Comparison of teicoplanin and vancomycin in vitro activity on clinical isolates of Staphylococcus aureus

Abstract

Ninety-one clinical isolates of Staphylococcus aureus have been tested with the Kirby Bauer and the Etest® method to determine the susceptibility to glycopeptides in the 2007–2010 period. Five strains (5·5%) were resistant to vancomycin and nine (9·9%) to teicoplanin. Teicoplanin showed a median minimal inhibitory concentration (MIC) of 1 mg/l (range 0·125–24 mg/l), an MIC50 of 1 mg/l, and an MIC90 of 2 mg/l; vancomycin had a median MIC of 1·5 mg/l (range 0·38–4 mg/l), an MIC50 of 1·5 mg/l, and an MIC90 of 2 mg/l. More isolates were distributed on higher values of MIC for vancomycin. Inhibition halos induced by vancomycin-impregnated paper diskettes were slightly larger than those by teicoplanin. Glycopeptide resistance among methicillin-resistant Staphylococcus aureus in Italy is an underestimated phenomenon, possibly due to the described underestimation of glycopeptides MICs by the automatic broth microdilution method, when compared to agar MIC assays. A teicoplanin MIC creep, as reported for vancomycin, cannot be assumed.     

Effect of vancomycin initial dosing on time to systemic inflammatory response syndrome resolution in patients with methicillin-resistant Staphylococcus aureus bacteremia

Current guidelines suggest using vancomycin-loading doses for complicated infections despite a lack of evidence to support this practice. To address this gap, we performed a single-centre cohort study of 124 patients with sepsis due to methicillin-resistant Staphylococcus aureus bacteremia. Patients were allocated into two groups based on initial dose of vancomycin, <20 mg/kg or ≥20 mg/kg, and evaluated for time to resolution of systemic inflammatory response syndrome (SIRS). Among a cohort of 124 patients, 87 received vancomycin initial doses <20 mg/kg and 37 received ≥20 mg/kg. The median time to SIRS resolution was 109 h in the <20 mg/kg group compared to 67 h in the ≥20 mg/kg group. Cox proportional hazard modelling showed a faster resolution of SIRS in the ≥20 mg/kg group (HR = 1.72[1.09–2.73]). Vancomycin initial doses of ≥20 mg/kg led to faster resolution of SIRS although further studies are needed to evaluate the safety and efficacy of this approach.     

Comparative in vitro activity of ceftaroline and comparator agents against nosocomial Gram-negative and Gram-positive clinically significant bacterial isolates from patients in a teaching hospital in Kuwait

The objective was to test the in vitro activities of ceftaroline and comparator agents against clinical isolates of Gram-negative and Gram-positive bacteria. Isolates were identified with VITEK II. Susceptibility testing was with E test. A total of 1264 isolates were tested. Compared to other cephalosporins, ceftaroline demonstrated excellent in vitro activities (MIC₉₀, ≤0.5 mg/L) against Escherichia coli, Salmonella spp. and Haemophilus influenzae. When matched with the comparator cephalosporins, ceftaroline demonstrated the greatest activity against methicillin-susceptible Staphylococcus aureus (MSSA), with MIC₉₀ of 0.25 mg/L. Ceftaroline’s MIC₉₀s against both community-associated methicillin-resistant S. aureus (MRSA) and hospital-acquired MRSA were 0.5 and 1 mg/L, respectively. Major discrepancies were noted between E test and disc diffusion tests for ceftaroline only against 16 Gram-negative and 16 Gram-positive isolates. Ceftaroline demonstrated an excellent in vitro activity against the majority of clinically significant Gram-negative and Gram-positive isolates obtained from proven cases of bacterial infections.     

Oxacillin- and Mupirocin-Resistant Staphylococcus aureus: In vitro Activity of Silver Sulphadiazine and Cerium Nitrate in Hospital Strains

Abstract

Nasal carriage is an important reservoir of oxacillin-resistant Staphylococcus aureus (ORSA). Mupirocin is a topical drug used to remove S. aureus from nares. However, isolates resistant to mupirocin have been reported all over the world. Silver sulphadiazine (SSD) is a topical agent, which when associated with cerium nitrate (CN), has been shown to be useful in the treatment of burn infections and could be an alternative drug for patient decolonization. Susceptibility to oxacillin in 203 S. aureus isolates was evaluated by the agar diffusion test, while the agar diffusion and agar dilution methods were used for mupirocin. A PCR-multiplex method was performed to detect the mecA and ileS-2 genes. Minimum inhibitory concentration (MICs) to SSD and CN, used alone or in association, were determined by the agar dilution method. One hundred and sixty-three (80.3%) strains were oxacillinresistant, and 37 (18.2%) were mupirocin resistant. The MIC of SSD alone or in association with CN was 64 μg/mL, while for CN alone was 2,048 μg/mL for all isolates. SSD presented anti-staphylococcal activity at concentrations (64 μg/mL) much lower than those commonly used in commercial preparations (10 mg/g) and had good activity against mupirocin-resistant strains, showing that this drug could be used for nasal decolonization in ORSA carries.     

Comparative in vitro activity of linezolid and five other antimicrobials against nosocomial isolates of methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecium

The activity of linezolid in comparison to vancomycin, teicoplanin, oxacillin, clindamycin and gentamicin was tested against 60 strains of methicillin-resistant Staphylococcus aureus, 60 strains of methicillin-resistant Staphylococcus epidermidis isolated from patients with nosocomial infections and 24 strains of vancomycin-resistant Enterococcus faecium isolated from feces of hospitalized patients. Minimum Inhibitory Concentrations (MICs) were determined by the Epsilometer test method. All tested strains were sensitive to linezolid and specifically all methicillin-resistant S. aureus had MIC range 0.25-3.00, MIC50 = 0.75, MIC90 = 1.5, all methicillin-resistant S. epidermidis had MIC range 0.125-1.5, MIC50 = 0.5, MIC90 = 1 and all vancomycin-resistant E. faecium had MIC range 0.5-1.5, MIC50 = 1, MIC90 = 1. Linezolid is the first of a novel antimicrobial class, the oxazolidinones, which is a promising treatment for serious Gram-positive infections, including multiresistant strains.     

In vitro susceptibility to quinolones and other antimicrobial agents of Staphylococcus species isolated from immunocompromised patients

A total of 237 Staphylococcus strains were isolated from different kinds of body tissues and fluids from immunocompromised patients admitted to the Hematology Department of Pescara Hospital (Italy). These strains, collected from November 1987 to September 1988, were studied for their susceptibility to methicillin and other drugs commonly used in therapy, and the minimum inhibitory and minimum bactericidal concentrations of five quinolones were determined. The killing curve of ciprofloxacin compared with nalidixic acid was determined. The results show a considerable activity of fluoroquinolones against all strains studied.     

Pharmacokinetically-based prediction of the effects of antibiotic combinations on resistant Staphylococcus aureus mutants: in vitro model studies with linezolid and rifampicin

To explore if combinations of linezolid (L) with rifampicin (R) are able to restrict Staphylococcus aureus resistance, the enrichment of L- and R-resistant mutants was studied in an in vitro dynamic model. L- and R-resistant mutants were enriched in all single drug treatments. In contrast, L-resistant mutants were not enriched and R-resistant mutants were similar to baseline amounts with only minimal regrowth at the end of the combination treatments. These effects appear to be explained by lowering the mutant prevention concentration (MPC) for L+R combinations (MPC_L+R) compared to the MPCs of L and R alone (MPC_L and MPC_R) and thereby the longer times above MPC_L+R (73–100% of the dosing interval for L and 42–58% for R) compared to the times above MPC_L (0–44%) and MPC_R (0%). These findings provide an opportunity to predict the selection of S. aureus resistance in L+R treatments using MPC_L+Rs.     

In Vitro Combinations of Five Intravenous Antibiotics with Dalfopristin-Quinupristin Against Staphylococcus aureus in a 3-Dimensional Model

Abstract

We compared the in vitro activity of dalfopristin and quinupristin combined with five intravenous antibiotics in a 3-dimensional model. We tested six strains of Staphylococcus aureus selected with different patterns of resistance to methicillin and eryth-romycin. Dalfopristin and quinupristin displayed a very synergistic activity against all the strains with a mean 16- or 32-fold decrease of inhibitory concentrations in combination. That synergy was even better against erythromycin-resistant strains. In combination with tigecycline or fosfomycin, the antibacterial activity could be consistently enhanced with the same decrease of inhibitory concentrations. A synergy was also observed, less regularly and at a lower level, with rifampin, gentamicin or vancomycin. Combinations of dalfopristin and quinupristin with tigecycline or fosfomycin could be very interesting in clinical practice because the inhibitory effect could be achieved with very low oncentrations of each component, even when erythromycin-resistant strains are concerned.     

Predicting effects of antibiotic combinations using MICs determined at pharmacokinetically derived concentration ratios: in vitro model studies with linezolid- and rifampicin-exposed Staphylococcus aureus

To predict the effects of combined use of antibiotics on their pharmacodynamics, the susceptibility of Staphylococcus aureus to linezolid–rifampicin combinations was tested at concentration ratios equal to the ratios of 24-area under the concentration–time curve (AUC₂₄) simulated in an in vitro dynamic model. The linezolid MICs in combination with rifampicin decreased 8- to 67-fold. The rifampicin MICs were similar with or without linezolid. The enhanced activity of linezolid combined with rifampicin increased the AUC₂₄/MIC ratios and provided more pronounced antibacterial effects compared with single treatments. The areas between the control growth and time-kill curves (ABBCs) determined in combined and single treatments with linezolid were plotted against AUC₂₄/MIC on the same graph (r² 0.94). These findings suggest that the effects of linezolid–rifampicin combinations can be predicted by AUC₂₄/MICs of linezolid using its MIC determined at pharmacokinetically derived linezolid-to-rifampicin concentration ratios.     

Linezolid as Rescue Drug: A Clinical Case of Soft Tissue Infection Caused by a Staphylococcus aureus Strain Resistant In Vivo to Teicoplanin

Abstract

The authors report and discuss a patient admitted to intensive care unit (ICU) for acute respiratory failure due to upper airway obstruction caused by face and neck soft tissue infection. An oxacillin-resistant Staphyloccoccus aureus was isolated from necrotic skin lesions and from skin biopsy. The strain was susceptible in vitro to teicoplanin, but it showed resistance In Vivo, despite appropriate dosage. After 6 days of full dose therapy, since the clinical course worsened, teicoplanin was interrupted and linezolid was started. In 48 hours signs of infection regressed, and the patient was discharged from the ICU after 10 days of linezolid treatment. Linezolid resulted as a rescue drug for a life-threatening infection.     

Activity of moxifloxacin in combination with vancomycin or teicoplanin against Staphylococcus aureus isolated from device-associated infections unresponsive to glycopeptide therapy

We tested the in vitro bactericidal activity of moxifloxacin, a new 8-methoxyquinolone, alone and in combination with vancomycin or teicoplanin at different multiples of minimum inhibitory concentration (MIC) against 8 methicillin-ciprofloxacin-resistant Staphylococcus aureus (M-C-RSA) and 1 methicillin-ciprofloxacin susceptible S. aureus (M-C-SSA) recently isolated from device-associated infections unresponsive to or relapsing after glycopeptide therapy, despite device removal. MICs of vancomycin ranged from 1 to 4 microg/ml, MICs of teicoplanin ranged from 2 to 8 microg/ml; MICs of moxifloxacin were always 2 microg/ml against M-C-RSA isolates and 0.125 microg/ml against the M-C-SSA isolate. The 9 strains resulted tolerant when tested for vancomycin, teicoplanin, and moxifloxacin used alone at 2 x MIC. In all cases the combination of moxifloxacin and teicoplanin or vancomycin appeared to be bactericidal already at MIC concentration for glycopeptides plus 0.5 x MIC concentration for moxifloxacin. If these results are confirmed in vivo in animal experiments, the combination of moxifloxacin with glycopeptides might be useful for treating device-associated infections, and in preventing the frightening phenomenon of increasing MICs for glycopeptides.     

In vitro activity of thiamphenicol against multiresistant Streptococcus pneumoniae,Haemophilus influenzae and Staphylococcus aureus in Italy

Thiamphenicol is a derivative of chloramphenicol characterized by a spectrum comparable to that of the parent compound against multiresistant pathogens but showing satisfactory tolerability. The in vitro activity of thiamphenicol and of 11 comparative drugs against 397 recently isolated antibiotic-resistant and/or invasive pneumococci and 52 multiply-resistant MRSA including 2 VISA strains was determined. Bactericidal activity against Haemophilus influenzae and the post-antibiotic effect on Streptococcus pneumoniae, H. influenzae, Staphylococcus aureus and Escherichia coli were also assessed. Against invasive pneumococci, thiamphenicol and chloramphenicol were the most potent non-beta-lactam molecules together with vancomycin and rifampin. Against high-level penicillin-resistant strains phenicol activities were superior to those of cefotaxime, ceftriaxone and imipenem. Against MRSA thiamphenicol and chloramphenicol were second only to the glycopetides and also inhibited the VISA strains. Thiamphenicol showed a significant PAE (0.33 to 2.9h) on all pathogens studied and a powerful bactericidal effect against beta-lactamase-positive and -negative H. influenzae. These results indicate a good in vitro activity of thiamphenicol against difficult-to-treat multiply resistant pathogens.     

Comparative in vitro activity of quinupristin/dalfopristin and seven other antimicrobials against methicillin-susceptible and methicillin-resistant nosocomial Staphylococcus aureus bloodstream isolates

Staphylococcus aureus strains resistant to a variety of antimicrobial agents are often found in the hospital environment and are responsible for many life-threatening infections. The activity of quinupristin/dalfopristin against 84 Staphylococcus aureus bloodstream isolates (both methicillin resistant and methicillin sensitive) was compared to the activity of vancomycin, teicoplanin, erythromycin, oxacillin, clindamycin, gentamicin, rifampicin. The Minimum Inhibitory Concentrations of these agents was evaluated with the Epsilometer Test. Quinupristin/dalfopristin inhibited all methicillin-sensitive strains at 1mg/L, and 75% of methicillin-resistant strains at 1.5mg/L. According to these results, quinupristin-dalfopristin shows promising in-vitro activity and may be a welcome alternative treatment for methicillin-resistant staphylococcal infections, resulting in reduced use of glycopeptides.     

Multicentric study in five African countries of antibiotic susceptibility for three main pathogens: Streptococcus pneumoniae,Staphylococcus aureus,and Pseudomonas aeruginosa

Antibiotic resistance is a growing clinical and epidemiological problem. We report on the antibiotic susceptibility of three pathogens isolated from patients in Algeria, Egypt, Morocco, Senegal, and Tunisia during 2010–2011. In total, 218 Streptococcus pneumoniae, 428 Staphylococcus aureus, and 414 Pseudomonas aeruginosa strains were collected. S. pneumoniae resistance was noted against penicillin (30.2%), erythromycin (27.4%), cefpodoxime (19.1%), amoxicillin (12.0%), cefotaxime (7.4%), and levofloxacin (3.2%). All the strains were teicoplanin susceptible. Staphylococcus aureus methicillin resistance differed between countries, from 5.0% in Senegal to 62.7% in Egypt. Levofloxacin resistance was low in all countries, and the highest rate (in Egypt) was still only 13.6% for intermediate and resistant strains combined. Most strains were susceptible to fosfomycin (99.3%) and pristinamycin (94.2%). P. aeruginosa resistance was found against levofloxacin (30.4%), ciprofloxacin (29.9%), tobramycin (19.7%), ceftazidime (19.2%), and imipenem (17.9%), but not colistin. Antibiotic susceptibility varied widely between countries, with resistance typically most prevalent in Egypt.     

A novel parameter to predict the effects of antibiotic combinations on the development of Staphylococcus aureus resistance: in vitro model studies at subtherapeutic daptomycin and rifampicin exposures

The search for optimal predictors of anti-mutant effects remains a pressing problem in studies of antibiotic-associated bacterial resistance. To relate the emergence of bacterial resistance with the antibiotic mutant prevention concentration (MPC), a novel integral parameter – the area around the resistance threshold, i.e. MPC level (AAMPC) is proposed. The AAMPC is the algebraic sum of the area under the antibiotic concentration–time curve that is above the MPC (positive area) and the area above the concentration–time curve that is under the MPC (negative area). To assess the predictive performance of AAMPC, the enrichment of resistant Staphylococcus aureus was studied by simulating treatment with daptomycin and rifampicin alone and in combination in an in vitro dynamic model. The enhanced anti-mutant effects of the antibiotic combinations were due to lowering the negative 24-h AAMPCs. These findings suggest that a novel MPC-related parameter is a reliable predictor of mutant enrichment.     

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).     

Characteristics and Outcomes of Methicillin‐Resistant Staphylococcus aureus Bloodstream Infections in Patients with Cancer Treated with Vancomycin: 9‐Year Experience at a Comprehensive Cancer Center

Background.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) can cause significant morbidity and mortality in patients with cancer. However, data on outcomes of patients treated with vancomycin are lacking.

Methods.

We identified 223 patients with cancer who developed MRSA BSIs between January 2001 and June 2009 and were treated with vancomycin. Treatment failure was defined as death within 60 days of infection, persistent bacteremia ≥5 days, fever ≥4 days, recurrence or relapse, and secondary MRSA infection.

Results.

The treatment failure rate was 52% (116 of 223 patients). These patients were more likely to have been hospitalized, been treated with steroids within the previous 3 months, developed acute respiratory distress syndrome, required mechanical ventilation, required intensive care unit care, and community-onset infections (all p < .05). Risk factors for MRSA-associated mortality (27 of 223 patients; 12%) included hematologic malignancy and hematopoietic stem cell transplantation, community-onset infection, secondary BSI, MRSA with minimum inhibitory concentration (MIC) ≥2.0 μg/mL, mechanical ventilation, and a late switch to an alternative therapy (≥4 days after treatment failure; all p < .05). On multivariate analysis, mechanical ventilation and recent hospitalization were identified as independent predictors of vancomycin failure, and community-onset infection, secondary BSIs, and MIC ≥2 μg/mL were identified as significant predictors of MRSA-associated mortality.

Conclusions.

We found a high treatment failure rate for vancomycin in patients with cancer and MRSA BSIs, as well as a higher mortality. A vancomycin MIC ≥2 μg/mL was an independent predictor of MRSA-associated mortality. An early switch to an alternative therapy at the earliest sign of failure may improve outcome.     

In vitro and in vivo susceptibility of human leukemic cells to lymphokine activated killer activity

The susceptibility of human myeloid and lymphoid leukemic blasts to the lytic action of recombinant interleukin-2 (rIL-2)-generated lymphokine activated killer (LAK) cells was analyzed. With the exception of the K562 cell line, all 9 leukemic cell lines tested were resistant to the natural killer activity of freshly isolated peripheral blood lymphocytes (PBL) from healthy donors but were susceptible to the lytic action of PBL cultured for 3 days in the presence of rIL-2. Of the 32 primary myeloid and lymphoid acute leukemia samples investigated, the great majority were natural killer cell-resistant but were variably sensitive to LAK effectors. Variations in LAK activity were observed according to the donor of PBL, while little or no difference was documented in the capacity to elicit LAK activity of PBL cultured with 100 or 1,000 U of rIL-2/ml. Pretreatment of the leukemic target cells with neuraminidase did not increase substantially their sensitivity to LAK activity. LAK cells generated from the PBL of patients at the onset of the disease or in complete clinicohematological remission lysed Raji cells as efficiently as normal LAK effectors. Finally, LAK cells were capable of abrogating the tumor growth in nude mice of a human leukemic T cell line. These findings demonstrate the susceptibility in vitro and in vivo of human leukemic blasts to the lytic effect of LAK cells and point to a possible clinical exploitment of this new form of adoptive immunotherapy in the management of acute leukemia.     

In vitro activity of clarithromycin alone or in combination with other antimicrobial agents against Mycobacterium avium-intracellulare. Complex strains isolated from AIDS patients.

The activity of clarithromycin and five other antimicrobial agents, namely amikacin, rifampicin, rifabutin, clofazimine and ciprofloxacin, was assessed both by an agar dilution and a radiometric method in broth on 11 Mycobacterium avium-intracellulare complex (MAC) strains, recently isolated from AIDS patients. Minimum inhibitory concentrations (MICs) radiometrically determined were, in general, several times lower than MICs assessed in agar, probably because of a partial degradation of antimicrobials during the long incubation period needed for tests in solid medium. When tested in broth, rifabutin and clofazimine showed very low MICs 90 (0.24 and 0.78 microgram/ml, respectively). Ciprofloxacin and clarithromycin also had MICs90 in the range of peak serum levels (1.93 and 3.76 micrograms/ml, respectively). Moreover, all these antimicrobials are known to concentrate several times in macrophages. MICs90 were higher for amikacin (11 micrograms/ml) and for rifampicin (8 micrograms/ml). When clarithromycin was tested against three MAC strains in combination with another drug, it showed a synergistic effect only when combined with rifampicin. Some synergistic effect was observed also when combining clarithromycin with rifampicin and amikacin, whereas in combination with rifabutin and clofazimine there was only an additive effect.     

In vitro activity of colistin as single agent and in combination with antifungals against filamentous fungi occurring in patients with cystic fibrosis

Because published reports indicate that the antibiotic colistin (COL) has antifungal properties, this study investigated the antifungal in vitro activity of COL as single agent and in combination with the antifungal compounds voriconazole (VRC), caspofungin (CAS) and amphotericin B (AMB) against Scedosporium/Pseudallescheria spp., Exophiala dermatitidis and Geosmithia argillacea. In total, susceptibility was determined for 77 Scedosporium/Pseudallescheria spp., 82 E. dermatitidis and 17 G. argillacea isolates. The minimal inhibitory concentrations (MICs) of COL and the antifungals as single compound and in combination were determined with MIC test strips. Drug interactions were detected by crossing the MIC test strips at a 90º angle. The fractional inhibitory concentration index was used to categorise the drugs’ interaction. The MIC₅₀ value of COL was 12 μg ml^?1 for S. prolificans, 16 μg ml^?1 for P. apiosperma, 16 μg ml^?1 for P. boydii, 12 μg ml^?1 for E. dermatiditis and 6 μg ml^?1 for G. argillacea. VRC was the most active drug in combination without any antagonism with the exception of few P. boydii isolates. COL as single agent and in most combinations with antifungals exhibits in vitro antifungal activity against filamentous ascomycetes occurring in cystic fibrosis patients and may offer a novel therapeutic option, especially for multidrug‐resistant S. prolificans.