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PubMed2006

[The combination effects of antibacterial agents against clinical isolated multiple-drug resistant Pseudomonas aeruginosa].

The effectiveness of antibacterial agents against 70 strains of clinically isolated multiple-drug resistant Pseudomonas aeruginosa (MDRP) was measured by the micro dilution method. Fifty of all strains (71%) produced metallo-beta-lactamase and the IMP-1 gene was detected by polymerase chain reaction (PCR). The MIC90 (the minimum inhibitory concentration of an antibiotic necessary to inhibit the growth of 90% of bacterial strains) values of biapenem (BIPM), meropenem (MEPM), tazobactam/piperacillin (TAZ/PIPC), sulbactam/ cefoperazone (SBT/CPZ), cefepime (CFPM), ciprofloxacin (CPFX), pazufloxacin (PZFX), amikacin (AMK) and aztreonam (AZT) were found to be 265, 512, 256, 512, 512, 64, 128, 128 and 128 microg/mL, respectively. The in vitro combination effects of antibacterial agents were examined against 62 strains of MDRP and the synergy or additive effects were evaluated by fractional inhibitory concentration (FIC) index calculated by the checkerboard method. The combination of AMK and AZT showed synergy effects on 15/59 (25.4%) strains of MDRP. The synergy and additive effects on the MDRP strains were also found by the other antibacterial agents combination such as TAZ/PIPC and AMK, CFPM and AMK, and SBT/CPZ and AZT. These results suggested the necessity of further investigation of clinical usefulness.

Amikacin↗

PubMedDate not supplied

[Antimicrobial susceptibility of phenotypically extended spectrum beta-lactamase producing Pseudomonas aeruginosa and Acinetobacter baumannii isolates].

The aim of this study was to investigate the antimicrobial susceptibilities of Pseudomonas aeruginosa and Acinetobacter baumannii strains that were identified as producers of extended spectrum beta-lactamases (ESBL) phenotypically. Fifty three P. aeruginosa and 53 A. baumannii strains that were isolated from patients with hospital infections followed-up by Infectious Diseases Unit of Hacettepe University Adult Hospital in 2002-2004, were included in the study. The susceptibilities of the isolates to ceftazidime, cefotaxime, cefepime, tobramycin, ciprofloxacin, piperacillin-tazobactam, imipenem and meropenem were determined by Etest (AB Biodisk, Solna, Sweden) method. The susceptibility rates of A. baumannii isolates against tobramycin and carbapenem group were 54.7% and 49.1%, respectively; whereas for the rest of the antimicrobial agents tested, these rates were lower than 25 percent. The susceptibility rates of P. aeruginosa isolates against ciprofloxacin, carbapenem group, piperacillin-tazobactam and tobramycin differed between 35-38 percent. Of the P. aeruginosa isolates, 37.5%, and of the A. baumannii isolates 37.7% were resistant against imipenem/meropenem, piperacillin-tazobactam, ciprofloxacin and tobramycin simultaneously. As a result, phenotypically ESBL producing P. aeruginosa and A. baumannii isolates were found highly resistant not only against the third and fourth generation cephalosporins, but also to the antibiotics currently used in the therapy including carbapenemes.

Acinetobacter baumannii↗

PubMed2006

[Antimicrobial susceptibility of Pseudomonas aeruginosa isolated from urine at one hospital to mainly carbapenem and fluoroquinolone drugs].

We tested the drug susceptibility to 8 anti-pseudomonal agents of 97 strains of Pseudomonas aeruginosa isolated from urine between January 1998 and May 2004. The results were as follows. 1. Antimicrobial activity was, in order of superiority to biapenem (BIPM), meropenem (MEPM), ciprofloxacin (CPFX), imipenem (IPM), pazufloxacin (PZFX), amikacin (AMK), ceftazidime (CAZ), piperacillin (PIPC). 2. The resistance rate (intermediate+resistance) to carbapenem drugs was 10.3% for BIPM and MEPM, and 13.4% for IPM. Many of the IPM-resistant strains showed crossover resistance with BIPM and MEPM. 3. The resistance rate (intermediate+resistance) to fluoroquinolone drugs was 23.7% for CPFX and 20.6% for PZFX. 4. One strain showed simultaneous resistance to IPM = 16 microg/mL, CPFX = 4 microg/mL, and AMK = 32 microg/mL, and produced IMP-1 metallo-beta-lactamase. Susceptibility of P. aeruginosa isolated from urine developed resistance to fluoroquinolone drugs. It is important to promote appropriate use of antimicrobial agents and continue to survey emerging resistance in the clinical isolates.

Amikacin↗

PubMed2006

[Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (2004). I. Susceptibility distribution].

The bacterial strains isolated from 490 patients diagnosed as having urinary tract infections (UTIs) in 14 institutions in Japan were collected between August 2004 and July 2005. The susceptibilities of them to many kinds of antimicrobial agents were measured. Of them, 577 strains were estimated as causative bacteria and used for the measurement. The strains consisted of 156 gram-positive bacterial strains (27.0%) and 421 gram-negative bacterial strains (73.0%). Against Staphylococcus aureus, arbekacin (ABK), vancomycin (VCM) showed the strongest activity and prevented the growth of all strains with 2 microg/mL. Against Enterococcus faecalis, ampicillin (ABPC) and VCM showed a strong antibacterial activity. The antibacterial activity of cephems to Escherichia coli was generally good, and especially cefozopran (CZOP) and cefpirome (CPR) showed the strongest activity (MIC90: < or = 125 microg/mL). Quinolone resistant E. coli [MIC of ciprofloxacin (CPFX): > or = 4 microg/mL] was detected at frequency of 18.8%, which was higher than that in the last year. Against Klebsiella pneumoniae, CZOP, meropenem (MEPM), and carumonam (CRMN) showed the strongest activity and prevented the growth of all strains with 0.125 microg/mL or less. The antibacterial activity of the other cephems was relatively good, and decrease in their activity observed in the last year study was not recognized. Against Serratia marcescens, imipenem (IPM) and gentamicin (GM) had the strongest antibacterial activity. Against Proteus mirabilis, CRMN showed the strongest activity and prevented the growth of all strains with 0.125 microg/mL or less. MEPM prevented the growth of all strains with 0.25 microg/mL. Next, cefmenoxime (CMX), ceftazidime (CAZ), CZOP, cefixime (CFIX), cefpodoxime (CPDX), and cefditoren (CDTR) showed a strong activity. The antibacterial activity of the drugs to Pseudomonas aeruginosa was generally low, and MIC90 of all the drugs was ranged from 32 to > 128 microg/mL except IPM and MEPM having 16 microg/mL. The antibacterial activities of CZOP and CAZ were considered to be relatively good on MIC50 comparison (MIC50: 2 microg/mL).

Aminoglycosides↗

PubMed2006

[Pyogenic spondylitis by Enterobacter cloacae as a postoperative complication of TURP: a case report].

We report a case of pyogenic spondylitis caused by Enterobacter cloacae as a rare complication of transurethral resection of the prostate (TURP). A 79-year-old man underwent TURP. Immediate after removal of urethral catheter on postoperative day (POD) 7, he developed high fever > 40 degrees C with increased acute inflammatory reaction. Urine and blood culture detected E. cloacae and methicillin-resistant Staplylococcus aureus. He complained of lumbago since POD 9. Two-week administration of imipenem and teicoplanin resulted in resolution of fever as well as laboratory data, so intravenous antibiotics were changed to oral gatifloxacin. However, his lumbago worsened and gait disturbance appeared. On POD 39, diagnosis of pyogenic spondylitis was finally obtained by Ga-scintigraphy and magnetic resonance imaging. Aspiration of the intervertebral disk (L4-5) revealed E. cloacae as the causative organism of pyogenic spondylitis. His condition improved after conservative treatment with teicoplanin, meropenem and ciplofloxacin for 9 weeks.

Aged↗

PubMed2006

Antibiotic-resistance patterns and frequency of extended-spectrum beta-lactamase-producing isolates of Klebsiella pneumoniae in Tehran.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing strains of Klebsiella pneumoniae have caused major therapeutic problems worldwide since the majority are resistant to various antibiotics. In this study, an investigation was conducted regarding antibiotic-resistant patterns of 128 isolates of K pneumonile cultured from Iranian patients at two teaching hospitals during 2004-2005. MATERIAL/METHODS: The susceptibility of isolates to 21 antimicrobial agents was determined using the disk diffusion method. Disks containing ceftazidime, cefotaxime, ceftazidime/clavulanic acid, and cefotaxime/clavulanic acid were used in the phenotypic confirmatory (PCT) method to detect ESBL isolates. A comparison between the confirmatory method and double-disk synergy test (aztreonam, ceftazidime, ceftriaxone, cefotaxime, and amoxicillin/clavulanic acid) was also made to assign the appropriate method of detection for ESBLs. The E-test was used to determine the susceptibility of isolates to cefepime. RESULTS: All strains were susceptible to imipenem and meropenem. Resistance to ciprofloxacin and gentamicin were found in 37% (n=47) and 33% (n=42) of isolates, respectively. Production of ESBL was detected in 44.5% of isolates. Resistance to cefepime was found in 40% of isolates. CONCLUSIONS: The prevalence of ESBL strains in the study hospitals is high. The double-disk synergy method is not preferable in successfully detecting ESBL strains. More importantly, 33% of ESBL strains were also resistant to ciprofloxacin and aminoglycosides. Based on the laboratory results, it is recommended that prescription of cephalosporins be restricted to susceptible isolates and that the usage of other effective antibiotics be considered.

Anti-Infective Agents↗

PubMed2006

[Catheter associated Staphylococcus sciuri sepsis in a patient with acute myeloid leukemia].

The coagulase-negative bacterial species Staphylococcus sciuri is widely distributed in the natural environment. Although principally found in animals, S. sciuri is occasionally isolated from human samples. In this paper, S. sciuri bacteremia which was associated with an indwelling catheter of a patient with acute myeloid leukemia (AML) and neutropenia was presented. An empirical intravenous antibiotic therapy (meropenem, vancomycin) was initiated with the preliminary diagnosis of febrile neutropenia and catheter infection. The catalase and oxidase positive, tube coagulase negative strain isolated from three of the concurrent blood cultures and intravenous catheter culture has been identified as S. sciuri. The isolate was found resistant to penicilin and oxacilline. This case has emphasized the importance of identification of coagulase-negative staphylococci isolated from the cultures of patients with haematological malignancy.

Anti-Bacterial Agents↗

PubMed1996

[Current problems in the treatment of bacterial meningitis].

This paper on bacterial meningitis looks at aspects inherent in the aetiology and mechanisms underlying neurological damage and pharmacological treatment. Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis are the pathogens most commonly responsible and are able to colonise the host's respiratory mucosae, invade the vascular space, cross the haematoliquoral barrier and survive in the cerebrospinal fluid. The presence of germs in the subarachnoid spaces leads to the onset of inflammation and neurological damage. The most often used pharmacological treatments include, apart from antibiotics, anti-inflammatory drugs (although we have clinical data for corticosteroids only), pentoxyphillin and monoclonal antibodies. Initially empiric, antibiotic therapy is based on the use of drugs that act against the probable pathogenic agents, are capable of surmounting the haematoliquoral barrier and are well tolerated. Prior to the Eighties, the antibiotic of choice was ampicillin associated or otherwise with aminoglycosides. Subsequently, the availability of new drugs (cefotaxime and ceftriaxone) and the appearance of resistance led to changes in therapeutic protocols. Of the carbapenemics, wide spectrum antibiotics with high resistance to beta lactamase, imipenem /cilastatin proved effective although there was a high risk of inducing convulsions in patients with previous neurological damage or kidney failure. Meropenem was able to surmount the haematoliquoral barrier in sufficient concentrations and was well tolerated in patients with prior neurological changes. It has proved effective in clinical studies carried out up to the present.

Aminoglycosides↗

PubMed1997

[In vitro combination effect of vancomycin and carbapenems against carbapenem-resistant MRSA].

We determined in vitro combined effects of vancomycin (VCM) plus carbapenems (CRBs) on 12 methicillin-resistant Staphylococcus aureus (MRSA) which are resistant to CRBs. Combinations of VCM plus imipenem (IPM) and VCM plus panipenem (PAPM) and VCM plus meropenem (MEPM) indicated synergistic effects, fractional inhibitory concentration (FIC) indices of < or = 0.05, against 67%, 75%, 67% of the strains, respectively. Against forty two percent of strains tested, 1 MIC of VCM was equal to 1 MBC, and similarly, IPM, PAPM and MEPM had 1 MIC = 1 MBC against 42%, 67% and 75% of the strains tested, respectively. Combinations of VCM plus IPM and VCM plus PAPM and VCM plus MEPM showed synergistic effects, hence a fractional bactericidal concentration (FBC) index of < or = 0.50, against 42%, 50%, 75% of the strains, respectively, and the combination of VCM plus MEPM was most synergistic. These results suggest that combination therapy of VCM with CRB is useful for the treatment of MRSA infection in patients with renal dysfunction.

Anti-Bacterial Agents↗

PubMed1997

[Febrile neutropenia: empiric antibiotic therapy from 1975 to 1997].

Monotherapy with ceftazidime, cefepime, imipenem or meropenem for the empiric treatment of febrile neutropenia appears as effective as the combination therapy involving aminoglycosides. However, empiric therapy with a combination of a beta-lactam plus an aminoglycoside is a reasonable decision under circumstances where Gram negative sepsis is very likely. Monotherapy is usually associated with a modest rate of response in infections caused by Gram positive organisms. In about 30% of the patients, a glycopeptide will be added at some point, because the response to the initial therapy is not considered optimal.

Aminoglycosides↗

PubMed1998

[The antimicrobial susceptibilities and serotypes of Pseudomonas aeruginosa isolated from sputum].

During the period of January 1992 and August 1995, 75 strains of Pseudomonas aeruginosa were isolated from sputum at the Hiroshima Prefectural Hiroshima Hospital. The antimicrobial susceptibilities and serotypes of those strains were investigated. The results are summarized as follows: 1. The analyses of antimicrobial susceptibilities revealed that meropenem (MEPM) was the most active among the carbapenems tested against those P. aeruginosa strains with MIC of < or = 6.25 micrograms/ml. All of the strains were thus found to be susceptible to MEPM, while 9 strains out of 75 (12%) were resistant to imipenem showing cross-resistance to biapenem. 2. The activities of the beta-lactams other than carbapenems were found to be the order of cefozopran > or = ceftazidime > aztreonam > piperacillin with MIC50 and MIC90 ranging of 3.13-6.25 micrograms/ml and 25- > or = 100 micrograms/ml, respectively. 3. Among aminoglycosides tested, 3 strains (4.0%) of the strains showed resistance to amikacin, however none of them were resistant to tobramycin. 4. Distribution of serotypes among the strains was; type G 22.7%, type M 21.3%, type A 16.0%, type B 13.3% and type E 8.0%. Strains of types M and E showed multiple resistance to beta-lactams except carbapenems. As documented in this study, the frequency of isolation of beta-lactam-resistant P. aeruginosa (including carbapenem-resistant) is steadily increasing. Continuous surveillance of antimicrobial susceptibility among clinically isolated P. aeruginosa seems to be necessary.

Anti-Bacterial Agents↗

PubMed1998

Antimicrobial susceptibility testing for Klebsiella pneumoniae isolates resistant to extended-spectrum beta-lactam antibiotics.

Detection of Klebsiella pneumoniae strains with extended-spectrum beta-lactamase (ESBL)-related resistance phenotypes is becoming important in clinical microbiology laboratories. In this study, we investigated the usefulness of three screening methods, the Etest ESBL screen, the double-disk synergy test, and the ceftazidime disk test, for identifying ESBL-producing K. pneumoniae strains. The agar dilution method was used as the standard. We also determined the in vitro activity of several new antimicrobial agents against these organisms. Strains that exhibited an increase in the minimum inhibitory concentration (MIC) to the third-generation cephalosporins or aztreonam of 2 micrograms/mL or more, but were susceptible to the three cephamycins tested, were considered to have ESBL-related resistance phenotypes. The frequency of ESBL-producing K. pneumoniae isolates (according to the disk-diffusion method) has increased markedly in recent years, from 3.4% in 1993 to 10.3% in 1997. A total of 93 preserved isolates of K. pneumoniae collected from December 1995 through March 1997 were found to be resistant to at least one of the third-generation cephalosporins (cefotaxime and ceftazidime) or aztreonam using the routine disk diffusion method. Among these isolates, 35 were classified as having an ESBL phenotype using the agar dilution method. The remaining 58 isolates were classified as cephamycin resistant, which indicated resistance to both cephamycins and third-generation cephalosporins or aztreonam. The susceptibility rates of the ESBL-producing isolates were 11% for cefotaxime, 14% for ceftazidime, and 6% for aztreonam. The susceptibility rates of these 35 isolates to imipenem, ciprofloxacin, and ofloxacin were 100%, 80%, and 86%, respectively. Both the MIC50 and MIC90 of meropenem were 0.06 microgram/mL, while the MIC50 and MIC90 of BAY 12-8039 were 0.125 and 2 micrograms/mL, respectively. Thirty-two (91%) of the 35 isolates of K. pneumoniae with the ESBL-related resistance phenotype were detected by the Etest ESBL screen, while the ceftazidime disk screen test detected 77% of these isolates, and the double-disk synergy test detected 74%. The Etest ESBL screen appears to be an acceptable, convenient, and sensitive method for the detection of ESBL-producing isolates in the clinical microbiology laboratory.

Anti-Infective Agents↗

PubMed1998

[Antimicrobial activity of carbapenem antibiotics against gram-negative bacilli].

Antimicrobial activities of meropenem (MEPM), imipenem (IPM), panipenem (PAPM), ceftazidime (CAZ), cefozopran (CZOP), aztreonam (AZT), norfloxacin (NFLX) and tetracycline (TC) against clinically isolated Gram-negative bacilli [271 strains of Enterobacteriaceae and 242 strains non-fermentative Gram-negative bacteria (NFB)] were investigated. Among carbapenem antibiotics, MEPM showed the lowest MIC90, which activity was about four-hold higher than those of IPM and PAPM. The activity of IPM was equal or slightly superior to that of PAPM. Resistance to IPM (> 16 micrograms/ml) was observed in 3 strains of Enterobacteriaceae (1.1%) and 14 strains of NFB (5.8%). It is conceivable that these strains produce metallo-beta-lactamase. Referring to the correlation among MICs of MEPM, IPM and PAPM, 3 strains in 3 species of Enterobacteriaceae showed cross resistance to carbapenems; while 14 strains of NFB showed cross resistance to MEPM and IPM, 15 strains to MEPM and PAPM, and 29 strains to IPM and PAPM, and all of these strains were Pseudomonas aeruginosa. Fifteen of 29 strains of IPM-resistant and 77 of 92 strains of PAPM-resistant P. aeruginosa were susceptible to MEPM. Thirty-three strains (12%) of the Enterobacteriaceae were resistant to CAZ and AZT (> or = 32 micrograms/ml) and these were considered as ESBL-producing strains.

Anti-Bacterial Agents↗

PubMed1998

[Imipenem resistance in Pseudomonas aeruginosa].

In 1997 in western Austria, 9.9% of Pseudomonas aeruginosa strains from patients of general practitioners were resistant to imipenem as well as 18.2% of the isolates from hospitals and 20.2% of the strains at a university teaching hospital. Within the hospital the imipenem resistance varied from 9.9% among out-patients to 28.7% in isolates from intensive care units. In medical/surgical words, up to 15.1% of P. aeruginosa strains were resistant to imipenem. The incidence of imipenem-resistant P. aeruginosa strains correlates to the use of carbapenems. In June 1997, 10 consecutive isolates from 8 patients were obtained and typed using restriction fragment length polymorphism analysis (RFLP) and Pyocin typing. All 10 isolates were resistant to meropenem as well as to imipenem. The finding (by RFLP and Pyocin typing) of individual bacterial types in each isolate strongly contradicts the spread of infection by cross infection. However, all patients were proven to have been treated with imipenem during the 3 months prior to testing. In 1997, 13,880 g of imipenem were used at the university hospital in Innsbruck. The use of carbapenems appears to be the main cause for the increased incidence of imipenem-resistant P. aeruginosa strains.

Austria↗

PubMed2002

Citywide clonal outbreak of multiresistant Acinetobacter baumannii and Pseudomonas aeruginosa in Brooklyn, NY: the preantibiotic era has returned.

BACKGROUND: Carbapenems are important agents for treating nosocomial gram-negative infections. Carbapenem-resistant bacteria have become increasingly problematic in certain regions. This study determined the citywide prevalence and molecular epidemiological features of carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa in Brooklyn, NY. METHODS: All unique patient isolates of A baumannii and P aeruginosa were collected from 15 Brooklyn hospitals from July 1, 1999, through September 30, 1999. Antibiotic susceptibilities, the genetic relatedness of resistant isolates, and the relationship between antibiotic use and resistance rates were determined. RESULTS: A total of 419 isolates of A baumannii and 823 isolates of P aeruginosa were collected. For A baumannii, 53% were resistant to meropenem and/or imipenem, and 12% were resistant to all standard antibiotics. Ribotyping revealed that a single clone accounted for 62% of the samples and was isolated from patients at all 15 hospitals. The rate of carbapenem resistance was associated with cephalosporin use at each hospital (P =.004). For P aeruginosa, 24% were resistant to imipenem, 5% to amikacin, and 15% to 29% to other antipseudomonal agents. Ribotyping revealed that 3 clones accounted for nearly half of the isolates and were shared by most hospitals. CONCLUSIONS: Approximately 400 patients were infected or colonized with carbapenem-resistant A baumannii and P aeruginosa during a 3-month period in 1999. A few strains have spread widely throughout hospitals in this region. The prevalence of resistant A baumannii seems to be correlated with cephalosporin use. Multiresistant hospital-acquired bacteria should be viewed as a serious public health issue rather than an individual hospital's problem. An intensive coordinated effort will be needed to effectively address this problem.

Acinetobacter↗

PubMed1998

Synthesis and antibacterial activities of new carbapenems having a proline reverse amide moiety at the C-2 position.

The synthesis of new 1 beta-methylcarbapenems (1a-l) having a proline reverse amide moiety at the C-2 position and their in vitro antibacterial activities are described. The compounds were evaluated by the Mueller-Hinton agar dilution method and compared with meropenem as control. Aliphatic amides (1a-h) are found to show greater antibacterial activity than aromatic amides (1i-l). Moreover, C-2 free amino compound (1m) reveals greater activity than any other amide compounds (1a-l).

Anti-Infective Agents↗

PubMed2002

Synthesis and antibacterial activity of 1beta-methylcarbapenems having a 2, 2-disubstituted-1, 3-diazabicyclo[3.3.0]octan-4-one moiety and related compounds. Part III.

The synthesis of new series of 1beta-methylcarbapenems having a 2, 2-disubstituted-1, 3-diazabicyclo[3.3.0]octan- and -[4.3.0]nonan-4-one moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent of the bicyclic ring was investigated. A particular compound (16 f) bearing a hydroxymethyl group showed the most potent antibacterial activity and the compound (17 a) with a 1, 3-diazabicyclo[4.3.0]nonane moiety exhibited excellent stability against renal dehydropeptidase-I (DHP-I) to Meropenem.

Anti-Bacterial Agents↗

PubMedDate not supplied

Bacteriologic and therapeutic considerations in intra-abdominal surgical infections.

The most important factor in the treatment of intra-abdominal infections are early diagnosis and prompt surgical intervention while antibiotics play a secondary role. The goals of surgical procedures should be to stop peritoneal contamination, to debride necrotic tissue, to remove debris and foreign bodies and to drain any pus collection. Antibiotics should be initiated before surgery and they must encompass both colonic aerobes and anaerobes including Bacteroides fragilis group but not necessary Enterococcus sp. Antibacterial agents with pure activity against anaerobes include chloramphenicol, clindamycin and the nitroimidazoles while ampicillin/sulbactam, amoxicillin/clavulanate, ticarcillin/clavulanate, cefoxitin, cefotetan, ceftizoxime imipenem/cilastatin, meropenem and some advanced quinolones like sparfloxacin, represent a single drug to cover both aerobic and anaerobic microflora. Although almost all clinical trials usually result in a 90% efficacy rate, the final outcome is dependant on the stage of the infection (early versus late), sepsis score, underlying diseases and the applied surgical procedures. On the other hand the choice of antibiotic(s) must be influenced by its toxicity, profiles local nosocomial susceptibility patterns, resistance inducing ability and price.

Journal Article↗