Julien Coussement

Nocardia Infection in Solid Organ Transplant Recipients: A Multicenter European Case-control Study

BACKGROUND Nocardiosis is a rare, life-threatening opportunistic infection, affecting 0.04% to 3.5% of patients after solid organ transplant (SOT). The aim of this study was to identify risk factors for Nocardia infection after SOT and to describe the presentation of nocardiosis in these patients. METHODS We performed a retrospective case-control study of adult patients diagnosed with nocardiosis after SOT between 2000 and 2014 in 36 European (France, Belgium, Switzerland, the Netherlands, Spain) centers. Two control subjects per case were matched by institution, transplant date, and transplanted organ. A multivariable analysis was performed using conditional logistic regression to identify risk factors for nocardiosis. RESULTS One hundred and seventeen cases of nocardiosis and 234 control patients were included. Nocardiosis occurred at a median of 17.5 (range, 2-244) months after transplant. In multivariable analysis, high calcineurin inhibitor trough levels in the month before diagnosis (odds ratio [OR], 6.11; 95% confidence interval [CI], 2.58-14.51), use of tacrolimus (OR, 2.65; 95% CI, 1.17-6.00) and corticosteroid dose (OR, 1.12; 95% CI, 1.03-1.22) at the time of diagnosis, patient age (OR, 1.04; 95% CI, 1.02-1.07), and length of stay in the intensive care unit after SOT (OR, 1.04; 95% CI, 1.00-1.09) were independently associated with development of nocardiosis; low-dose cotrimoxazole prophylaxis was not found to prevent nocardiosis. Nocardia farcinica was more frequently associated with brain, skin, and subcutaneous tissue infections than were other Nocardia species. Among the 30 cases with central nervous system nocardiosis, 13 (43.3%) had no neurological symptoms. CONCLUSIONS We identified 5 risk factors for nocardiosis after SOT. Low-dose cotrimoxazole was not found to prevent Nocardia infection. These findings may help improve management of transplant recipients.

Treatment of the Syndrome of Inappropriate Secretion of Antidiuretic Hormone with Urea in Critically Ill Patients

Background: Hyponatremia occurring as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common and potentially lethal complication in critically ill patients. Urea, by inducing renal water excretion and promoting sodium (Na) retention, has been well described as a treatment for chronic SIADH. However, there are limited data on its use for the treatment of SIADH as encountered in patients admitted to the intensive care unit (ICU). We assessed the effects of urea administration for treatment of SIADH in ICU patients. Methods: Data from ICU patients treated with urea for SIADH between January 2000 and August 2010 were reviewed. The time courses of Na and urea concentrations were analyzed by variance analysis (ANOVA). Results: Records from 24 patients were analyzed. The most common etiology of SIADH was neurological (18 patients). Before urea administration, the mean serum Na concentration was 124.8 ± 5.9 mEq/l. There was a significant increase in serum Na from the second day of treatment (131.4 ± 3.5 mEq/l, p < 0.001) and a normalization of mean serum Na by the fourth day (136.2 ± 4.1 mEq/l, p < 0.001). The mean serum urea concentration also increased (from 29.8 ± 11.1 mg/dl before urea to 57.6 ± 24.0 mg/dl on the first day of treatment, p < 0.001). Conclusions: Urea administration appears useful for the treatment of SIADH-associated hyponatremia in critically ill patients. Prospective randomized controlled studies are needed to confirm these results.

Clinical presentation and determinants of mortality of invasive pulmonary aspergillosis in kidney transplant recipients: a multinational cohort study.

The prognostic factors and optimal therapy for invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT) remain poorly studied. We included in this multinational retrospective study 112 recipients diagnosed with probable (75.0% of cases) or proven (25.0%) IPA between 2000 and 2013. The median interval from transplantation to diagnosis was 230 days. Cough, fever, and expectoration were the most common symptoms at presentation. Bilateral pulmonary involvement was observed in 63.6% of cases. Positivity rates for the galactomannan assay in serum and bronchoalveolar lavage samples were 61.3% and 57.1%, respectively. Aspergillus fumigatus was the most commonly identified species. Six‐ and 12‐week survival rates were 68.8% and 60.7%, respectively, and 22.1% of survivors experienced graft loss. Occurrence of IPA within the first 6 months (hazard ratio [HR]: 2.29; p‐value = 0.027) and bilateral involvement at diagnosis (HR: 3.00; p‐value = 0.017) were independent predictors for 6‐week all‐cause mortality, whereas the initial use of a voriconazole‐based regimen showed a protective effect (HR: 0.34; p‐value = 0.007). The administration of antifungal combination therapy had no apparent impact on outcome. In conclusion, IPA entails a dismal prognosis among KT recipients. Maintaining a low clinical suspicion threshold is key to achieve a prompt diagnosis and to initiate voriconazole therapy.

Should we treat asymptomatic bacteriuria after renal transplantation

Infections remain a major cause of morbidity and mortality in the modern kidney transplantation era [1]. Symptomatic urinary tract infections (UTIs), which are defined as the association of a positive urine culture with the presence of symptoms or signs referable to UTI, are usually divided into lower tract (cystitis) and upper tract (pyelonephritis) infections. It is the most common infection in this population, both short-term as well as long-term post-transplantation [2]. As a consequence, UTI is the leading cause of antibiotic administration in kidney transplant recipients [3]. The highest incidence of symptomatic UTIs occurs during the first months after transplantation [4, 5]. In a registry study conducted by the Spanish Network for Research on Infection in Transplantation (RESITRA) in 2052 kidney transplant recipients with at least 1 year of follow-up, symptomatic UTIs occurred in 150 patients (7.3%) with an incidence rate of 0.45 episodes per 1000 transplantation days [4]. Escherichia coli and Enterococcus are known to account for more than half of bacterial UTIs post-kidney transplantation [2–5]. In a time of increasing resistance to antimicrobial agents and rising health-related costs, factors that trigger UTIs need to be understood, and if possible prevented. As in the general population, female gender is the strongest risk factor for UTI in kidney transplant recipients [4, 6, 7]. In comparison with men, the shorter urethra contributes to this phenomenon. Other risk factors such as advanced age, diabetes mellitus, primary end-stage renal disease, urinary tract abnormalities, cadaveric donor kidney, graft dysfunction and rejection, CMV infection and prolonged time on dialysis prior to transplantation have been pinpointed in some series [2, 6–10]. Identification of treatable risk factors is of interest as it may lead to a reduction in the frequency of symptomatic UTIs. Whether asymptomatic bacteriuria is a modifiable risk factor for symptomatic episodes and could impact the global prognosis of the transplanted patient (and should therefore be screened for and treated) remains controversial [11]. The Infectious Diseases Society of America (IDSA) defines asymptomatic bacteriuria as isolation of a specified quantitative count of bacteria (≥10 CFU/mL) in an appropriately collected urine sample obtained from a person without symptoms or signs referable to a UTI [12]. While a single urine specimen is sufficient to define asymptomatic bacteriuria in men, it is usually defined in women as two consecutively voided urine specimens with isolation of the same bacterial strain in quantitative counts ≥10 CFU/mL. This definition stems from a study showing that, in non-transplanted women, when the first specimen contains at least 10 bacteria per millilitre of urine, there is an 80% probability that the patient has true bacteriuria [13]. That 20% of women have a negative second culture is thought to reflect transient bacteriuria rather than contamination [14]. Asymptomatic bacteriuria is a common event after renal transplantation. For instance, Fiorante et al. showed that 51% of the recipients develop asymptomatic bacteriuria—as defined by the IDSA guidelines—during the 3 years following transplantation [15]. Therefore, the question of its management remains a daily unsolved problem for transplant physicians. Antibiotic overuse could lead to the emergence of bacterial resistance and antimicrobial agents’ side effects. In addition, important costs are associated with the strategy of systematic screening and treatment of post-kidney transplantation asymptomatic bacteriuria, such as the costs of urinalyses, antibiotics and even hospitalization of asymptomatic patients. This is a matter of concern in a time of limited health-care resources. To date, no study has demonstrated a clear benefit in treating asymptomatic bacteriuria with antimicrobial agents in kidney transplant recipients [15–17]. Of the studies published addressing this question, only one was prospective. This small trial, conducted in 88 Iranian patients, did not show a statistically significant decreased rate of symptomatic UTIs when kidney transplant recipients with asymptomatic bacteriuria were treated with a 10-day course of antibiotics [17]. Nine of the 43 treated patients (21%) developed symptomatic UTI during the 9–12 months of follow-up, in comparison with 14 F U L L R E V IE W

Risk Factors Associated With Early Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: Results From a Multinational Matched Case–Control Study

Risk factors for invasive pulmonary aspergillosis (IPA) after kidney transplantation have been poorly explored. We performed a multinational case–control study that included 51 kidney transplant (KT) recipients diagnosed with early (first 180 posttransplant days) IPA at 19 institutions between 2000 and 2013. Control recipients were matched (1:1 ratio) by center and date of transplantation. Overall mortality among cases was 60.8%, and 25.0% of living recipients experienced graft loss. Pretransplant diagnosis of chronic pulmonary obstructive disease (COPD; odds ratio [OR]: 9.96; 95% confidence interval [CI]: 1.09–90.58; p = 0.041) and delayed graft function (OR: 3.40; 95% CI: 1.08–10.73; p = 0.037) were identified as independent risk factors for IPA among those variables already available in the immediate peritransplant period. The development of bloodstream infection (OR: 18.76; 95% CI: 1.04–339.37; p = 0.047) and acute graft rejection (OR: 40.73, 95% CI: 3.63–456.98; p = 0.003) within the 3 mo prior to the diagnosis of IPA acted as risk factors during the subsequent period. In conclusion, pretransplant COPD, impaired graft function and the occurrence of serious posttransplant infections may be useful to identify KT recipients at the highest risk of early IPA. Future studies should explore the potential benefit of antimold prophylaxis in this group.

Outcome and treatment of nocardiosis after solid organ transplantation: new insights from a European study

Background Solid organ transplant (SOT) recipients are at risk of nocardiosis, a rare opportunistic bacterial infection, but prognosis and outcome of these patients are poorly defined. Our objectives were to identify factors associated with 1-year mortality after nocardiosis and describe the outcome of patients receiving short-course antibiotics (≤120 days). Methods We analyzed data from a multicenter European case-control study that included 117 SOT recipients with nocardiosis diagnosed between 2000 and 2014. Factors associated with 1-year all-cause mortality were identified using multivariable conditional logistic regression. Results One-year mortality was 10-fold higher in patients with nocardiosis (16.2%, 19/117) than in control transplant recipients (1.3%, 3/233, P < .001). A history of tumor (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8), invasive fungal infection (OR, 1.3; 95% CI, 1.1-1.5), and donor age (OR, 1.0046; 95% CI, 1.0007-1.0083) were independently associated with 1-year mortality. Acute rejection in the year before nocardiosis was associated with improved survival (OR, 0.85; 95% CI, 0.73-0.98). Seventeen patients received short-course antibiotics (median duration 56 [24-120] days) with a 1-year success rate (cured and surviving) of 88% and a 5.9% risk of relapse (median follow-up 49 [6-136] months). Conclusions One-year mortality was 10-fold higher in SOT patients with nocardiosis than in those without. Four factors, largely reflecting general medical condition rather than severity and/or management of nocardiosis, were independently associated with 1-year mortality. Patients who received short-course antibiotic treatment had good outcomes, suggesting that this may be a strategy for further study.

Clinical case of cfr-positive MRSA CC398 in Belgium.

Sir, Linezolid, the first member of the oxazolidinone class of antibiotics, is one of the major antimicrobial agents used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. This drug inhibits bacterial protein synthesis by binding to domain Vof the 23S ribosomal RNA (rRNA) of the 50S subunit. Several mechanisms conferring linezolid resistance have been described in staphylococci, including point mutations in genes encoding 23S rRNA and mutations in ribosomal proteins L3, L4 and L22 [1, 2]. Even more problematic is the identification of cfr, a horizontally transferable resistance gene that encodes a ribosomal methyltransferase conferring cross-resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin A (PhLOPSA phenotype) [1, 2]. Recently, a new gene (optrA) coding for an ABC transporter which confers resistance to oxazolidinones and phenicol resistance has been described. Yet, this new gene has only been found in enterococci and S. sciuri [3, 4]. Despite its clinical use for more than 15 years, linezolid resistance remains scarce and is mostly due to the presence of chromosomal mutations. A recent study regarding the continuous long-term and stable in vitro activity of linezolid against different bacteria (including S. aureus, coagulasenegative staphylococci, Enterococcus spp. and Streptococcus spp.) [5] showed that none of the 7541 collected organisms harboured the cfr gene. However, wewere recently confronted with the management of one case of a human infection caused by a cfr-positive MRSA belonging to the livestock-associated (LA-) clone ST398, which is, to the best of our knowledge, the first clinical case reported in Belgium. A 74-year-old man was admitted to hospital for a postoperative skin and soft tissue infection complicating a left carotid endarterectomy performed 2 weeks earlier. Cultures of the purulent discharge grew mixed abundant organisms consisting of Escherichia coli and an MRSA. Amoxicillin– clavulanic acid was the only antimicrobial agent administered in the last several years. After surgical drainage, antimicrobial therapy was started with intravenous vancomycin to achieve serum concentrations of 20 to 30 mg/L plus piperacillin–tazobactam (4/0.5 g q.i.d.). The therapy was switched after 6 days to an oral combination of cefuroxime axetil 500 mg t.i.d. and trimethoprim–sulphamethoxazole 160/800 mg b.i.d. for a total period of 14 days. This medico-surgical management lead to total resolution and cure of infection. As the MRSA isolate collected from the patient’s sample was tested to be resistant to linezolid by the VITEK 2 system, it was sent for confirmation to the National Reference Centre (NRC) for staphylococci. At the NRC, the identification was further confirmed genotypically by polymerase chain reaction (PCR) for the detection of 16S, mecA and nuc genes, as previously described [6]. Isolates were further tested by multilocus sequence typing (MLST) (http://saureus.mlst. net/). Antimicrobial susceptibility was determined by the disc diffusion method for the following antibiotics: cefoxitin, gentamicin, kanamycin, tobramycin, fusidic acid, * H. Paridaens henry.paridaens@gmail.com

When polymerase chain reaction does not help: cytomegalovirus pneumonitis associated with very low or undetectable viral load in both blood and bronchoalveolar lavage samples after lung transplantation.

Cytomegalovirus (CMV) pneumonitis occurs frequently among solid organ transplant recipients and is classically associated with significant viral replication in both blood and bronchoalveolar lavage (BAL) samples. We present a case of a 64‐year‐old lung transplant recipient who presented with CMV pneumonitis that was diagnosed based on the association of viral inclusion in the BAL sample, rapid response to ganciclovir, and absence of other infectious etiology. Surprisingly, we observed very low or undetectable viral load both in blood and BAL samples. Diagnosis of CMV pneumonitis should rely on the association of clinical, pathological, radiological, and microbiological signs, while quantitative nucleic acid amplification testing should be interpreted with caution.

Old habits die hard: screening for and treating asymptomatic bacteriuria after kidney transplantation

The process of screening for and treating asymptomatic bacteriuria is an old habit in many kidney transplantation centers. This strategy is largely driven by theoretical concerns, including the fact that symptoms of urinary tract infection may be impeded by graft denervation, the alteration of inflammatory signs by immunosuppressive medications, and fear that rapidly progressing infections can occur in immunosuppressed patients.

Nocardia infections in solid organ and hematopoietic stem cell transplant recipients

Purpose of review Nocardia spp. is a gram-positive bacteria that may cause infections in humans. Nocardiosis has been described since the early years of transplantation. This review aims to provide an overview of present knowledge regarding posttransplant nocardiosis, with a focus on recent findings. Recent findings Nocardiosis is not rare among transplant recipients, especially after thoracic transplantation and/or in case of intense immunosuppressive regimen or use of tacrolimus. Low-dose cotrimoxazole is not effective to prevent nocardiosis. Although lung is the most common site of infection, more than 40% of organ transplant patients have a disseminated infection. As central nervous system involvement is frequent (about 1/3 of the patients) and possibly asymptomatic, brain imaging is mandatory. Diagnosis relies on direct examination and culture; molecular species identification is useful to guide treatment. Although cotrimoxazole is the drug for which we have the strongest clinical experience, other antibiotics such as linezolid, parenteral cephalosporins, carbapenems, and amikacin can be used to treat nocardiosis. Although treatment duration has historically been set to at least 6 months, shorter durations (<120 days) seem associated with a good outcome in selected patients. Summary Physicians in charge of transplant patients should be aware of nocardiosis. Diagnosis and management of transplant recipients with nocardiosis require a multidisciplinary approach.