Evaluation of In Vitro Interaction of Daptomycin with Gentamicin or Beta-lactam Antibiotics Against taphylococcus aureus and Enterococci by FIC Index and Timed-Kill Curves

Abstract

The interactions of daptomycin with gentamicin and 5 β-lactam agents were determined by checkerboard and timed-kill studies. Eighty isolates were tested by checkerboard: 20 each of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), vancomycin-susceptible Enterococcus faecalis (VSEF) and vancomycin-resistant enterococci (VRE). Time kill curves were performed on 8 selected isolates: 2 each of MRSA, MSSA, VSEF and VRE. Checkerboard results showed highest frequency of synergistic effects against VSEF (35-75%) with daptomycin combined with ceftriaxone, cefepime or imipenem; a modest effect with most combinations against VRE and MRSA (5-20%); and indifference with daptomycin and most agents against MSSA (0-5%); except with daptomycin with oxacillin where 10-20% synergy was observed.

Synergistic interaction was confirmed by time kill studies in seven of ten isolates where checkerboard suggested synergy. A bactericidal effect was exerted in 5/7 synergistic combinations.

The in vitro data suggest that daptomycin combined with other antibiotics may be microbiologically beneficial and not antagonistic.     

In vitro activity of daptomycin alone and in combination with various antimicrobials against Gram-positive cocci

The increasing prevalence of resistant Gram-positive cocci requires the need to search for more effective agents and synergistic combinations. Forty-two vancomycin-resistant Enterococcus faecium (VREF), 30 methicillin-resistant Staphylococcus aureus (MRSA) and 36 Staphylococcus epidermidis (MRSE) strains were studied. Minimum inhibitory concentrations (MICs) were determined and synergy testing was performed by using E test for daptomycin, ampicillin-sulbactam, piperacillin-tazobactam and ticarcillin-clavulanate against staphylococci; for daptomycin, ampicillin, rifampin, and gentamicin against enterococci. Daptomycin in combination with ampicillin, rifampin, and gentamicin was tested against enterococci; daptomycin in combination with ampicillin-sulbactam, piperacillin-tazobactam, and ticarcillin-clavulanate was tested against staphylococci. Interaction categories were defined by the fractional inhibitory concentration (FIC) index. All strains of staphylococci and enterococci were susceptible to daptomycin. All three combinations showed synergy against more than 70% of the MRSA strains. Daptomycin in combination with ampicillin, rifampin, and gentamicin against enterococci showed synergies of 64.2%, 57.1% and 21.4%, respectively. This study indicates that daptomycin alone and combined with beta-lactams seems to be effective against MRSA, but further in vitro and in vivo studies on the subject are required before clinical use can be recommended.     

In vitro activity of telithromycin, quinupristin/dalfopristin, linezolid and comparator antimicrobial agents against Staphylococcus aureus clinical isolates

We have studied the prevalence of the different macrolide, lincosamide, streptograminB (MLS(B)) phenotypes among clinical Staphylococcus aureus isolates erythromycin- and/or oxacillin-resistant; and also the activity of other antimicrobial agents including telithromycin, quinupristin/dalfopristin, linezolid, aminoglycosides, chloramphenicol and vancomycin. We found that 64.86% of S. aureus were oxacillin-resistant. While the most prevalent MLS(B) phenotype among methicillin-resistant S. aureus (MRSA) was constitutive MLS(B) (cMLS) (83%), among methicillin-susceptible S. aureus (MSSA) it was inducible MLS(B) (iMLS(B)) (90%). Kanamycin resistance was more frequent than resistance to other aminoglycosides, being 100% for MRSA. Telithromycin was only active against iMLS(B), MS and erythromycin-susceptible isolates, although resistance rates were found among iMLS(B) MSSA (2.78%). Quinupristin/dalfopristin showed greater activity, with resistance rates of 2.5% for MRSA and 1.53% for MSSA. Both vancomycin and linezolid were fully active against all the isolates tested, with the highest MIC value being 2 microg/ml and 4 microg/ml, respectively. Among MRSA strains, 81.67% displayed resistance to five or more antimicrobials. This multiresistance was more frequently found among cMLS(B) strains (96.38% MRSA resistant to 6-9 agents).     

In vitro combined effects of cefozopran/teicoplanin and cefozopran/vancomycin on methicillin-resistant Staphylococcus aureus

We determined the in vitro effects of teicoplanin (TEIC) or vancomycin (VCM) added to cefozopran (CZOP) on 50 methicillin-resistant Staphylococcus aureus (MRSA) strains, using a modified checkerboard method with serial 1.25-fold dilutions, and assessed the time-kill curve. CZOP + TEIC was synergistic (fractional inhibitory concentration index < or = 0.5) against 98% and CZOP + VCM against 20% of strains. Both drug combinations were additive against the remaining strains. A comparison of the fractional bactericidal concentration indices for 32 strains showed synergistic bactericidal effects for CZOP + TEIC in 88%, and in 48% for CZOP +VCM, confirming that CZOP + TEIC is superior to CZOP + VCM. The time-kill curve confirms that the bactericidal potency of these drugs is increased through combined use with CZOP. These results suggest that treatment using TEIC or VCM with CZOP may be useful in treating MRSA infections, including polymicrobial infections and those involving Gram-negative rods.     

Determination of synergy between sulbactam,meropenem and colistin in carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii isolates and correlation with the molecular mechanism of resistance

Treatment of infections with carbapenem-resistant Gram negative organism is a major challenge especially among intensive care patients. Combinations of sulbactam, meropenem and colistin was studied for its synergistic activity against 100 invasive isolates of carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii-calcoaceticus complex by checkerboard assay and time kill assay (TKA). In addition, presence of carbapenemase production was determined by multiplex PCR. Time kill assay detected more synergy than checkerboard assay. Good bactericidal activity of 70–100% was noted with the combinations tested. Among K. pneumoniae, isolates producing NDM carbapenemase alone showed significantly more synergy than isolates producing OXA-48-like carbapenemases. In treatment of infection with carbapenem-resistant organisms, the site of infection and the type of carbapenemase produced may help to determine the most effective combination of antimicrobials.     

In-vitro activity of ceftriaxone combined with newer agents against MRSA

In this study, in vitro synergism in combinations of agents as ceftriaxone/dalbavancin, ceftriaxone/linezolid and ceftriaxone/daptomycin against MRSA strains were investigated. Thirty clinical MRSA strains were tested. The minimum inhibitory concentrations of all antibiotics were determined using reference broth microdilution method. In-vitro activities of antibiotics combined against the strains were tested using two-dimensional checkerboard microdilution method. Results were interpreted as follows: synergy = FICI ≤0.5; ‘no interaction’ effect = FICI ?0.5-≤4; antagonism = FICI ?4. The MIC₅₀, MIC₉₀ and MIC_range of ceftriaxone, daptomycin, dalbavancin and linezolid were found as 128, 1024 and 16-2048 mg/L; 1, 1 and 0.5–1 mg/L; 0.12, 0.12 and 0.03–0.12 mg/L; and 1, 2 and 1–2 mg/L, respectively. Our results showed that the frequency of synergistic effects (FICI: ≤0.5) of three combinations were all at the same rate of 77% (23/30). No in vitro antagonism (FICI >4) was observed.     

In vitro activities of antimicrobial cationic peptides; melittin and nisin,alone or in combination with antibiotics against Gram-positive bacteria

Abstract

The in vitro activities of two antimicrobial cationic peptides, melittin and nisin alone and in combination with frequently used antibiotics (daptomycin, vancomycin, linezolid, ampicillin, and erythromycin), were assessed against clinical isolates of methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus and Enterococcus faecalis. Using the broth microdilution method, minimum inhibitory concentration (MIC) ranges of melittin and nisin against all strains were 2–8 μg/ml and 2–32 μg/ml respectively. In combination studies performed with the microdilution checkerboard method using a fractional inhibitory concentration index of ?0·5 as borderline, synergistic interactions occurred more frequently with nisin–ampicillin combination against MSSA and nisin–daptomycin combination against E. faecalis strains. The results of the time-killing curve analysis demonstrated that the concentration dependent rapid bactericidal activity of nisin, and that synergism or early synergism was detected in most strains when nisin or melittin was used in combination with antibiotics even at concentrations of 0·5×MIC.     

Antimicrobial spectrum and potency of dalbavancin tested against clinical isolates from Europe and North America (2003): initial results from an international surveillance protocol

Dalbavancin is a bactericidal dimethylaminopropyl amide glycopeptide derivative possessing an extended serum elimination half-life in humans that allows once-weekly dosing for the therapy of Gram-positive infections. Strains from this baseline surveillance protocol in North America (NA; USA and Canada) and Europe (EU, 14 countries) were sampled in 2003. A total of 7,765 Gram-positive isolates (3,695 from NA and 4,070 from EU) were tested by reference broth microdilution methods against dalbavancin and 10 comparator agents. Species were analyzed separately by resistance phenotypes such as methicillin- (oxacillin-) resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae. Dalbavancin and other glycopeptides were very active against staphylococci (n=4648) with dalbavancin being 16- to 32-fold more potent than vancomycin (MIC90, 0.06 versus 2 mg/L). MRSA rates were greater (31.6%) in NA than in EU (26.1%). Quinupristin/dalfopristin resistance (MIC, > or = 2 mg/L; 0.1-0.5%) was documented more often in EU compared to NA. Dalbavancin (MIC50, 0.03-0.06 mg/L) was active against enterococci, except VanA resistance phenotypes. VRE rates were lower in EU (8.3%) then in NA (35.9%) from this resistance-enhanced enterococcal collection. Streptococci (dalbavancin MIC90, 0.016-0.03 mg/L) were generally most susceptible to glycopeptides (100.0%), quinupristin/dalfopristin (98.6-100.0%) and linezolid (100.0%); but dalbavancin was 16-fold more active than comparators. All vancomycin-susceptible enterococci and > 90% of vanB VRE had dalbavancin MIC values at < or = 1 mg/L,but vanA VRE strains had dalbavancin MIC results ranging from 0.06 to > 8 mg/L (median MIC, > or = 8 mg/L). Dalbavancin MIC values were not adversely influenced by geographic region or resistance phenotype (except vanA VRE). Infrequently isolated Gram-positive organisms such as Bacillus spp. (MIC90, 0.12 mg/L), Corynebacterium spp. (MIC90, 0.12 mg/L), Listeria monocytogenes (MIC90, 0.25 mg/L) and Micrococcus spp. (MIC90, 0.03 mg/L) were very susceptible to dalbavancin. In conclusion, these 2003 baseline resistance surveillance findings confirm the potent dalbavancin activity compared to several comparator agents against important Gram-positive pathogens. This high volume international survey indicates potential therapeutic roles for dalbavancin against many troublesome resistant Gram-positive phenotypes.     

Antimicrobial activity of daptomycin tested against gram-positive strains collected in European hospitals: results from 7 years of resistance surveillance (2003-2009)

Daptomycin is a cyclic lipopeptide approved by the European medicines Agency (EMEA) for the treatment of complicated skin and soft tissue infections (cSSTI) and Staphylococcus aureus bacteremia and endocarditis. We evaluated the in vitro activity of daptomycin and comparators tested against clinical isolates from european hospitals over a 7-year period (2003-2009). A total of 36,769 consecutive isolates were collected in 34 medical centers located in 13 European countries, Turkey and Israel. the collection included S. aureus (18,352; 27.2% oxacillin-resistant [MRSA]); coagulase-negative staphylococci (CoNS; 6,874), Enterococcus spp. (7,241; 9.4% vancomycin-resistant), β-hemolytic (3,009), viridans group streptococci (1,176), and Streptococcus bovis/gallolyticus (107). The organisms were isolated mainly from patients with bloodstream infection (56%) or cSSTI (23%). Daptomycin was very active against S. aureus and CoNS (MIC(50/90), 0.25/0.5 mg/l for both organisms), and its activity was not adversely influenced by oxacillin resistance. All Enterococcus faecalis strains were susceptible to daptomycin (MIC(50/90), 1/1 mg/l). Daptomycin (MIC(50/90), 2/2 mg/l; 100.0% susceptible) and linezolid (MIC(50/90), 1/2 mg/l; 99.7% susceptible) were the most active agents tested against vancomycin-resistant E. faecium. Vancomycin- resistant and -susceptible enterococcal strains were equally susceptible to daptomycin. Daptomycin was also active against β-hemolytic streptococci (MIC(50/90), 0.06/0.25 mg/l; 100.0% susceptible), viridans group streptococci (MIC(50/90), 0.25/0.5 mg/l; 99.8% susceptible) and S. bovis (MIC(50/90), 0.06/0.12 mg/l; 100.0% susceptible).In summary, daptomycin was very potent against this large collection (36,769) of Gram-positive organisms isolated in european hospitals, and its activity remained stable across the 7-year period evaluated (2003-2009), using reference methods and interpretive criteria. Decreases in daptomycin potency were not observed since EMEA approval and widespread clinical use, and emerging resistance to other compounds did not adversely influence daptomycin activity against contemporary Gram-positive species.     

mecA-positive methicillin-sensitive Staphylococcus aureus clinical isolates in Zenica-Doboj Canton,Bosnia and Herzegovina

Forty-four mecA-positive and eight mecA-negative Staphylococcus aureus isolates confirmed by PCR were further tested by disc-diffusion (DD) oxacillin and cefoxitin, oxacillin Epsilon (E)-test, and oxacillin and cefoxitin minimal inhibitory concentration (MIC) Strip methicillin-resistant phenotype in S. aureus (MRSA) tests. Among 44 mecA-positive S. aureus isolates, two (4·5%) were detected as MRSA by DD-oxacillin, 17 (38·6%) by DD-cefoxitin test, and seven (15·9%) by the E-test. In the cefoxitin MIC Strip MRSA test, 19 (43·2%) isolates were resistant. In the oxacillin MIC Strip MRSA test, 18 (40·9%) isolates were resistant and 26 (59·1%) were sensitive, i.e. oxacillin-sensitive MRSA (OS-MRSA) (MIC range 0·25-≤0·25 mg/l). Fifteen out of 26 OS-MRSA (57·7%) belonged to spa-CC 355/595, 78% of which belonged to the largest PFGE clone. Some discrepancies between the phenotypic methods for MRSA identification obtained in this study were caused by large proportion of OS-MRSA. Misidentification of OS-MRSA as MSSA might result in an appearance of highly resistant MRSA in patients treated with beta-lactam antibiotics.     

In vitro synergy and selection of resistance by fluoroquinolones plus amikacin or beta-lactams against extended-spectrum beta-lactamase-producing Escherichia coli

This study compared the potential synergy of levofloxacin and ciprofloxacin in combination with cefepime, ceftazidime, imipenem, piperacillin/tazobactam or amikacin, against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli by using checkerboard and time kill studies. Moreover, selection of resistance was determined by frequency of mutations and by calculating the increase in minimum inhibitory concentrations (MICs) after five serial subcultures on antibiotic-containing plates. Synergy occurred more often with levofloxacin combined with imipenem (7/10 strains) and with levofloxacin or ciprofloxacin with amikacin (10/10) than for the other combinations. Time kill studies showed synergy for levofloxacin combined with amikacin, ceftazidime, imipenem or piperacillin/tazobactam, and for ciprofloxacin combined with amikacin, cefepime or imipenem. Antibiotic combinations selected for resistance less frequently than antibiotics alone. Mutation frequency was <10(-12) for all combinations. In conclusion, the combination of a fluoroquinolone with a beta-lactam or amikacin may provide improved antimicrobial activity and help limit the occurrence of resistance in ESBL-producing E. coli strains.     

Antimicrobial efficacy of gatifloxacin and moxifloxacin with and without benzalkonium chloride compared with ciprofloxacin and levofloxacin against methicillin-resistant Staphylococcus aureus

We compared the antimicrobial activity of gatifloxacin and moxifloxacin with and without benzalkonium chloride (BAK) against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). Minimum inhibitory concentrations (MICs) against clinical isolates of MRSA were evaluated. Approximately 10(5 )CFU/ml of methicillinresistant S. aureus was added to Mueller-Hinton broth containing two-fold concentration increments of drug. For the evaluation of gatifloxacin with BAK, 50 microg/ml of BAK were added to the first well of the plate with gatifloxacin or moxifloxacin and then serially diluted. The combination of gatifloxacin or moxifloxacin with BAK was more active than either fluoroquinolone without BAK. The MICs ranged from 相似文献   

Versatility of targeted antibiotic-loaded gold nanoconstructs for the treatment of biofilm-associated bacterial infections

Abstract

Background: We previously demonstrated that a photoactivatable therapeutic approach employing antibiotic-loaded, antibody-conjugated, polydopamine (PDA)-coated gold nanocages (AuNCs) could be used for the synergistic killing of bacterial cells within a biofilm. The approach was validated with a focus on Staphylococcus aureus using an antibody specific for staphylococcal protein A (Spa) and an antibiotic (daptomycin) active against Gram-positive cocci including methicillin-resistant S. aureus (MRSA). However, an important aspect of this approach is its potential therapeutic versatility.

Methods: In this report, we evaluated this versatility by examining the efficacy of AuNC formulations generated with alternative antibodies and antibiotics targeting S. aureus and alternative combinations targeting the Gram-negative pathogen Pseudomonas aeruginosa.

Results: The results confirmed that daptomycin-loaded AuNCs conjugated to antibodies targeting two different S. aureus lipoproteins (SACOL0486 and SACOL0688) also effectively kill MRSA in the context of a biofilm. However, our results also demonstrate that antibiotic choice is critical. Specifically, ceftaroline and vancomycin-loaded AuNCs conjugated to anti-Spa antibodies were found to exhibit reduced efficacy relative to daptomycin-loaded AuNCs conjugated to the same antibody. In contrast, gentamicin-loaded AuNCs conjugated to an antibody targeting a conserved outer membrane protein were highly effective against P. aeruginosa biofilms.

Conclusions: These results confirm the therapeutic versatility of our approach. However, to the extent that its synergistic efficacy is dependent on the ability to achieve both a lethal photothermal effect and the thermally controlled release of a sufficient amount of antibiotic, they also demonstrate the importance of carefully designing appropriate antibody and antibiotic combinations to achieve the desired therapeutic synergy.     

In-vitro activities of imipenem–colistin,imipenem–tigecycline,and tigecycline–colistin combinations against carbapenem-resistant Enterobacteriaceae*

The aim of the study is to determine in-vitro effects of imipenem–tigecycline, imipenem–colistin and tigecycline–colistin against carbapenem-resistant Enterobacteriaceae (CRE) isolates. A total of 25 CRE isolates were included to the study. The minimum inhibition concentrations of imipenem, colistin-sulphate and tigecycline were determined with broth dilution method. Synergistic effects of imipenem–tigecycline, imipenem–colistin and tigecycline–colistin were investigated by microdilution checkerboard technique. All of the isolates were resistant to imipenem, whereas 25% of the isolates were resistant to colistin and tigecycline. Imipenem–colistin, imipenem–tigecycline and tigecycline–colistin combinations were synergistic against 40% (10/25), 24% (6/25), and 36% (9/25) of the isolates, respectively. Antagonism was observed in 8% (2/25) of the isolates in tigecycline–colistin combination. Tigecycline–colistin was the most effective (70% synergy) combination in Klebsiella spp. strains; whereas imipenem–colistin was the most effective (75% synergy) combination in Escherichia coli strains. Synergistic effect was variable and strain-depended against CRE isolates that have been tested.     

Antimicrobial Spectrum and Potency of Dalbavancin Tested Against Clinical Isolates from Europe and North America (2003): Initial Results from an International Surveillance Protocol

Abstract

Dalbavancin is a bactericidal dimethylaminopropyl amide glycopeptide derivative possessing an extended serum elimination half-life in humans that allows onceweekly dosing for the therapy of Gram-positive infections. Strains from this baseline surveillance protocol in North America (NA; USA and Canada) and Europe (EU, 14 countries) were sampled in 2003. A total of 7,765 Gram-positive isolates (3,695 from NA and 4,070 from EU) were tested by reference broth microdilution methods against dalbavancin and 10 comparator agents. Species were analyzed separately by resistance phenotypes such as methicillin- (oxacillin-) resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- resistant Streptococcus pneumoniae. Dalbavancin and other glycopeptides were very active against staphylococci (n=4648) with dalbavancin being 16- to 32- fold more potent than vancomycin (MIC₉₀, 0.06 versus 2 mg/L). MRSA rates were greater (31.6%) in NA than in EU (26.1%). Quinupristin/dalfopristin resistance (MIC, ≥ 2 mg/L; 0.1 - 0.5%) was documented more often in EU compared to NA. Dalbavancin (MIC₅₀, 0.03 - 0.06 mg/L) was active against enterococci, except VanA resistance phenotypes. VRE rates were lower in EU (8.3%) then in NA (35.9%) from this resistance-enhanced enterococcal collection. Streptococci (dalbavancin MIC₉₀, 0.016 - 0.03 mg/L) were generally most susceptible to glycopeptides (100.0%), quinupristin/dalfopristin (98.6 - 100.0%) and linezolid (100.0%); but dalbavancin was 16-fold more active than comparators. All vancomycin-susceptible enterococci and > 90% of vanB VRE had dalbavancin MIC values at ≤ 1 mg/L, but vanA VRE strains had dalbavancin MIC results ranging from 0.06 to > 8 mg/L (median MIC, ≥ 8 mg/L). Dalbavancin MIC values were not adversely influenced by geographic region or resistance phenotype (except vanA VRE). Infrequently isolated Gram-positive organisms such as Bacillus spp. (MIC₉₀, 0.12 mg/L), Corynebacterium spp. (MIC₉₀, 0.12 mg/L), Listeria monocytogenes (MIC₉₀, 0.25 mg/L) and Micrococcus spp. (MIC₉₀, 0.03 mg/L) were very susceptible to dalbavancin. In conclusion, these 2003 baseline resistance surveillance findings confirm the potent dalbavancin activity compared to several comparator agents against important Gram-positive pathogens. This high volume international survey indicates potential therapeutic roles for dalbavancin against many troublesome resistant Gram-positive phenotypes.     

Daptomycin in vitro activity tested against Gram-positive strains collected from European and Latin American medical centers in 2003

Daptomycin, a cyclic lipopeptide, was susceptibility tested against clinical bacterial isolates consecutively collected in hospitals located in Europe (4,731 strains) and Latin America (1,007 strains) in 2003 as part of a continuing surveillance program. The bacterial isolates tested were Gram-positive pathogens that included staphylococci, streptococci and enterococci. The isolates were tested for susceptibility using broth microdilution methods (broth with 50 mg/L Ca++ for testing daptomycin). All isolates, except two Enterococcus faecium strains from Europe, were inhibited at daptomycin MIC of < or = 4 mg/L. In addition, 99.4 and 97.3% of isolates were inhibited at daptomycin MIC of < or = 2 and < or = 1 mg/L, respectively. Except for one Staphylococcus aureus and one viridans group streptococci from Europe and one coagulase-negative staphylococci from Latin America, all staphylococcal and streptococcal isolates were inhibited by 1 mg/L of daptomycin. Resistance to other compounds (vancomycin, oxacillin, and penicillin) did not influence daptomycin activity. The activity of daptomycin was very similar in both geographic regions evaluated and demonstrated the same MIC distribution as isolates evaluated in studies in the United States. The results of this study showed that daptomycin continues to be very active against clinical isolates of Gram-positive cocci isolated in Europe and Latin America.     

Antimicrobial Activity of Daptomycin Tested Against Gram-Positive Strains Collected in European Hospitals: Results from 7 Years of Resistance Surveillance (2003-2009)

Abstract

Daptomycin is a cyclic lipopeptide approved by the European medicines Agency (EMEA) for the treatment of complicated skin and soft tissue infections (cSSTI) and Staphylococcus aureus bacteremia and endocarditis. We evaluated the in vitro activity of daptomycin and comparators tested against clinical isolates from European hospitals over a 7-year period (2003-2009). A total of 36,769 consecutive isolates were collected in 34 medical centers located in 13 European countries, turkey and Israel. the collection included S. aureus (18,352; 27.2% oxacillin-resistant [MRSA]); coagulase-negative staphylo-cocci (CoNS; 6,874), Enterococcus spp. (7,241; 9.4% vancomycin-resistant),β-hemolytic (3,009), viridans group streptococci (1,176), and Streptococcus bovis/gallolyticus (107). The organisms were isolated mainly from patients with bloodstream infection (56%) or cSSTI (23%). Daptomycin was very active against S. aureus and CoNS (MIC_50/90, 0.25/0.5 mg/L for both organisms), and its activity was not adversely influenced by oxacillin resistance. All Enterococcus faecalis strains were susceptible to daptomycin (MIC_50/90, 1/1 mg/L). Daptomycin (MIC_50/90, 2/2 mg/L; 100.0% susceptible) and linezolid (MIC_50/90, 1/2 mg/L; 99.7% susceptible) were the most active agents tested against vancomycin-resistant E. faecium. Vancomycin-resistant and -susceptible enterococcal strains were equally susceptible to daptomycin. Daptomycin was also active against β-hemolytic streptococci (MIC_50/90, 0.06/0.25 mg/L; 100.0% susceptible), viridans group streptococci (MIC_50/90, 0.25/0.5 mg/L; 99.8% susceptible) and S. bovis (MIC_50/90, 0.06/0.12 mg/L; 100.0% susceptible).

In summary, daptomycin was very potent against this large collection (36,769) of Gram-positive organisms isolated in European hospitals, and its activity remained stable across the 7-year period evaluated (2003-2009), using reference methods and interpretive criteria. Decreases in daptomycin potency were not observed since EMEA approval and widespread clinical use, and emerging resistance to other compounds did not adversely influence daptomycin activity against contemporary Gram-positive species.     

In-vitro synergistic effect of fluconazole with nonsteroidal anti-inflammatory agents against Candida albicans strains

The in-vitro interaction and synergistic activity of the combination of fluconazole with some nonsteroidal anti-inflammatory drugs (sodium salicylate, piroxicam, tenoxicam and diclofenac sodium) were investigated in Candida albicans strains (n=7) by the microdilution checkerboard assay. The results were evaluated visually and by a spectrophotometric microplate reader at 492 nm wavelength. Fractional inhibitory index was calculated for every strain and combination according to the minimal inhibitory concentration (MICs). The combination of fluconazole with sodium salicylate, tenoxicam and diclofenac sodium showed synergy against 5, 5 and 3 of the C. albicans strains, respectively. The effect of fluconazole with piroxicam was synergistic against one strain but indifferent/additive against the others. These data suggest that combinations of sodium salicylate, tenoxicam and diclofenac sodium with fluconazole may prove to be useful as chemotherapeutic agents for the treatment of C. albicans infections caused by especially fluconazole-resistant strains. However, additional preclinical work and in vivo studies are necessary to determine their definite clinical use.     

Antimicrobial activity of isepamicin (SCH21420, 1-N-HAPA gentamicin B) combinations with cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, imipenem, mezlocillin and piperacillin tested against gentamicin-resistant and susceptible gram-negative bacilli and enterococci.

Isepamicin, formerly SCH21420 or 1-N-HAPA gentamicin B, is an aminoglycoside that was tested alone or in combination with one of seven broad spectrum drugs against 80 clinical isolates. Half of the strains were gentamicin-resistant but only one isolate (1.3%) was resistant to isepamicin. The broadest spectrum comparison drugs tested alone (ciprofloxacin at 3.8% resistance and imipenem at 5.0% resistance) were associated with the lowest synergy rates when combined with isepamicin. The rank order of synergy (complete or partial) was; cefotaxime = ceftazidime = ceftriaxone = mezlocillin = piperacillin (75% to 80%) greater than imipenem (66%) greater than ciprofloxacin (38%). Isepamicin/ampicillin combinations produced synergistic killing of those enterococci not having high-grade resistance to gentamicin or kanamycin. Enterococcus faecium strains were also refractory to isepamicin/ampicillin synergy. Isepamicin appears to be widely useable against gentamicin-resistant gram-negative bacilli either alone or combined with most commonly used broad spectrum beta-lactams.     

In vitro activity of ertapenem against common clinical isolates in relation to human pharmacokinetics

The in vitro activity of ertapenem against bacterial pathogens isolated from patients with moderate to severe complicated intra-abdominal, complicated skin/skin structure, acute pelvic, or complicated urinary tract infection or community acquired pneumonia was compared to ceftriaxone and piperacillin-tazobactam and related to known plasma concentrations of the three agents. Ertapenem was more potent against methicillin-susceptible Staphylococcus aureus (MSSA) than ceftriaxone and piperacillin-tazobactam and was more potent and more active than both of these agents against Enterobacteriaceae and anaerobes. Piperacillin-tazobactam was the most active agent against enterococci and Pseudomonas aeruginosa. All isolates of Enterobacteriaceae (n=1088), Streptococcus pyogenes (n=37), Streptococcus agalactiae (n=48), MSSA (n=187), Haemophilus influenzae (n=59), and Moraxella catarrhalis (n=9) were susceptible to ertapenem; < 1% of 1284 anaerobes and only 1 of 113 Streptococcus pneumoniae (a penicillin-resistant isolate) were resistant to ertapenem. The MIC value at which 90% of all Enterobacteriaceae, streptococci, MSSA, H. influenzae, M. catarrhalis, and anaerobes were inhibited (MIC90) was < or = 1 microg/ml and below the mean plasma concentration of total ertapenem following a 1 g intravenous infusion for at least 24 hours, i.e., the entire recommended dosing interval, and below the free drug concentration for at least 8 h.