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Protection of chickens against highly pathogenic avian influenza virus (H5N2) by recombinant fowlpox viruses.

Two recombinant fowlpox viruses containing the avian influenza H5 hemaglutinin (HA) gene were evaluated for their ability to protect chickens against challenge with a highly pathogenic isolate of avian influenza virus (H5N2). Susceptible chickens were vaccinated with the parent fowlpox vaccine virus or recombinant viruses either by wing-web puncture or comb scarification. Following challenge 4 weeks later with highly pathogenic avian influenza virus, all birds vaccinated by the wing-web method were protected by both recombinants, while 50% and 70% mortality occurred in the two groups of birds vaccinated by comb scarification. Birds vaccinated with the unaltered parent fowlpox vaccine virus or unvaccinated controls experienced 90% and 100% mortality, respectively, following challenge. Hemagglutination-inhibition (HI) antibody levels were low, and agar-gel precipitin results were negative before challenge. Very high HI titers and positive precipitating antibody responses were observed in all survivors following challenge.

Animals↗

[A survey of nosocomial infection by Salmonella typhimurium].

140 cases of infections by Salmonella typhimurium were studied from June 1987 to the end of 1988. Among those patients 56% of the cases were hospital-acquired. The nosocomial infection rate of the disease in the hospital was 14.6%. The majority of these cases were found in infants and young children. The sources of infections were the sporadic out patients. Improper isolation and disinfection caused the spreading of the infection in the hospital. As we noticed, nosocomial infection by S. typhimurium could occur during the whole year and had an increased incidence in winter. Due to pathogens isolated from those patients were highly resistant to antibiotics so the nosocomial infection could delay the hospitalization time, therefore how to control it became an important aspect of the hospital.

Adult↗

Aetiology and prognosis of bacteraemia in Italy.

A prospective multi-centre study was conducted to assess the microbiological pattern and prognostic factors of bacteraemia and their impact on clinical outcome. All patients admitted to 41 Italian hospitals over 2 months, from whom one or more clinically significant organisms were isolated from blood culture, were studied according to a standardized protocol and case definition. A total of 156 episodes of bacteraemia were identified in 20,601 patients. There were 3.9 episodes of nosocomially acquired bacteraemia and 3.7 episodes of community-acquired bacteraemia per 1000 admissions. The most frequent pathogens isolated were Gram-negative bacteria (44.9%) but Gram-positive species accounted for 40.4 % of episodes. Fungal infections due to Candida spp. were found in 3.8 % of episodes, and multiple pathogens were recovered from 9.6% of episodes. The clinical response to bacteraemia was classified as sepsis in 90 episodes (577%), severe sepsis in 21 (13.5%) and septic shock in 26 (167%); 19 episodes (12.2%) showed no clinical response. The total in-hospital mortality was 25.0%. By multivariate logistic regression, the variables which independently predicted mortality were increasing age, the presence of septic shock, infection with Gram-positive bacteria or fungi and nosocomial acquisition.

Adolescent↗

Pathogen occurrence and antimicrobial susceptibility of urinary tract infection cases during a 20-year period (1983-2002) at a single institution in Japan.

Urinary tract infections are one of the most common infectious diseases diagnosed in outpatients as well as in hospitalized patients. Recently, urinary tract infections have become more complicated and difficult to treat. Therefore, the present study analyzed the occurrence and antimicrobial susceptibility of uropathogens isolated at Kobe University Hospital between 1983 and 2002. This study was performed with three patient groups: urology inpatients, urology outpatients, and inpatients of other departments. During the 20-year study period, we studied 15,925 urine isolates obtained from those patients who were diagnosed with urinary tract infection. Overall, Enterococcus faecalis was the most frequently isolated pathogen, followed by Pseudomonas aeruginosa and Escherichia coli. The frequency of Staphylococcus aureus increased over time, corresponding to an increase in the occurrence of methicillin-resistant S. aureus (MRSA). In addition, the rate of isolation of Serratia marcescens also increased over time, especially among patients with urinary tract catheters. Our results demonstrate that the uropathogens isolated at a single institution have shown a trend of increasing resistance to various classes of antimicrobial agents. In addition, serious problems should be anticipated in the treatment of multidrug-resistant P. aeruginosa, fluoroquinolone-resistant E. coli, and arbekacin-resistant MRSA.

Drug Resistance, Bacterial↗

Five-year surveillance of nosocomial infections in Ankara Training and Research Hospital.

The objective of this study was to assess the rate of nosocomial infections (NIs), frequency of nosocomial pathogens and antimicrobial susceptibility changes in a 530-bed hospital over a five-year period. Hospital-wide laboratory-based NI surveillance was performed prospectively between 1999 and 2003. The Centers for Disease Control and Prevention's definitions were used for NIs and nosocomial surgical site infections, and NI rates were calculated by the number of NIs per number of hospitalized patients on an annual basis. NI rates ranged between 1.4% and 2.4%. Higher rates were observed in the neurology, neurosurgery, paediatric and dermatology departments; the low rate of NIs overall may be due to the surveillance method used. The most commonly observed infections were urinary tract, surgical site and primary bloodstream infections, and the most frequently isolated pathogens were Escherichia coli, Klebsiella pneumoniae, Enterococcus spp. and Staphylococcus aureus. Carbapenems were the most effective agents against enterobacteriaceae. Meticillin resistance among S. aureus isolates was less than 50%, and all S. aureus and Enterococcus spp. isolates were susceptible to glycopeptides apart from one glycopeptide-resistant E. faecium isolate identified in 2003. Data obtained by the same method enabled comparison between years and assisted in the detection of recent changes. Antimicrobial susceptibility data on nosocomial pathogens provided valuable guidance for empirical antimicrobial therapy of NIs.

Anti-Bacterial Agents↗

Genetic identification and detection of human pathogenic Rhizopus species, a major mucormycosis agent, by multiplex PCR based on internal transcribed spacer region of rRNA gene.

BACKGROUND: Mucormycosis is an invasive opportunistic infection caused by fungi belonging to the order Mucorales. Due to the lack of laboratory tests, the diagnosis of mucormycosis is notoriously difficult. Added with its rapid progression as well as the debilitated state of the patients who contract the disease, mortality is extremely high. OBJECTIVE: The goal of this study was to genetically identify human pathogenic Rhizopus species, a major mucormycosis agent, by the internal transcribed spacer (ITS) region of rRNA gene. METHODS: Primers were designed to identify five Rhizopus species known to cause human disease by multiplex PCR. PCR was done not only with test strains and clinical isolates, but also with clinical samples from cutaneous mucormycosis patients. Sporangiospore morphology was observed by scanning electron microscopy to confirm the correlation of phenotypic and genotypic features. RESULTS: Multiplex PCR identified five Rhizopus species including Rhizopus oryzae, where R. azygosporus could only be distinguished from R. microsporus by certain polymorphisms that were present in its sequence. When this multiplex PCR was applied to clinical samples from three mucormycosis patients (paraffin sections from all and sera from one patient), Rhizopus DNA corresponding to the isolated pathogens were specifically detected. CONCLUSION: While fungal DNA detection from clinical samples is a rigorously studied area, this is the first report to genetically identify and detect Rhizopus species from human mucormycosis specimens. This may expand the possibility of this multiplex PCR system not only to identify isolated fungi, but also as a screening method for visceral mucormycosis.

Adolescent↗

Comparison of the Oxoid Signal blood culture system with supplemented peptone broth in a pediatric hospital.

We compared the Oxoid Signal bottle (Oxoid, U.S.A.) with supplemented peptone broth (SPB) tubes (B-D Vacutainer; Becton Dickinson Vacutainer Systems) for performing blood cultures in a pediatric hospital. Blood from 3,066 samples was divided equally between the two systems. Of 131 probable pathogens isolated, 121 were detected in the Signal bottle and 111 were detected in the SPB tubes (P greater than 0.05). Of 167 probable contaminants, 122 grew in the Signal bottle and 109 grew in the SPB tubes (P greater than 0.05). The recovery of staphylococci, both probable pathogens and probable contaminants, was increased in the Signal bottle. The recoveries of other organisms, including streptococci, members of the family Enterobacteriaceae, and yeasts, were similar in the two systems. However, the Signal bottle failed to detect three isolates of Haemophilus influenzae, and the time to availability of isolated colonies of other isolates of H. influenzae was delayed. Overall, the Signal bottle was easy and convenient to use, and its innovative detection system should facilitate the early recognition of positive cultures. If its ability to recover H. influenzae can be improved, the Signal bottle could be a useful alternative to existing systems for use in a pediatric setting.

Bacteria↗

Sternal surgical-site infection following coronary artery bypass graft: prevalence, microbiology, and complications during a 42-month period.

OBJECTIVE: Surgical-site infection (SSI) is a serious and costly complication following coronary artery bypass graft (CABG). We analyzed surgical factors, microbiology, and complications at a 608-bed community teaching hospital to identify opportunities for prevention. METHODS: All patients undergoing CABG procedures from June 1997 through December 2000 were analyzed. Hospital records and postdischarge surveillance data were reviewed for demographics, surgical information, timing and classification of infection, microbiology, and bacteremic events. RESULTS: Of 3,443 patients undergoing CABG, sternal SSI developed in 122 (3.5%); 71 (58.2%) were classified as superficial SSI and 51 (41.8%) as deep SSI. Surgical antimicrobial prophylaxis was employed in all cases. On average, infection occurred 21.5 days (range, 4 to 315) after CABG. Most cases were diagnosed on readmission (59%); 20 cases (16%) were identified by postdischarge surveillance. Microbiological data were positive in 109 (89.3%), with a single pathogen implicated in most (86.2%). Gram-positive cocci were most frequently recovered (81%); gram-negative bacilli (17%), gram-positive bacilli (1%), and yeast (1%) were less common. Staphylococcus aureus was the most frequently isolated pathogen (49%). Bacteremia was noted in 22 instances (18%). It was significantly associated with deep SSI (P =. 002) and identified only in S. aureus cases. CONCLUSIONS: SSI complicated 3.5% of the procedures. S. aureus was implicated in most of the cases and was significantly associated with deep SSI. It was the only pathogen associated with secondary bacteremia. In addition to standard guidelines, targeted methods against S. aureus should help reduce the overall rate of SSI.

Aged↗

Molecular epidemiology of extended-spectrum beta-lactamases produced by clinical isolates in a university hospital in Greece: detection of SHV-5 in Pseudomonas aeruginosa and prevalence of SHV-12.

To assess the nature and diversity of various types of SHV and TEM derivatives in our hospital a survey was conducted. Sixty-seven extended-spectrum beta-lactamases (ESBL)-producing nosocomial pathogens, isolated over a 12-month period, were analyzed by means of PCR and direct sequencing. SHV-5 was the predominant ESBL found in our region (38 strains). Other less frequent variants included SHV-2 and SHV-12 with two and three isolates, respectively. For the first time, an outbreak of 11 Pseudomonas aeruginosa producing SHV-5 was encountered. All blaTEM-positive strains carried the non-ESBL TEM-1. The incidence of non-SHV non-TEM ESBLs was remarkably high as almost one out of three isolates harbored such an ESBL. The epidemiological and clinical impact of these findings must be carefully investigated and interpreted.

DNA, Bacterial↗

Current and future management of serious skin and skin-structure infections.

The purpose of this study was to compare in a randomized, open-label clinical study, the efficacy and safety of cefepime (1 g every 12 hours) with that of ceftazidime (1 g every 8 hours) in patients with serious skin and skin-structure infections. Of 298 patients enrolled in the study, 130 with serious skin and skin-structure infections were evaluable. Demographics and underlying medical conditions were comparable in both groups. The most common infections were cellulitis, abscesses, ulcers, and postoperative wound infections. The most common pathogens isolated were Staphylococcus aureus, group A streptococci, Enterobacteriaceae, and Pseudomonas aeruginosa. Duration of therapy in the 93 patients treated with cefepime was 3-18 days and in the 37 ceftazidime-treated patients was 4-16 days. Pathogen bacteriologic response rates were high: 92% (124 of 135) of pathogens were eradicated by cefepime and 95% (55 of 58) by ceftazidime. Clinical response rates were satisfactory in 88% (82 of 93) of cefepime-treated patients and in 89% (33 of 37) of ceftazidime-treated patients. Adverse events occurred with similar frequency in both groups. Events probably related to study drugs affected 3% (6 of 198) of patients treated with cefepime and 4% (4 of 100) of ceftazidime-treated patients. Cefepime, a new parenteral cephalosporin administered every 12 hours, is an extremely well tolerated and effective alternative to ceftazidime given every 8 hours for the treatment of serious skin and skin-structure infections.

Bacteria↗

[Observational study investigating the use of levofloxacin in ICU patients].

INTRODUCTION: There is little information on the use of levofloxacin, a new quinolone, in ICU patients. OBJECTIVE: To investigate the criteria for the use of levofloxacin (indications, forms of prescription, doses, and routes of administration) and to study tolerance in patients admitted to the ICU. Method. Prospective, observational study performed from October 2000 to November 2001 in 35 ICUs and including the first 15 patients receiving levofloxacin as monotherapy or combined treatment. Descriptive data are expressed as mean and percentage. Statistical significance was set at P < .05. RESULTS: A total of 543 indications for treatment with levofloxacin were analyzed. The patients were 70.7% men, with a mean (SD) age of 60.2 (16.7) years, mean APACHE II score of 18.9 (7.9), and a medical underlying disease in 79.2% of cases. The ICU mortality rate was 24.1%. A total of 60% of patients required mechanical ventilation and 44.3% needed inotropic drug treatment. Levofloxacin was predominantly prescribed for treating community-acquired infections (67.8%), mainly in the respiratory tract (88.1%). An etiological diagnosis was established in only 55.6% of cases. The most common pathogens were Streptococcus pneumoniae (12.7%), Haemophilus influenzae (9.1%), Escherichia coli (7.4%), methicillin-sensitive Staphylococcus aureus (7.2%), Pseudomonas aeruginosa (4.9%), and Legionella pneumophila (4.7%). In 87.1% of indications, levofloxacin was prescribed as empirical treatment. Susceptibility of the isolated pathogens to this antibiotic was confirmed in 32.2% of cases. The initial dose was 500 mg/24 h in 48.5% of indications and 500 mg/12 h in 48.3%. Combined treatment was given in 49.7% of cases. In 32.2% of cases, parenteral administration of levofloxacin was changed to oral route. Adverse events probably or possibly associated with levofloxacin occurred in only 12.5% of patients and mainly included increased ALT/ALS levels (4.4%), diarrhea (2.3%), and heart rhythm alterations (2.1%). CONCLUSIONS: This study describes the profile of critically ill patients receiving levofloxacin and the different forms of its use in the ICU.

Administration, Oral↗

[Treatment of bacterial pneumonias with cefuroxime-axetil. Predictive value of measurement of the in vitro susceptibility].

Cefuroxime axetil is an oral cephalosporin with proven efficacy in adult lower respiratory tract infections. Indeed, it has a broad spectrum of activity in vitro, covering most pathogens isolated in this setting and showing good stability in the presence of betalactamases. In vitro susceptibility data are a major element in the choice of antimicrobial agent. The aim of this study was to determine the predictive value of the cefuroxime minimal inhibitory concentration (MIC) on the clinical outcome of infections treated with cefuroxime axetil. One hundred-and-seventeen (117) patients with radiologically confirmed community-acquired pneumonia of presumed bacterial origin were enrolled in a prospective multicenter trial of cefuroxime axetil therapy (500 mg twice daily). The pathogen was identified in 44 patients who were treated for a mean of 8.8 days. Most isolates were S. pneumoniae (65.9%) and H. influenzae (15.9%). The MIC was known for 35 isolates and was < or = 4 micrograms/ml in 30 cases (85.7%). The MIC value was a good predictor of clinical efficacy with a sensitivity of 100%, a specificity of 83% and a positive predictive value of 97%; the latter value indicates that therapeutic success is virtually certain when the bacterium causing pneumonia is susceptible to cefuroxime.

Adolescent↗

Evaluation of aztreonam in difficult-to-treat infections with prolonged posttreatment follow-up.

Aztreonam at doses of 1 or 2 g given intramuscularly or intravenously every 8 h for 7 to 42 days was given to 55 patients, most of them suffering from difficult-to-treat infections either because the isolated pathogens were multiresistant or because of the location of the infection. Infections included: urinary tract (23 cases), deep soft tissue phlegmon (12 cases), chronic osteomyelitis in exacerbation (7 cases), abscesses (7 cases), pneumonia (4 cases), and external otitis (2 cases). In culture specimens, Pseudomonas aeruginosa (24 isolates) and various Enterobacteriaceae species (37 isolates) were isolated with MICs ranging from 0.25 to 16 micrograms/ml. Clinically, at the completion of treatment and after a 6-week posttreatment follow-up, 45 (81.6%) patients were cured, 4 (7.2%) improved, 3 (5.6%) relapsed, and 3 (5.6%) failed to respond to therapy. Bacteriologically, at the end of treatment, the pathogen was eradicated in 50 patients (91%) and persisted in 5 (9%). After a 6-week follow-up, cultures remained sterile in 33 patients (60.0%), 16 (29.1%) relapsed, in 6 (10.9%) bacteria persisted, and superinfection was reported in 4 (7.3%) patients. No appreciable adverse effects or toxicity was observed. From the reported results, it is concluded that aztreonam is a valuable addition to the field of antimicrobial chemotherapy that can be used effectively and safely in the treatment of a variety of gram-negative infections.

Adult↗

Etiology of community-acquired pneumonia. Evaluation by transtracheal aspiration, blood culture, or serology.

In a 5-year period, 254 patients with community-acquired pneumonia were attended to. Transtracheal aspiration (TTA) could be performed on 119 patients, blood cultures were performed on 201 patients, and 74 patients underwent serologic examinations. By use of these procedures, an etiologic diagnosis was established in 93 cases. Streptococcus pneumoniae was the most common pathogen as it was found in 35 cases. Eleven of these 35 patients (31.4 percent) had pneumococcemia, and the mortality in this group was 27.3 percent. None of the patients with pneumococcal pneumonia and negative blood culture died. Haemophilus influenzae was the only isolated pathogen from transtracheal aspirated sputum in 16 cases and accounted for 17.5 percent of pneumonias in previous healthy individuals under 50 years of age. Mycoplasma pneumonia infections, Legionella pneumophila infections, and Chlamydia infections were found in ten, eight, and three cases, respectively. The overall agreement between microscopy and culture of respiratory secretions obtained by TTA was 58.8 percent, and microscopy can be a guide when choosing the initial antibiotic treatment. No statistically significant difference in the rate of isolating bacteria among patients treated with antibiotics prior to TTA and patients not previously treated with antibiotics was seen. When contraindications were respected, we found TTA to be a safe procedure.

Adolescent↗

Antimicrobial resistance of bacterial pathogens associated with diarrheal patients in Indonesia.

The antimicrobial susceptibility patterns for 2,812 bacterial pathogens isolated from diarrheal patients admitted to hospitals in several provinces in the cities of Jakarta, Padang, Medan, Denpasar, Pontianak, Makassar, and Batam, Indonesia were analyzed from 1995 to 2001 to determine their changing trends in response to eight antibiotics: ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol, tetracycline, cephalothin, ceftriaxone, norfloxacin, and ciprofloxacin. Vibrio cholerae O1 (37.1%) was the pathogen most frequently detected, followed by Shigella spp. (27.3%), Salmonella spp. (17.7%), V. parahaemolyticus (7.3%), Salmonella typhi (3.9%), Campylobacter jejuni (3.6%), V. cholerae non-O1 (2.4%), and Salmonella paratyphi A (0.7%). Of the 767 Shigella spp. isolated, 82.8% were S. flexneri, 15.0% were S. sonnei, and 2.2% were S. dysenteriae (2.2%). The re-emergence of Shigella dysenteriae was noted in 1998, after an absence of 15 years. Shigella spp. were resistant to ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline. Salmonella typhi and Salmonella paratyphi A were susceptible to all antibiotics tested, while Salmonella spp. showed various resistance patterns according to species grouping. A small number of V. cholerae O1 were resistant to ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline; however, they were still sensitive to ceftriaxon, norfloxacin, and ciprofloxacin. Similar results were shown for V. cholerae non-O1. Campylobacter jejuni showed an increased frequency of resistance to ceftriaxone, norfloxacin, and ciprofloxacin, but was susceptible to erythromycin. This study shows that except for C. jejuni and V. parahaemolyticus, which appeared to be resistant to ciprofloxacin, the majority of the enteric pathogens tested were still susceptible to fluoroquinolones.

Adolescent↗

A controlled study of endemic sporadic diarrhoea among adult residents of southern Brazil.

The aetiology of sporadic summer diarrhoea and enterotoxin (LT) antibody titres was studied among 43 adult patients in southern Brazil who had an acute, untreated diarrhoeal illness and 43 age- and sex-matched controls from the same area. A potential pathogen was identified in 33 of 34 patients and in 17 of 43 controls (p less than 0.01). 10 Shigella, one invasive Escherichia coli, one Salmonella and one Entamoeba histolytica were identified in 17 patients with inflammatory diarrhoea (faecal polymorphonuclear neutrophil leucocytes (PMN) present). In the other four only enterotoxigenic strains of E. coli were identified. Among 26 patients with non-inflammatory (no faecal PMN) diarrhoea, heat-stable (ST) toxin-producing coliforms were the most common pathogens isolated (27%). Heat-labile (LT) toxin-producing coliforms or serological rises to LT were seen in five patients, Strongyloides larvae in five, Giardia lamblia trophozoites in four and an LT-producing Salmonella in one. No pathogen was found in 10 patients with non-inflammatory diarrhoea. Among 43 controls, 11 LT coliforms, two Shigella and two Strongyloides larvae were found. 40 of 41 controls had detectable serum anti-LT antibody. A single ST-producing E. coli was found in one other control. No pathogen was identified in 26 controls. No rotaviruses or Norwalk-like viral agents were seen by direct or immune electron microscopy of stool filtrates. While LT-producing E. coli are frequently associated with endemic summer childhood diarrhoea in southern Brazil and are recognized causes of travellers' diarrhoea, this study shows that they are often carried asymptomatically by adults living in this region.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Head and neck space infections in infants and children.

A retrospective study was performed in 117 children with head and neck space infections treated at the Children's Hospital of Pittsburgh from January 1986 through June 1992. Peritonsillar space infections were the most common (49%), followed by retropharyngeal (22%), submandibular (14%), buccal (11%), parapharyngeal (2%), and canine (2%) space infections. The most common pathogens isolated (N = 78) were the aerobes beta-hemolytic streptococcus (18%) and Staphylococcus aureus (18%), the anaerobes Bacteroides melaninogenicus (17%) and Veillonella (14%), and the gram-negative organism Haemophilus parainfluenzae (14%). beta-Lactamase production by aerobic pathogens was detected in 22% of cultures. Computed tomography scans (N = 16) were reviewed in blinded fashion and compared with operative findings. The sensitivity of computed tomography scan in detecting the presence of an abscess vs. cellulitis was high (91%), whereas the specificity was rather low (60%). Treatment of head and neck space infections in children should consist of accurate physical diagnosis aided by imaging studies, empiric antibiotic therapy that covers gram-negative and beta-lactamase--producing organisms as well as gram-positive organisms and anaerobes, and timely surgical intervention, when indicated.

Abscess↗

[Diagnostics and management of central venous line infections in pediatric cancer patients].

Otherwise unexplained clinical signs of infection in patients with tunneled or totally implanted central venous access devices (CVAD) are highly suspicious of an underlying CVAD-associated infection. Diagnostic methods include catheter swabs, blood cultures and cultures of the catheter tip or port reservoir. In case of a suspected CVAD-related blood stream infection in pediatric cancer patients in situ treatment without prompt removal of the device can be tried. The removal of the CVAD should be considered, if bacteremia persists or relapses 72 hours or longer after the initiation of an (in vitro effective) antibacterial therapy administered through the line. The CVAD should be removed even earlier, if the patient suffers from hypotension or other signs of severe organ dysfunction related to the infection. If S. aureus, Pseudomonas aeruginosa, multiresistant Acinetobacter baumannii or Candida spp.are isolated from blood cultures taken through a CVAD, patients are at a high risk for severe complications and immediate device removal is also recommended. Duration of therapy depends on the immunological recovery of the patient (neutrophils counts), the pathogen isolated and on the presence of related complications like thrombosis, pneumonia, endocarditis, osteomyelitis. Antibiotic-lock techniques in addition to systemic treatment are beneficial in Gram-positive infections. Although prospectively controlled studies are missing, the concomitant use of urokinase- or taurolidine seems to favour catheter salvage.

Antineoplastic Agents↗