Roberto Andini

Colistin and Rifampicin Compared With Colistin Alone for the Treatment of Serious Infections Due to Extensively Drug-Resistant Acinetobacter baumannii: A Multicenter, Randomized Clinical Trial

BACKGROUND Extensively drug-resistant (XDR) Acinetobacter baumannii may cause serious infections in critically ill patients. Colistin often remains the only therapeutic option. Addition of rifampicin to colistin may be synergistic in vitro. In this study, we assessed whether the combination of colistin and rifampicin reduced the mortality of XDR A. baumannii infections compared to colistin alone. METHODS This multicenter, parallel, randomized, open-label clinical trial enrolled 210 patients with life-threatening infections due to XDR A. baumannii from intensive care units of 5 tertiary care hospitals. Patients were randomly allocated (1:1) to either colistin alone, 2 MU every 8 hours intravenously, or colistin (as above), plus rifampicin 600 mg every 12 hours intravenously. The primary end point was overall 30-day mortality. Secondary end points were infection-related death, microbiologic eradication, and hospitalization length. RESULTS Death within 30 days from randomization occurred in 90 (43%) subjects, without difference between treatment arms (P = .95). This was confirmed by multivariable analysis (odds ratio, 0.88 [95% confidence interval, .46-1.69], P = .71). A significant increase of microbiologic eradication rate was observed in the colistin plus rifampicin arm (P = .034). No difference was observed for infection-related death and length of hospitalization. CONCLUSIONS In serious XDR A. baumannii infections, 30-day mortality is not reduced by addition of rifampicin to colistin. These results indicate that, at present, rifampicin should not be routinely combined with colistin in clinical practice. The increased rate of A. baumannii eradication with combination treatment could still imply a clinical benefit. CLINICAL TRIALS REGISTRATION NCT01577862.

Emergence of colistin resistance without loss of fitness and virulence after prolonged colistin administration in a patient with extensively drug-resistant Acinetobacter baumannii.

The spread of extensively drug-resistant (XDR) gram-negative bacteria has boosted colistin use, with a resultant selection of colistin-resistant, often pandrug-resistant strains. Whether acquisition of further resistance mechanisms translates into a reduced virulence is the subject of active research. In this report, we describe clinical features of an immunocompromised patient who developed infection due to colistin-resistant Acinetobacter baumannii while on long-term colistin therapy. We analyzed phenotypic and genotypic characteristics, molecular mechanisms of colistin resistance, and in vitro and in vivo fitness of sequential colistin-sensitive and colistin-resistant strains isolated from the patient. Both colistin-sensitive and colistin-resistant strains were XDR and showed identical ST78 genotype. At variance with prior reports on colistin-resistant strains of A. baumannii, resistance to colistin due to P233S mutation in PmrB sensor kinase did not associate with any measurable reduction in strain fitness, growth characteristics, and virulence.

Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial

BACKGROUND Colistin-carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. METHODS A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual. FINDINGS Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference -5·7%, 95% CI -13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83-1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87-1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury). INTERPRETATION Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria. FUNDING EU AIDA grant Health-F3-2011-278348.

Safety of treatment with high-dose daptomycin in 102 patients with infective endocarditis.

Daptomycin is commonly used at doses >6 mg/kg/day for various indications, including infective endocarditis (IE). A systematic assessment of skeletal muscle, renal, haematological, hepatic and pulmonary toxicity of high-dose daptomycin (HDD) in IE is lacking. A total of 102 IE patients treated with HDD were included in this non-comparative, observational, single-centre cohort study conducted from 2007 to 2014. The incidence, timing, severity and evolution of adverse events (AEs) were assessed. Patients had a median age of 61.5 years and a high prevalence of co-morbidities. Staphylococci were cultured in 87.2% of cases (62.2% meticillin-resistant). The median daptomycin dose was 8.2 mg/kg/day for a median of 20 days (range, 1-60 days). HDD was withdrawn due to AEs in 12 patients (11.8%). On-treatment death occurred in 4 cases (3.9%, none HDD-related). Muscle toxicity occurred in 15 patients in a median of 15 days after HDD starts, which was largely mild and reversible with ongoing HDD use. Mild renal toxicity was observed in 9 patients (8.8%) after a median of 12 days of HDD (RIFLE-Risk in 8, Injury in 1). A rise of peripheral blood eosinophils occurred in 16 patients (15.7%). There were three cases of eosinophilic interstitial pneumonia. Four patients (3.9%) had mild allergic or idiosyncratic reactions. No other hepatic or haematological AEs were observed. Our current experience with 102 patients suggests that HDD is safe in significantly ill IE patients with multiple co-morbidities. Muscle toxicity was clinically negligible. Most importantly, there was no significant renal toxicity. Eosinophils should be carefully monitored.

Infective endocarditis due to multidrug resistant gram-negative bacilli: Single centre experience over 5 years

BACKGROUND Infective endocarditis (IE) due to gram-negative (GN) bacilli is uncommon. Although multi- and extensively-drug resistant (MDR/XDR) GN infections are emerging, very few data are available on IE due to these microrganisms. METHODS In this study, we describe the clinical characteristics, course and outcome of five contemporary, definite, MDR/XDR GNIE cases seen at our centre. RESULTS All patients had been admitted to a hospital during the 6months before IE onset, 2 were on hemodialysis and 3 on intravenous medications. Three of the 5 cases were hospital-acquired. Intracardiac prosthetic devices were present in all cases (3 central venous lines, 2 prosthetic heart valves, 2 pacemakers). Mean Charlson comorbidity index was 5.8. Causative pathogens were XDR Pseudomonas aeruginosa (2 cases), XDR Acinetobacter baumannii, MDR Burkolderia cepacia and MDR Escherichia coli (1 case each). Concomitant pathogens with a MDR/XDR phenotype were isolated in 4 patients. Both valves and intracardiac devices and left and right sides of the heart were involved. The rate of complications was high. Antibiotic treatment hinged on the use of colistin, a carbapenem or both. Cardiovascular surgical procedures were performed in 3 patients. Despite aggressive therapeutic regimens, outcomes were poor. Clearance of bacteremia was obtained in 3 patients, in-hospital death occurred in 3 patients, only 1 patient survived during follow up. CONCLUSIONS MDR/XDR GN are emerging as a cause of IE in carriers of intracardiac prostheses with extensive healthcare contacts and multiple comorbidities. Resistant GNIE has a complicated course and shows a dismal prognosis.

Direct antiviral treatment of chronic hepatitis C in heart transplant recipients

Direct‐acting antiviral agents (DAAs) are a safe and effective treatment for chronic hepatitis C (CHC). This may be particularly valuable for patients with severe comorbidities or baseline conditions, including non‐liver solid organ transplant. We report cases of two heart transplant recipients with CHC treated with DAAs (sofosbuvir and daclatasvir) achieving sustained virological response. Treatment was well tolerated and no relevant side effects were observed. The drug‐drug interactions and graft function were carefully monitored.

Hepatitis B virus reactivation after heart transplant: Incidence and clinical impact

BACKGROUND Occult hepatitis B infection consists of persistence of HBV genomes in hepatocytes,absence of serum HBsAg, low/undetectable serum HBVDNA. Reactivation of HBV infection may occur during immunosuppression, but few data are available in heart transplant. OBJECTIVES We followed-up heart recipients with or without markers of previous HBV infection,evaluating prevalence of HBV markers, incidence of HBV reactivation and its virological and clinical features. STUDY DESIGN Heart failure patients listed for heart transplant (2007-2013) were screened for current or past HBV infection. Transplanted patients with past HBV infection (anti-HBc+/±anti-HBs+/HBVDNA-) were followed up as cases, and an equal number of HBV negative patients as controls. Virological reactivation was detected by standard real-time and home-made highly sensitive PCR (surface/core HBVDNA regions). Clinical status and progression were assessed by liver histology, ultrasound or elastography. RESULTS 67 patients underwent heart transplant, including 4 (5.9%) HBsAg+ subjects. Cases were 11/67 (16.4%). During a median follow-up of 30 months, only one of these 11 patients presented viral reactivation (HBVDNA 209IU/mL) at month 22, and started antiviral treatment. Four other recipients showed virological events of uncertain significance (sensitive PCR-only intermittently positive). Clinical signs of liver disease were observed in only one case at the last follow-up. A nonsignificant difference in survival was observed between cases and all other heart recipients without prior HBV contact (death rate 5/11 vs 15/52, respectively; p=0.097). CONCLUSIONS HBV genotypic reactivation in HBsAg-/anti-HBc+/HBVDNA- heart recipients is uncommon. Virological events of uncertain significance occur more frequently; their clinical impact seems to be negligible.

Efficacy and safety of tenofovir, entecavir, and telbivudine for chronic hepatitis B in heart transplant recipients

Treatment of chronic hepatitis B (CHB) with polymerase inhibitors is key to prevent disease flares and progression toward advanced liver disease. Efficacy and tolerability of newer agents has been reported anecdotally in transplant recipients.

Clinical significance of hyperhomocysteinemia in infective endocarditis: A case-control study.

AbstractBlood coagulation plays a key role in the pathogenesis of infective endocarditis (IE). Conditions associated with thrombophilia could enhance IE vegetation formation and promote embolic complications.In this study, we assessed prevalence, correlates, and clinical consequences of hyper-homocysteinemia (h-Hcy) in IE.Homocysteine (Hcy) plasma levels were studied in 246 IE patients and 258 valvular heart disease (VHD) patients, as well as in 106 healthy controls.IE patients showed Hcy levels comparable to VHD patients (14.9 [3–81] vs 16 [5–50] &mgr;mol/L, respectively; P = 0.08). H-Hcy was observed in 48.8% of IE patients and 55.8% of VHD (P = 0.13). Vegetation size and major embolic complications were not related to Hcy levels. IE patients with h-Hcy had a higher prevalence of chronic kidney disease and a higher 1-year mortality (19.6% vs 9.9% in those without h-Hcy; OR 2.21 [1.00–4.89], P = 0.05). However, at logistic regression analysis, h-Hcy was not an independent predictor of 1-year mortality (OR 1.87 [95% CI 0.8–4.2]; P = 0.13).Our data suggest h-Hcy in IE is common, is related to a worse renal function, and may be a marker of cardiac dysfunction rather than infection. H-Hcy does not appear to favor IE vegetation formation or its symptomatic embolic complications.

Recipient-born bloodstream infection due to extensively drug-resistant Acinetobacter baumannii after emergency heart transplant: report of a case and review of the literature.

Infections due to drug-resistant Gram-negative rods are an emerging risk factor for increased mortality after solid organ transplant. Extensively drug-resistant (XDR) Acinetobacter baumannii (Acb) is a major threat in several critical care settings. The limited available data on the outcome of XDR Acb infections in organ transplant recipients mostly comes from cases of donor-derived infections. However, recipients of life-saving organs are often critically ill patients, staying long term in intensive care units, and therefore at high risk for nosocomial infections. In this report, we describe our experience with the exceedingly complex management of a recipient-born XDR Acb bloodstream infection clinically ensued shortly after heart transplant. We also review the current literature on this mounting issue relevant for intensive care, transplant medicine and infectious diseases.