Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study ...aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment.
Rationale: Pneumocystis jiroveci polymerase chain reaction (PCR) has higher sensitivity than conventional stains but cannot distinguish colonization from
infection.
Methods: We compared P jiroveci ...PCR and conventional stains in HIV-uninfected immunocompromised patients.
Results: Among the 448 patients, 296 (66%) patients had hematologic malignancies; 72 (16.1%), bone marrow transplants; 44 (9.8%),
solid tumors; 21 (4.7%), renal transplants; and 15 (3.4%) were taking immunosuppressants for systemic diseases. Diagnostic
strategy consisted of BAL in 351 patients and induced sputum (IS) in 97 patients. Conventional pneumocystic pneumonia (PCP)
stain was positive in 39 (8.7%) patients, including 34 with positive PCR. In addition, PCR was positive in 32 patients, including
21 with complete follow-up, of whom 14 were diagnosed with probable or definitive PCP (a 36% increase). PCR was 87.2% sensitive
and 92.2% specific; positive and negative predictive values were 51.5% and 98.7%, respectively. Sensitivity and negative predictive
value were 100% on IS.
Conclusions: In HIV-uninfected immunocompromised patients with acute pulmonary infiltrates, P jiroveci PCR correlates with clinical evidence of PCP. A negative PCR allows withdrawing anti-PCP therapy.
Toxoplasmosis is a life-threatening infection in immunocompromised patients (ICPs). The definitive diagnosis relies on parasite DNA detection, but little is known about the incidence and burden of ...disease in HIV-negative patients. A 3-year retrospective study was conducted in 15 reference laboratories from the network of the French National Reference Center for Toxoplasmosis, in order to record the frequency of Toxoplasma gondii DNA detection in ICPs and to review the molecular methods used for diagnosis and the prevention measures implemented in transplant patients. During the study period, of 31,640 PCRs performed on samples from ICPs, 610 were positive (323 patients). Blood (n = 337 samples), cerebrospinal fluid (n = 101 samples), and aqueous humor (n = 100 samples) were more frequently positive. Chemoprophylaxis schemes in transplant patients differed between centers. PCR follow-up of allogeneic hematopoietic stem cell transplant (allo-HSCT) patients was implemented in 8/15 centers. Data from 180 patients (13 centers) were further analyzed regarding clinical setting and outcome. Only 68/180 (38%) patients were HIV(+); the remaining 62% consisted of 72 HSCT, 14 solid organ transplant, and 26 miscellaneous immunodeficiency patients. Cerebral toxoplasmosis and disseminated toxoplasmosis were most frequently observed in HIV and transplant patients, respectively. Of 72 allo-HSCT patients with a positive PCR result, 23 were asymptomatic; all were diagnosed in centers performing systematic blood PCR follow-up, and they received specific treatment. Overall survival of allo-HSCT patients at 2 months was better in centers with PCR follow-up than in other centers (P < 0.01). This study provides updated data on the frequency of toxoplasmosis in HIV-negative ICPs and suggests that regular PCR follow-up of allo-HSCT patients could guide preemptive treatment and improve outcome.
Pneumocystis pneumonia is a severe opportunistic infection in immunocompromised patients caused by the unusual fungus Pneumocystis jirovecii. Transmission is airborne, with both immunocompromised and ...immunocompetent individuals acting as a reservoir for the fungus. Numerous reports of outbreaks in renal transplant units demonstrate the need for valid genotyping methods to detect transmission of a given genotype. Here, we developed a short tandem repeat (STR)-based molecular typing method for P. jirovecii. We analyzed the P. jirovecii genome and selected six genomic STR markers located on different contigs of the genome. We then tested these markers in 106 P. jirovecii PCR-positive respiratory samples collected between October 2010 and November 2013 from 91 patients with various underlying medical conditions. Unique (one allele per marker) and multiple (more than one allele per marker) genotypes were observed in 34 (32%) and 72 (68%) samples, respectively. A genotype could be assigned to 55 samples (54 patients) and 61 different genotypes were identified in total with a discriminatory power of 0.992. Analysis of the allelic distribution of the six markers and minimum spanning tree analysis of the 61 genotypes identified a specific genotype (Gt21) in our hospital, which may have been transmitted between 10 patients including six renal transplant recipients. Our STR-based molecular typing method is a quick, cheap and reliable approach to genotype Pneumocystis jirovecii in hospital settings and is sensitive enough to detect minor genotypes, thus enabling the study of the transmission and pathophysiology of Pneumocystis pneumonia.
•Echinocandins recommended for candidemia and fluconazole, as an alternative.•Emergence of Candida resistance to echinocandins.•Local guidelines for candidemia according to clinical practice and ...local epidemiology.•Fluconazole suggested to be a reasonable alternative to echinocandins in ICU.•To be incorporated in local guidelines through antifungal stewardship activities.
Candidemia is a major cause of mortality in the intensive care unit (ICU). According to the Infectious Diseases Society of America (IDSA), an echinocandin is recommended as initial therapy and fluconazole as an alternative. In a context of echinocandin resistance development, the question arising is whether azoles are a suitable alternative to echinocandins for the treatment of candidemia in critically ill patients.
A 3-year (2015–2017) retrospective multicentric cohort study was conducted. Adult patients with a diagnosis of candidemia during the ICU stay and treated with echinocandins or azoles were included. Demographic, clinical data, mycological data, and antifungal treatments were collected. Kaplan–Meier survival analysis, univariate analysis, and a multivariate logistic regression analysis using a propensity score with the inverse probability of treatment weighting method were performed.
Seventy-nine patients (n = 79) were analyzed. Treatment success, as well as survival on day 90 (Kaplan–Meier survival analysis, log rank test, p = 0.542), were comparable between patients who received echinocandins (caspofungin (n = 47)) or azoles (fluconazole (n = 29) or voriconazole (n = 3)). A multivariable analysis demonstrated that higher SOFA score on the day of candidemia diagnosis and absence of adequate Candida source control were independently associated with a greater risk of 90-day mortality, whereas azoles treatment was not associated with an excess 90-day mortality.
This study confirms that the use of azoles recommended for candidemia, mostly fluconazole, as a first-line therapy is a reasonable alternative to caspofungin for ICU patients in our institution. This needs to be included in local guidelines through antifungal stewardship programs.
Pneumocystis pneumonia (PCP) is common in patients with HIV infection but may also occur in patients with other causes of immunodeficiency, including hematologic and solid malignancies.
To better ...describe the clinical picture of PCP as to maintain a high level of suspicion in adequate cases, we studied 56 cancer patients with PCP and compared them to 56 cancer patients with bacterial pneumonia.
Among 56 PCP patients, 44 patients (78.6%) had hematologic malignancies (18 recipients of bone marrow transplantation) and 12 patients had solid tumors. The time since diagnosis was 24 months (range, 4 to 49 months). All patients with solid tumors and 20 patients (45.4%) with hematologic malignancies were receiving steroids. Only six patients were receiving PCP prophylaxis. The main symptoms were fever (85.7%), dyspnea (78.6%), and cough (57.1%). Time from symptom onset was 7 days (range, 3 to 14 days). PCP presented as severe pneumonia (Pao2, 58 mm Hg range, 50 to 70 mm Hg) with bilateral interstitial infiltrates (80.4%) and bilateral ground-glass attenuation (89.3%) by CT. Of the 24 ICU patients (42.9%), 16 patients (19.6%) required mechanical ventilation. Eleven patients (19.6%) died. Compared to 56 patients with bacterial pneumonia, PCP patients were more likely to have non-Hodgkin lymphoma and be receiving long-term steroids; they had longer times since diagnosis, longer symptom duration, higher frequencies of fever and of diffuse lung disease (diffuse crackles, bilateral infiltrates, and hypoxemia), higher frequency of ground-glass opacities, and lower frequency of pleural involvement.
PCP presents as subacute, febrile, hypoxemic, and diffuse pulmonary involvement in patients with solid tumors or hematologic malignancies receiving long-term steroids.
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