcomes were collected and analysed. RESULTS: Fifteen patients with COVID-19 and rhino-orbital mucormycosis were observed. The median age of patients was 52 years (range 14-71), and 66% were male. The median interval time between COVID-19 disease and diagnosis of mucormycosis was seven (range: 1-37) days. Among all, 13 patients (86%) had diabetes mellitus, while 7 (46.6%) previously received intravenous corticosteroid therapy. Five patients (33%) underwent orbital exenteration, while seven (47%) patients died from mucormycosis. Six patients (40%) received combined antifungal therapy and none that received combined antifungal therapy died. CONCLUSION: Clinicians should be aware that mucormycosis may be complication of COVID-19 in high-risk patients. Poor control of diabetes mellitus is an important predisposing factor for CAM. Systematic surveillance for control of diabetes mellitus and educating physician about the early diagnosis of CAM are suggested.

The double-edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis.

Acute respiratory distress syndrome is a common complication of severe viral pneumonia, such as influenza and COVID-19, that requires critical care including ventilatory support, use of corticosteroids and other adjunctive therapies to arrest the attendant massive airways inflammation. Although recommended for the treatment of viral pneumonia, steroid therapy appears to be a double-edged sword, predisposing patients to secondary bacterial and invasive fungal infections (IFIs) whereby impacting morbidity and mortality. Mucormycosis is a fungal emergency with a highly aggressive tendency for contiguous spread, associated with a poor prognosis if not promptly diagnosed and managed. Classically, uncontrolled diabetes mellitus (DM) and other immunosuppressive conditions including corticosteroid therapy are known risk factors for mucormycosis. Upon the background lung pathology, immune dysfunction and corticosteroid therapy, patients with severe viral pneumonia are likely to develop IFIs like aspergillosis and mucormycosis. Notably, the combination of steroid therapy and DM can augment immunosuppression and hyperglycaemia, increasing the risk of mucormycosis in a susceptible individual. Here, we report a case of sinonasal mucormycosis in a 44-year-old woman with hyperglycaemia secondary to poorly controlled diabetes following dexamethasone therapy on a background of influenza pneumonia and review 15 available literatures on reported cases of influenza and COVID-19 associated mucormycosis.

Proven Aspergillus flavus pulmonary aspergillosis in a COVID-19 patient: A case report and review of the literature.

Severe COVID-19 patients complicated with aspergillosis are increasingly reported. We present a histopathological proven case of fatal COVID-19-associated pulmonary aspergillosis (CAPA), due to Aspergillus flavus. This report and existing published literature indicate diagnostic challenges and poor outcomes of CAPA in ICU patients.

Virulence Factors and Azole-Resistant Mechanism of Candida Tropicalis Isolated from Candidemia.

BACKGROUND: Limited knowledge exists on the virulence factors of Candida tropicalis and the mechanisms of azole resistance that lead to an intensified pathogenicity and treatment failure. We aimed to evaluate the virulence factors and molecular mechanisms of azole resistance among C. tropicalis isolated from patients with candidemia. MATERIALS AND METHODS: Several virulence factors, including extracellular enzymatic activities, cell surface hydrophobicity (CSH), and biofilm formation, were evaluated. Antifungal susceptibility pattern and expression level of ERG11, UPC2, MDR1, and CDR1 genes of eight (4 fluconazole resistance and 4 fluconazole susceptible) clinical C. tropicalis isolates were assessed. The correlation between the virulence factors and antifungal susceptibility patterns was analyzed. RESULTS: During a 4 year study, forty-five C. tropicalis isolates were recovered from candidemia patients. The isolates expressed different frequencies of virulence determinants as follows: coagulase 4 (8.9%), phospholipase 5 (11.1%), proteinase 31 (68.9%), esterase 43 (95.6%), hemolysin 44 (97.8%), biofilm formation 45 (100%) and CSH 45(100%). All the isolates were susceptible to amphotericin B and showed the highest resistance to voriconazole. There was a significant positive correlation between micafungin minimum inhibitory concentrations (MICs) and hemolysin production (rs = 0.316). However, we found a negative correlation between fluconazole MICs and esterase production (rs = -0.383). We observed the high expression of ERG11 and UPC2 genes in fluconazole-resistant C. tropicalis isolates. CONCLUSION: C. tropicalis isolated from candidemia patients extensively displayed capacities for biofilm formation, hemolysis, esterase activity, and hydrophobicity. In addition, the overexpression of ERG11 and UPC2 genes was considered one of the possible mechanisms of azole resistance.