Current clinical practice in antibiotic treatment of Staphylococcus aureus bacteraemia: results from a survey in five European countries.

OBJECTIVES: To determine clinical practice variation and identify knowledge gaps in antibiotic treatment of Staphylococcus aureus bacteraemia (SAB). METHODS: A web-based survey with questions addressing antibiotic treatment of SAB was distributed through the ESGAP network among infectious disease specialists, clinical microbiologists and internists in Croatia, France, Greece, the Netherlands and the UK between July 2021 and November 2021. RESULTS: A total number of 1687 respondents opened the survey link, of whom 677 (40%) answered at least one question. For MSSA and MRSA bacteraemia, 98% and 94% preferred initial monotherapy, respectively. In patients with SAB and non-removable infected prosthetic material, between 80% and 90% would use rifampicin as part of the treatment. For bone and joint infections, 65%-77% of respondents would consider oral step-down therapy, but for endovascular infections only 12%-32% would. Respondents recommended widely varying treatment durations for SAB with different foci of infection. Overall, 48% stated they used 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG-PET/CT) to guide antibiotic treatment duration. Persistent bacteraemia was the only risk factor for complicated SAB that would prompt a majority to extend treatment from 2 to 4-6 weeks. CONCLUSIONS: This survey in five European countries shows considerable clinical practice variation between and within countries in the antibiotic management of SAB, in particular regarding oral step-down therapy, choice of oral antibiotic agents, treatment duration and use of 18F-FDG-PET/CT. Physicians use varying criteria for treatment decisions, as evidence from clinical trials is often lacking. These areas of practice variation could be used to prioritize future studies for further improvement of SAB care.

Prevalence and molecular epidemiology of Staphylococcus aureus nasal colonization in four nursing home residents in Crete, Greece.

Nursing homes are considered as reservoirs for methicillin-resistant Staphylococcus aureus (MRSA). The present study investigated the point prevalence and molecular epidemiology of S. aureus colonization among nursing home residents. The study population comprised of 227 residents, living in four nursing homes of the Heraklion, Crete, Greece area, between January and December 2015. From each nursing home, swabs from the anterior nares of all eligible participants were obtained within a 2-week period. The isolated S. aureus strains were identified and screened by standard microbiological and molecular epidemiological methods. S. aureus carriage was found in 62 out of 227 participants (38.4%) with 33 out of 62 (53.2%) being MRSA. The median age was 83 years (range 52-103). Females were more frequently colonized [47 (75.8%)]. All 33 methicillin resistant Staphylococcus aureus (MRSA) isolates were mecA-positive carrying SCCmec type IV, 30 (91%) the fnbA, and 17 (51.5%) the PVL genes. Thirty-two (97%) belonged to a single pulsotype C; among them, the PVL-positives belonged to ST80 clone, whereas, the PVL-negatives to ST225. Among the 33 MRSA isolates, 32 (97%) were clindamycin-resistant, carrying the ermA gene. Methicillin-susceptible Staphylococcus aureus (MSSA) strains showed polyclonality and 76% were PVL-positive. In conclusion the present study has shown that nursing homes in our area can be regarded as important reservoirs for community-associated MRSA (CA-MRSA).

Multidrug-resistant Gram-negative osteomyelitis: a 10-year study.

AIM: Few series of osteomyelitis due to multi-drug (MDR) or extensively-drug resistant (XDR) gram-negative bacteria exist. A retrospective study of MDR and XDR gram-negative osteomyelitis cases was performed, aiming to investigate causative organisms, proper surgical and medical management, as well as outcome. PATIENTS AND METHODS: All patients, treated at the University hospital of Crete between 2007 and 2016 for acute osteomyelitis, due to MDR or XDR gram-negative pathogens were evaluated. RESULTS: A total of 14 patients (8 males) were identified with a mean age of 50.6 years. Five Acinetobacter baumanii cases, 3 XDR and 2 MDR, were found. Furthermore, 3 MDR Klebsiella pneumoniae and 3 MDR Enterobacter cloacae isolates were identified. Additionally, 2 MDR Escherichia coli, as well as 2 Pseudomonas aeruginosa, 1 XDR and 1 MDR, were isolated. One case of Roseomonas gilardii was also identified. In 5 cases the same pathogen was also isolated from blood. Five out of the 14 patients were smokers, 6 were suffering severe injury, 4 had diabetes-mellitus, 2 chronic renal disease and 2 were obese. Most causative organisms had hospital origin. All patients received first line empirical combination antimicrobial treatment, proven effective in 4. Thirteen patients were also subjected to surgical treatment. The study included mainly young individuals, most likely due to the high incidence of traffic accidents involving young adults in Crete. CONCLUSIONS: Antimicrobial regimens are important supplements to surgical treatment of acute osteomyelitis. However, due to emergence of resistant microorganisms, compliance with strict rules of antimicrobial strategy is of utmost importance.

Clostridium difficile in Crete, Greece: epidemiology, microbiology and clinical disease.

We studied the epidemiology and microbiology of Clostridium difficile and the characteristics of patients with C. difficile infection (CDI) in Crete in three groups of hospitalized patients with diarrhoea: group 1 [positive culture and positive toxin by enzyme immunoassay (EIA)]; group 2 (positive culture, negative toxin); group 3 (negative culture, negative toxin). Patients in group 1 were designated as those with definitive CDI (20 patients for whom data was available) and matched with cases in group 2 (40 patients) and group 3 (40 patients). C. difficile grew from 6% (263/4379) of stool specimens; 14·4% of these had positive EIA, of which 3% were resistant to metronidazole. Three isolates had decreased vancomycin susceptibility. Patients in groups 1 and 2 received more antibiotics (P = 0·03) and had more infectious episodes (P = 0·03) than patients in group 3 prior to diarrhoea. Antibiotic administration for C. difficile did not differ between groups 1 and 2. Mortality was similar in all three groups (10%, 12·5% and 5%, P = 0·49). CDI frequency was low in the University Hospital of Crete and isolates were susceptible to metronidazole and vancomycin.

Trends of isolation of intrinsically resistant to colistin Enterobacteriaceae and association with colistin use in a tertiary hospital.

The objective of this investigation was to evaluate the association between colistin consumption and the isolation of intrinsically resistant to colistin Enterobacteriaceae (IRCE) in a university hospital in Crete, Greece. The database of the microbiological laboratory was reviewed retrospectively during 2006-2010. All positive cultures for IRCE were retrieved. We assessed the total consumption of colistin in medical, surgical, and intensive care units (ICUs). A total of 1,304 single-patient IRCE isolates were recorded. Of these, 466 (35.7%) were hospital-acquired, while 838 (64.3%) were community-acquired. Proteus spp. accounted for 72% of them, Serratia spp. for 16.6%, Morganella morganii for 8.4%, and Providencia spp. for 3%. Urine (44.8%), pus (20.4%), and lower respiratory tract specimens (12.8%) accounted for the majority of specimens. IRCE isolated during the first half (2006 to 1st semester of 2008) and second half (2nd semester of 2008 to 2010) of the study period accounted for 5.8% and 7.4% of Gram-negative isolates, respectively (p < 0.001). Colistin consumption was not different in the two periods in the hospital, but in the ICU, it was higher in the second half of the study period (p = 0.013). Colistin consumption was associated with the isolation of hospital-acquired IRCE (p = 0.037); a trend was noted between colistin consumption and the isolation of IRCE in the ICU (p = 0.057). In this study, colistin consumption was associated with the isolation of hospital-acquired IRCE. The use of colistin increased in the ICU during the study period. Prudent use of colistin is essential for the prevention of nosocomial outbreaks due to resistant IRCE.

Characteristics, risk factors and outcomes of adult cancer patients with extensively drug-resistant Pseudomonas aeruginosa infections.

OBJECTIVE: To evaluate the characteristics and outcomes of cancer patients with extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. METHODS: This was a retrospective cohort of P. aeruginosa infections in cancer patients in Crete, Greece. Patients were followed until discharge. Mortality, predictors of mortality and risk factors for XDR P. aeruginosa infection were studied. RESULTS: Ninety seven episodes (89 patients) of P. aeruginosa infections (52 with bacteremia) were included in the study. In 22 cases, the infection was due to XDR isolates. All XDR isolates were susceptible to colistin and variably resistant to almost all other antibiotics. The multivariate analysis showed that the independent risk factors for XDR P. aeruginosa infection were hematologic malignancy (OR 40.7, 95 % CI 4.5-367.6) and prior fluoroquinolone use (OR 11.0, 95 % CI 2.0-60.5); lymphopenia was inversely associated with XDR infections (OR 0.16, 95 % CI 0.03-0.92). Mortality was 43 %; infection-related mortality was 24 %. Bacteremia (OR 8.47, 95 % CI 2.38-30.15), infection due to XDR isolates (OR 5.11, 95 % CI 1.15-22.62) and age (OR 1.05, 95 % CI 1.00-1.09) were independently associated with mortality. CONCLUSION: Mortality in cancer patients with P. aeruginosa infections was high. Infection due to XDR isolates was independently associated with mortality.

Limited impact of colistin resistance on mortality of intensive care patients with carbapenem-resistant bacteraemia.

BACKGROUND: Increasing incidence of carbapenem-resistant Gram-negative bacteraemia (CR-GNB) has triggered increased use of polymyxins, likely fuelling the emergence and spread of colistin resistance. AIM: To estimate the excess clinical burden of colistin resistance in intensive care patients with CR-GNB. METHODS: A cohort of patients with CR-GNB during their stay in the intensive care unit (ICU) of a university hospital in Greece over a 4-year period (2020-2023) was constructed. Competing risks survival analysis was performed to estimate the burden associated with colistin resistance. FINDINGS: Of the 177 ICU patients with CR-GNB, 134 (76%) had colistin-resistant isolates, predominantly Acinetobacter baumannii (79%), identified by broth microdilution. Patients with colistin-resistant infection were similar to those with colistin-susceptible infection with respect to age, sex, APACHE II score, Charlson comorbidity index score, Pitt bacteraemia score, prior surgery and the occurrence of polymicrobial cultures. However, patients in the colistin-resistant group had lower risk of mortality compared with those in the colistin-susceptible group (31% vs 44%, P = 0.004 at 14 days, respectively; 46% vs 56% at 28 days, respectively; P = 0.173). Multi-variable regression analysis confirmed that colistin-resistant CR-GNB was associated with significantly lower risk of inpatient death compared with colistin-susceptible CR-GNB within 14 days [cause-specific hazard ratio (csHR) 0.53, 95% CI 0.28-1.01) and 28 days (csHR 0.55, 95% CI 0.31-0.95) of infection onset. CONCLUSION: Limited impact of colistin resistance on mortality was demonstrated in a large contemporary cohort of ICU patients with CR-GNB, possibly reflecting the recent shift away from colistin-based treatment regimens.

Antimicrobial susceptibility of non-fermenting Gram-negative isolates to isepamicin in a region with high antibiotic resistance.

The alarmingly increasing resistance rates among non-fermenting Gram-negative species, particularly Pseudomonas aeruginosa and Acinetobacter baumannii, intensified the interest in alternative antibiotic treatment options. Isepamicin, an old aminoglycoside, may play a role in the treatment of patients with infections caused by those multi-drug resistant pathogens. We evaluated the antimicrobial activity of isepamicin against non-fermenting Gram-negative isolates collected of the microbiological laboratory at the University Hospital of Heraklion, Crete, Greece from 2004 to the first trimester of 2011. We tested a total of 4,219 isolates (66.2 % Pseudomonas spp., 30 % Acinetobacter spp., 3.8 % other non-fermenters). The lower respiratory tract, pus, and urine were the most frequent sites of isolation (29.7 %, 19.9 %, and 12.9 %, respectively). Overall, 2768 (65.6 %) of the evaluated isolates were susceptible to isepamicin (including 79.9 % of Pseudomonas spp, 37.2 % of Acinetobacter spp, 43.1 % of other non-fermenters). Isepamicin exhibited higher antimicrobial activity compared to broad spectrum penicillins, cephalosporins, other aminoglycosides, carbapenems, and fluoroquinolones. Only colistin was more active than isepamicin. Additionally, 41.7 % of carbapenem-resistant and 53.2 % of colistin-resistant P. aeruginosa isolates were susceptible to isepamicin. The susceptibility rates for the respective types of A. baumannii isolates were 12 % and 6.2 %. Yet, isepamicin was active against 29.2 % of A. baumannii that were resistant to all other tested aminoglycosides. Isepamicin exhibits considerable antimicrobial activity against Gram-negative non-fermenters in a region with high antimicrobial resistance. Particularly, isepamicin may provide a therapeutic option for infections from carbapenem- and colistin-resistant P. aeruginosa and other aminoglycoside-resistant A. baumannii. Further modifications in the aminoglycoside molecule may provide formulations with enhanced antimicrobial activity.

Serratia infections in a general hospital: characteristics and outcomes.

We aimed to present our experience regarding infections caused by Serratia spp. in a region with relatively high antimicrobial resistance rates. We retrospectively reviewed the databases of the microbiological laboratory of the University Hospital of Heraklion, Crete (2/2004-12/2009). A total of 77 patients [67.5% men, mean age ± standard deviation (SD) = 56.9 ± 24.5 years) were identified; 37.7% were outpatients. Sixty-five (84.4%) of the 77 included patients had a Serratia marcescens isolate; the remaining 12 patients had a non-marcescens Serratia spp. The most frequently observed infections were respiratory tract infection (32.5%) and keratitis/endophthalmitis (20.8%). Seventy-three (94.9%) patients were cured. Four deaths were observed; three of them were considered as attributed to the Serratia infection. No difference was found regarding the characteristics and outcomes between patients with Serratia marcescens and non-marcescens infections. In addition, antipseudomonal penicillins and their combinations with beta-lactamase inhibitors, as well as carbapenemes, and fluoroquinolones exhibited high antimicrobial activity against both the tested Serratia marcescens and non-marcescens isolates. Our study adds useful information regarding the characteristics and outcomes of patients with Serratia infection, as well as the susceptibilities of the respective Serratia marcescens and non-marcescens isolates, in a region with relatively high levels of antimicrobial resistance.

Effects of levofloxacin, moxifloxacin and prulifloxacin on murine gut colonization by Candida albicans.

Fluoroquinolones are broad-spectrum antibiotics increasingly utilized as empirical or prophylactic therapy in the management of cancer patients. We evaluated the effects of newer generation fluoroquinolones on the level of gastrointestinal (GI) colonization by Candida albicans in a previously established mouse model. Adult male Crl:CD1 (ICR) BR mice were fed chow containing Candida albicans or regular chow. The mice fed the Candida chow had their gut colonized by the yeast. Both groups were subsequently given levofloxacin, moxifloxacin, prulifloxacin or normal saline for 10 days. Stool cultures were performed immediately before, at the end, and one week after discontinuation of treatment to determine the level of intestinal yeast colonization. Candida-colonized mice treated with fluoroquinolones had substantially higher yeast counts in their stools than control mice fed Candida containing chow but treated with saline. Mice fed regular chow and treated with the study antibiotics or saline did not have any Candida in their stools. Dissemination of Candida to internal organs was not observed in any animal. In conclusion, we have shown that all fluoroquinolones tested induced substantial increases in the murine intestinal concentration of C. albicans.

Saccharomyces boulardii and Candida albicans experimental colonization of the murine gut.

Saccharomyces boulardii has been and continues to be extensively used as a probiotic, with only rare associations with fungemia. This study evaluated the virulence of this yeast when given as a probiotic, and its role in preventing gastrointestinal (GI) colonization by Candida. Adult male Crl:CD1 (ICR) BR mice were given S. boulardii orally in three different doses or normal saline for 14 days. Stool cultures were performed at the time of discontinuation of yeast administration, as well as 1 and 2 weeks later. Gut colonization was proportional to the given dose but lasted only 1 week and no dissemination of the yeast was detected. S. boulardii was also given for 2 and 4 weeks to mice fed chow containing Candida albicans. S. boulardii in the gut did not affect Candida GI colonization. These findings suggest that oral administration of S. boulardii induces a substantial but short term increase of this yeast in the intestinal lumen and administration of the probiotic does not prevent subsequent GI colonization by C. albicans.

Citrobacter infections in a general hospital: characteristics and outcomes.

In this investigation, we sought to investigate the characteristics of Citrobacter spp. infections. A retrospective cohort study in a 700-bed, tertiary care, university hospital was carried out during the period from June 1994 to January 2006. Seventy-eight patients (70 adults) with Citrobacter spp. isolates were identified. C. freundii was more common (71.8%), followed by C. koseri (23.1%) and C. braakii (3.8%). The most common associated clinical syndromes were urinary tract infections (52.6% of cases, including eight cases of asymptomatic bacteriuria), as well as intra-abdominal (14.1%), surgical site (7.7%), skin and soft tissue (6.4%), and respiratory tract infections (6.4%). In 29.5% of patients, Citrobacter spp. isolates were associated to polymicrobial infections, principally at sites other than the urinary tract. Antibiograms of 38 consecutive Citrobacter spp. isolates (29 C. freundii) were available. Most active agents were colistin (100%), fosfomycin (100%), imipenem (97.4%), gentamicin (89.5%), nitrofurantoin (89.5%), ciprofloxacin (80.6%), and cefepime (73.7%). Most patients (82.1%) had at least one underlying illness. Combination antimicrobial therapy was administered in 28.2% of cases. One patient died during hospitalization. The length of hospital stay was longer in patients with polymicrobial compared to monomicrobial infections (23 versus 13 days, respectively, p = 0.02). The isolation of Citrobacter species, although rather infrequent, was clinically relevant in the great majority of cases. Further attention should be paid to these pathogens.

Antimicrobial susceptibilities of 930 Haemophilus influenzae clinical strains isolated from the island of Crete, Greece.

BACKGROUND: Haemophilus influenzae is an important human pathogen. MATERIALS AND METHODS: The purpose of the present retrospective study is to describe the antibiotic susceptibility to several common antibiotics of 930 consecutive clinical isolates of H. influenzae over the period of 1996-2005 in a tertiary general hospital on the island of Crete, Greece. RESULTS: Overall, 9.5% of the isolates were beta-lactamase producing. Resistance to ampicillin and amoxicillin-clavulanate was observed in 11 and 0.6% of the strains, respectively, remaining stable throughout the study period. Resistance to tetracycline increased from 1.6% in 1996 to 38% in 2005, while resistance to ciprofloxacin and ofloxacin was <1%. A significant decrease in resistance to trimethoprim-sulfamethoxazole was observed during the study period. No significant changes in resistance to other antimicrobials were seen. CONCLUSIONS: Amoxicillin-clavulanate and older quinolones remain potent agents against H. influenzae. Constant surveillance ofantibiotic susceptibility of H. influenzae clinical isolates is important in order to guide appropriate empirical antibiotic therapy.

Gastric Carcinoid in a Young Woman with Systemic Lupus Erythematosus and Atrophic Autoimmune Gastritis.

BACKGROUND: Gastric carcinoid is a rare tumour that is associated with chronic atrophic gastritis in the majority of cases. It usually occurs in the 6th or 7th decade of life and is rarely diagnosed in patients under 30 years of age. METHODS: We describe a case of multiple gastric carcinoids in a 23-year-old woman with systemic lupus erythematosus and atrophic autoimmune gastritis--an association that has not been reported previously. RESULTS: The combination of atrophic autoimmune gastritis and gastric carcinoid with other autoimmune disorders has rarely been reported in the English medical literature. CONCLUSION: The fact that it mostly concerns (relatively) young patients may suggest a potential causative relation between those autoimmune disorders and the early development of atrophic gastritis with hypergastrinaemia, which subsequently leads to the occurrence of gastric carcinoid tumours at a young age.

Successful treatment of rhinocerebral mucormycosis with liposomal amphotericin B and surgery in two diabetic patients with renal dysfunction.

The zygomycetes are a class of fungi that can cause a variety of infections in humans. Rhinocerebral mucormycosis is a rare disease and usually affects diabetic or immunosuppressed patients. The disease progresses rapidly and is usually fatal despite aggressive surgical and medical therapy. We report the management of two cases of rhino-sinusal and orbital mucormycosis in diabetic patients on treatment with corticosteroids, and mild renal impairment, successfully treated with a combination of aggressive surgical debridement and liposomal amphotericin B.

Staphylococcus aureus nasal carriage might be associated with vitamin D receptor polymorphisms in type 2 diabetes.

Vitamin D receptor (VDR) gene polymorphisms have been associated with susceptibility to several diseases, including type 1 diabetes (T1D), type 2 diabetes (T2D), and various infections. The study investigated whether VDR gene polymorphisms influence nasal carriage of Staphylococcus aureus in individuals with T2D, an important source for bloodstream, surgical site and other nosocomial infections. In 173 patients with T2D genotyped for the VDR gene polymorphisms on FokI (rs10735810) F>f, BsmI (rs1544410) B>b, ApaI (rs7975232) A>a, and TaqI (rs731236) T>t, a nasal swab was obtained to detect colonization by S. aureus. A repeat swab was obtained in 162/173 subjects for the estimation of persistent S. aureus carriage. The prevalence of S. aureus nasal colonization was 19.7% and of persistent carriage was 8.6%. Nasal colonization by S. aureus was more common in individuals with FokI f allele than F allele (p 0.05; OR 1.69, 95% CI 1.00-2.89) and individuals with FokI ff genotypes were more frequently colonized than those with FokI FF and Ff genotypes combined (p 0.03; OR 2.61, 95% CI 1.14-5.99). The presence of the FokI f allele was related to higher rates of S. aureus persistent nasal colonization (p 0.002; OR 3.53, 95% CI 1.56-7.98), and individuals with a FokI ff genotype were more often persistent carriers than those with FokI FF and Ff genotypes combined (p <0.001; OR 7.32, 95% CI 2.39-22.41). This study is the first, to our knowledge, to show an association between FokI polymorphism in the VDR gene and nasal carriage of S. aureus in individuals with T2D.

A prospective, cohort, multicentre study of candidaemia in hospitalized adult patients with haematological malignancies.

Invasive candidiasis is a life-threatening infection in patients with haematological malignancies. The objective of our study was to determine the incidence, microbiological characteristics and clinical outcome of candidaemia among hospitalized adult patients with haematological malignancies. This is a population-based, prospective, multicentre study of patients ≥ 18 years admitted to haematology and/or haematopoietic stem cell transplantation units of nine tertiary care Greek hospitals from January 2009 through to February 2012. Within this cohort, we conducted a nested case-control study to determine the risk factors for candidaemia. Stepwise logistic regression was used to identify independent predictors of 28-day mortality. Candidaemia was detected in 40 of 27,864 patients with haematological malignancies vs. 967 of 1,158,018 non-haematology patients for an incidence of 1.4 cases/1000 admissions vs. 0.83/1000 respectively (p <0.001). Candidaemia was caused predominantly (35/40, 87.5%) by non-Candida albicans species, particularly Candida parapsilosis (20/40, 50%). In vitro resistance to at least one antifungal agent was observed in 27% of Candida isolates. Twenty-one patients (53%) developed breakthrough candidaemia while receiving antifungal agents. Central venous catheters, hypogammaglobulinaemia and a high APACHE II score were independent risk factors for the development of candidaemia. Crude mortality at day 28 was greater in those with candidaemia than in control cases (18/40 (45%) vs. 9/80 (11%); p <0.0001). In conclusion, despite antifungal prophylaxis, candidaemia is a relatively frequent infection associated with high mortality caused by non-C. albicans spp., especially C. parapsilosis. Central venous catheters and hypogammaglobulinaemia are independent risk factors for candidaemia that provide potential targets for improving the outcome.

Effectiveness and nephrotoxicity of intravenous colistin for treatment of patients with infections due to polymyxin-only-susceptible (POS) gram-negative bacteria.

The prospective case series study presented here was conducted to assess the outcome of patients with infections caused by polymyxin-only-susceptible (POS) gram-negative bacteria managed with intravenous colistin. Between July 2003 and April 2005 a total of 27 patients were infected with a POS gram-negative bacterium and received intravenous colistin at a dose of 2 million international units (MIU) (160 mg or 66.7 mg colistin base) every 8 h for a mean (+/-SD) duration of 13.9 (+/-7.5) days. Nine patients had ventilator-associated pneumonia and received, in addition to the intravenous colistin therapy, 1 MIU (80 mg or 33.3 mg colistin base) aerosolized colistin every 12 h for a mean (+/-SD) duration of 13 (+/-6.5) days. The predominant pathogens were Pseudomonas aeruginosa (n = 17) and Acinetobacter baumannii (n = 12); in two patients both pathogens were isolated from one clinical specimen. In-hospital mortality and clinical response were 15% and 85%, respectively. Colistin-associated nephrotoxicity was observed in two of the 27 patients. POS gram-negative pathogens represent a major threat for hospitalized patients. Colistin appears to be an effective and safe treatment, even in patients with severe underlying diseases.