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R Quintiliani

Publications and source records attributed to R Quintiliani.

At least 73 records · Page 4Linked to original sources
PubMed1996

Mechanisms of glycopeptide resistance in enterococci.

Inducible resistance to high levels of glycopeptide antibiotics in clinical isolates of enterococci is mediated by Tn1546 or related transposons. Tn1546 encodes the VanH dehydrogenase which reduces pyruvate to D-lactate (D-Lac) and the VanA ligase which catalyses synthesis of the depsipeptide D-alanyl-D-lactate (D-Ala-D-Lac). The depsipeptide replaces the dipeptide D-Ala-D-Ala leading to production of peptidoglycan precursors which bind glycopeptides with reduced affinity. In addition, Tn1546 encodes the VanX dipeptidase and the VanY D,D-carboxypeptidase that hydrolyse the dipeptide D-Ala-D-Ala and the C-terminal D-Ala residue of the cytoplasmic precursor UDP-MurNAC-L-Ala-gamma-D- Glu-L-Lys-D-Ala-D-Ala, respectively. These two proteins act in series to eliminate D-Ala-D-Ala-containing precursors. VanX is required for resistance whereas VanY only slightly increases the level of resistance mediated by VanH, VanA and VanX.

Amino Acid Sequence↗
PubMed1996

Genetics of glycopeptide resistance in enterococci.

Glycopeptide resistance in enterococci is phenotypically and genotypically heterogeneous. The genes responsible for inducible resistance to high levels of vancomycin and teicoplanin (VanA phenotype) are carried by the 10,851-bp Tn1546 transposon. Transposition of Tn1546 into self-transferable plasmids and subsequent transfer by conjugation appears to be responsible for the dissemination of this type of resistance. Nine polypeptides are encoded by Tn1546 that belong to five functional groups: transposition functions (ORF1 and ORF2), regulation of resistance gene expression (VanR and VanS), synthesis of depsipeptide D-Ala-D-lactate (VanH and VanA), hydrolysis of D-Ala-D-Ala-containing peptidoglycan precursors (VanX and VanY), and low-level teicoplanin resistance (VanZ). VanB-type resistance (various levels of resistance to vancomycin and susceptibility to teicoplanin) is also due to production of D-Ala-D-Lac. The VanB ligase of VanB-type strains is structurally and functionally similar to VanA. The vanB gene was found on composite transposon Tn1547, which, in turn, was part of larger conjugative chromosomally located elements (90 to 250 kb). In contrast to acquired VanA- and VanB-type resistance, VanC-type resistance (low level of resistance to vancomycin and susceptibility to teicoplanin) is an intrinsic property of motile enterococci. Resistance in these species is due to synthesis of dipeptide D-Ala-D-Ser by VanC ligases leading to production of cell wall precursors with reduced vancomycin affinity.

Anti-Bacterial Agents↗
PubMed1996

Once-daily aminoglycoside dosing: impact on requests and costs for therapeutic drug monitoring.

Recently, much interest has focused on the use of once-daily aminoglycosides (ODA) in the medical literature. In late 1992, we implemented a hospital-wide ODA program for adult patients at our 850-bed community-teaching hospital. In the first phase of implementation, therapeutic drug monitoring (TDM) was accomplished with the use of a random serum concentration and a nomogram that had been developed at our institution. In the second phase, serum drug concentrations were eliminated on patients with normal renal function. The fully implemented program resulted in a 40% decrease in the request for gentamicin and tobramycin serum concentrations as compared with historic ordering patterns for conventional aminoglycoside dosing regimens. In addition, the incidence of nephrotoxicity was also reduced from 3 to 5% with conventional aminoglycoside dosing, to 1.2 and 1.3% for phases 1 and 2, respectively. Furthermore, the elimination of TDM requests totaling 300 for gentamicin and 50 for tobramycin per month is expected to result in an annual institutional savings of > $100,000.

Adult↗
PubMed1996

Efficacy of vancomycin and teicoplanin alone and in combination with streptomycin in experimental, low-level vancomycin-resistant, VanB-type Enterococcus faecalis endocarditis.

The efficacy of vancomycin (VM) and teicoplanin (TE), alone and in combination with streptomycin (SM), against enterococci that express low-level VanB-type VM resistance was investigated in experimental endocarditis using isogenic strains of Enterococcus faecalis susceptible to glycopeptides and aminoglycosides or inducibly resistant to low levels of VM (MIC = 16 micrograms/ml). VM was significantly less active against the resistant strain than against the susceptible strain, establishing that low-level VanB-type VM resistance can influence therapeutic efficacy. By contrast, TE had equally good activity against both strains. VM or TE combined with SM was synergistic and bactericidal against the resistant strain in vitro. While both combinations were efficient in reducing bacterial density in vivo, TE plus SM was significantly superior to VM plus SM if valve sterilization was considered. These data suggest that despite the presence of low-level VanB-type resistance, combination therapy with a glycopeptide and SM (and presumably other aminoglycosides to which there is not high-level resistance) will nevertheless provide effective bactericidal activity.

Animals↗
PubMed1996

Serum bactericidal activity of ceftazidime: continuous infusion versus intermittent injections.

Since beta-lactam antibiotics have concentration-independent killing, bacterial eradication is a function of the time the serum drug concentration remains above the drug's MIC (T > MIC). We compared the serum bactericidal titers (SBTs) of ceftazidime given by continuous infusion (CI) or by intermittent bolus dosing (BD) against two clinical isolates each of Pseudomonas aeruginosa and Escherichia coli to determine if CI would allow lower daily dosing while still providing equal bactericidal activity compared with BD. This was an open-labeled, randomized, steady-state, four-way crossover study with 12 healthy volunteers. The ceftazidime regimens were 1 g every 8 h (q8h) BD, 1 g q12h BD, 3 g over 24 h CI, and 2 g over 24 h CI. The areas under the bactericidal curves were calculated by the trapezoidal rule using the reciprocal of the SBT. For all organisms the areas under the bactericidal curves for intermittent versus the CI regimens were the same for equal doses (P > 0.05). For both strains of E. coli all four regimens provided SBTs of > or = 1:2 over the dosing interval and 100% T > MIC. The 1-g q8h BD and q12h BD regimens provided T > MIC of 82 and 52%, respectively, for both P. aeruginosa isolates (MICs, 4 micrograms/ml). In comparison, the 2- and 3-g CI regimens always maintained SBTs of > or = 1:2 and T > MIC over the 24-h period as serum drug concentrations were 12.8 +/- 3.0 and 18.2 +/- 4.5 micrograms/ml, respectively. CI optimizes the pharmacodynamic and pharmacoeconomic profile of ceftazidime by providing adequate antibacterial activity over the 24-h dosing period with a reduction in the total daily dose of the antimicrobial agent.

Adult↗
PubMed1996

Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin.

The bronchopulmonary and plasma pharmacokinetics of clarithromycin (CLA; 500 mg given twice daily for nine doses) or azithromycin (AZ; 500 mg for the first dose and then 250 mg once daily for four doses) were assessed in 41 healthy nonsmokers. Bronchoalveolar lavage was performed at 4, 8, 12, or 24 h after administration of the last dose. The concentrations (mean +/- standard deviation) of CLA, 14-hydroxyclarithromycin, and AZ were measured in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) cells by high-performance liquid chromatography assay. The concentrations of CLA achieved in ELF were 34.02 +/- 5.16 micrograms/ml at 4 h, 20.63 +/- 4.49 micrograms/ml at 8 h, 23.01 +/- 11.9 micrograms/ml at 12 h, and 4.17 +/- 0.29 microgram/ml at 24 h, whereas at the same time points AZ concentrations remained below the limit of assay sensitivity (0.01 microgram/ml) for all but two subjects. The concentrations of CLA in the AM cells were significantly higher than those of AZ at 8 h (703 +/- 235 and 388 +/- 53 micrograms/ml, respectively). However, the ratio of the concentration in AM cells/concentration in plasma was significantly higher for AZ than for CLA for all time points because of the lower concentration of AZ in plasma. These results indicate that while AZ has higher tissue concentration to plasma ratios, as shown by other investigators, the absolute concentrations of CLA in AM cells and ELF are higher for up to 8 and 12 h, respectively, after administration of the last dose.

Adult↗
PubMed1996

Comparative serum bactericidal activities of ceftizoxime and cefotaxime against intermediately penicillin-resistant Streptococcus pneumoniae.

In a randomized crossover study involving 12 healthy volunteers, 1 g of ceftizoxime or cefotaxime was administered intravenously every 12 h for a total of three doses on two separate weekends. The duration of serum bactericidal titers (SBTs) greater than 1:2 and the time serum drug concentrations remained above the MIC (T > MIC) were determined against three clinical isolates of Streptococcus pneumoniae with intermediate resistance to penicillin. The duration of SBTs and T > MIC for both antimicrobial agents exceeded 50% of the dosing interval for all isolates. Ceftizoxime's T > MIC was statistically greater than that of cefotaxime, indicating that its longer half-life in serum (1.7 h) compared with that of cefotaxime (approximately 1 h) compensates for its slightly lower microbiologic activity against the penicillin-resistant pneumococci tested in this study.

Adult↗
PubMed1996

Characterization of bactericidal activity of clindamycin against Bacteroides fragilis via kill curve methods.

Kill curves were determined for five isolates of Bacteroides fragilis with clindamycin at concentrations equal to the MIC or to 4, 16, and 64 times the MIC. Examination of plots of log CFU per milliliter versus time revealed no association between the clindamycin concentration and the rate and extent of the bactericidal activity against B. fragilis at or below 64 times the MIC.

Anti-Bacterial Agents↗
PubMed1996

Pharmacoeconomics of Pneumocystis carinii pneumonia in HIV-infected and HIV-noninfected patients.

Despite the proven effectiveness of Pneumocystis carinii pneumonia (PCP) prophylaxis in both HIV-infected and HIV-noninfected patients, PCP remains an important cause of serious pulmonary infection. Because PCP is a frequent event requiring inpatient admission at our institution, we conducted a study to define the pharmacoeconomics of this infection and the incidence of adverse events associated with anti-PCP therapy. In a retrospective review, 133 patients (101 HIV-positive, 32 HIV-negative) with documented PCP were identified. Significant differences in age, initial arterial oxygen tension (paO2), intensive care unit admission and mortality were evident between HIV-infected and non-HIV-infected patients; however, there were no differences in the duration of hospitalisation or the duration of anti-PCP therapy. The incidence of biochemical abnormalities was similar between the groups. Leucopenia occurred at an incidence of 52 and 31%, while thrombocytopenia occurred at a rate of 7 and 44%, in HIV-positive and HIV-negative patients, respectively. Drug toxicity or treatment failure necessitated a change of therapy in 43% of HIV-positive and 59% of HIV-negative patients. PCP treatment cost, pharmacy cost, hospital cost and net loss (i.e. the difference between hospital cost and reimbursement) were all significantly greater in HIV-negative than in HIV-positive patients. The duration of anti-PCP therapy and the hospital cost for cotrimoxazole (trimethoprim-sulfamethoxazole)- and pentamidine-treated patients were similar, although the treatment cost and pharmacy cost were statistically different in favour of cotrimoxazole. Overall, cotrimoxazole is an inexpensive treatment option. However, the high incidence of adverse events attributed to this agent often necessitates a change to a more costly therapy.

AIDS-Related Opportunistic Infections↗
PubMed1995

In vitro antimicrobial susceptibility of glycopeptide-resistant enterococci.

The results of susceptibility testing of 48 phenotyped strains of glycopeptide antibiotic-resistant enterococci are reported. Minimum inhibitory and bactericidal concentrations (MICs and MBCs) were determined for 27 vanA, 17 vanB, and 4 vanC strains. Antibiotics exhibiting the greatest activity included novobiocin (MIC90 = 8 micrograms/ml and MBC90 = 32 micrograms/ml), ramoplanin (MIC90 = 2 micrograms/ml and MBC90 = 4 micrograms/ml), and the streptogramin RP59500 (MIC90 = 4 micrograms/ml and MBC90 = 32 micrograms/ml). These antibiotics warrant further investigation as potentially useful agents, either alone or in combination, for treating enterococcal infections.

Anti-Bacterial Agents↗
PubMed1995

Antibiotic formulary selection.

Physicians worldwide are being forced to consider economics in the care of patients. In most hospitals, antibiotics are a steadily increasing segment of the pharmacy budget. This article discusses how the authors used drug pharmacokinetics, restriction policies, and cost benefit analysis to design a cost-effective antibiotic formulary.

Anti-Bacterial Agents↗
PubMed1995

Antibiotic kinetics and dynamics for the clinician.

In recent decades considerable data have been acquired concerning the complex interactions of the organism-antimicrobial-host triad. Using the current understanding of drug disposition in the body, pharmacokinetics, and in vitro microbiologic activity, optimal dosing strategies can be derived to maximize clinical efficacy and minimize potential toxicities. This article discusses pharmacokinetics, pharmadynamics, and the application of this principle in clinical practice.

Algorithms↗
PubMed1995

Bioavailability of fluconazole administered via a feeding tube in intensive care unit patients.

Fluconazole, a triazole compound with potent activity against many medically important fungi, undergoes rapid oral absorption, and has been shown in healthy volunteers to exhibit virtually complete bioavailability. The purpose of this study is to evaluate the bioavailability of fluconazole administered via a feeding tube with concomitant enteral feeds in intensive care unit patients. Once prescribed by the attending physician, fluconazole was administered either as an intravenous infusion over 1 h or the tablet was crushed and given via a feeding tube with concomitant enteral feeds. Once blood samples were obtained (not before the fifth dose) of the first regimen, the patient could be switched over to the alternate route and blood samples were again obtained after at least five doses. All patients had normal gastrointestinal motility, normal renal, and hepatic function. Serum concentrations were determined by a validated HPLC method. The area under concentration-time curve (AUC) was calculated using the trapezoidal rule; bioavailability was determined from the ratio of AUC(tube)/AUC(intravenous). The bioavailability for five patients was calculated to be 97.2 +/- 9.8%. Fluconazole retained excellent bioavailability when crushed and administered via a feeding tube with or without concomitant enteral feeding in critically ill patients. This alternative route of administration promotes cost savings and decreases the chance for secondary infection from indwelling intravenous catheters.

Adult↗
PubMed1995

Determination of the in vivo post-antibiotic effects of ciprofloxacin and rifampicin.

A modified rabbit meningitis model is described for determining the PAE in vivo, which utilised a self-standing device for repeatedly sampling pure CSF. The model allowed the PAEs of ciprofloxacin and rifampicin on Escherichia coli ATCC 25922 to be determined following PAE induction in vitro, or in vivo in CSF after intrathecal injection or during the last 1.5 h of a 7 h iv continuous infusion. The estimated volumes of distribution of ciprofloxacin and rifampicin in CSF were 0.68 +/- 0.24 mL and 0.74 +/- 0.04 mL, respectively, and the terminal elimination half lives were 1.8 +/- 0.5 h and 2.2 +/- 0.3 h, respectively. PAEs of approximately 2 h were obtained in vivo and in vitro after exposing E. coli to 3 x MIC of ciprofloxacin in vitro and to 1 x MIC of drug in vivo. When the organism was exposed to rapidly declining concentrations in vivo, only a minimal PAE was observed for both antibiotics. Moreover, a PAE of 3.1 +/- 1.3 h of rifampicin was obtained in vivo, being smaller than the 4.8 h PAE observed in vitro, which might be explained by the binding of 45 +/- 6.5% rifampicin to proteins in the CSF.

Animals↗
PubMed1995

Comparison of the bactericidal activities of ofloxacin and ciprofloxacin alone and in combination with ceftazidime and piperacillin against clinical strains of Pseudomonas aeruginosa.

On the basis of MIC data, ciprofloxacin exhibits superior activity against Pseudomonas aeruginosa than the other currently available fluoroquinolones do. Despite the antipseudomonal advantage noted for ciprofloxacin monotherapy, it is unknown whether this advantage is maintained when the fluoroquinolones are used in combination with antipseudomonal beta-lactams such as ceftazidime and piperacillin. Twelve healthy volunteers were enrolled in this open-label, randomized, steady-state, six-way cross-over, comparative trial. All subjects received the following regimens: (i) 400 mg of ofloxacin given intravenously (i.v.) every 12 h (q12h), (ii) 400 mg of ciprofloxacin given i.v. q12h, (iii) 400 mg of ofloxacin given i.v. q12h plus 1 g of ceftazidime given i.v. every 8 h (q8h), (iv) 400 mg of ciprofloxacin given i.v. q12h plus 1 g of ceftazidime given i.v. q8h, (v) 400 mg of ofloxacin given i.v. q12h plus 4 g of piperacillin given i.v. q8h, and (vi) 400 mg of ciprofloxacin given i.v. q12h plus 4 g of piperacillin given i.v. q8h. Serum bactericidal titers with subsequent calculation of the area under the bactericidal curve were determined against three clinical isolates of P. aeruginosa. As monotherapy, ciprofloxacin demonstrated superior antipseudomonal activity than ofloxacin did; however, combination of these agents with ceftazidime yielded remarkably similar and statistically comparable activity profiles. In contrast, ciprofloxacin-piperacillin retained a bactericidal advantage over ofloxacin-piperacillin. Although ciprofloxacin exhibits superior antipseudomonal activity when used as monotherapy, combination of ofloxacin or ciprofloxacin with ceftazidime yielded equivalent activity profiles against susceptible strains of P. aeruginosa.

Adult↗
PubMed1995

Experience with a once-daily aminoglycoside program administered to 2,184 adult patients.

Once-daily aminoglycoside (ODA) regimens have been instituted to maximize bacterial killing by optimizing the peak concentration/MIC ratio and to reduce the potential for toxicity. We initiated an ODA program at our institution that utilizes a fixed 7-mg/kg intravenous dose with a drug administration interval based on estimated creatinine clearance: > or = 60 ml/min every 24 h (q24h), 59 to 40 ml/min q36h, and 39 to 20 ml/min q48h. Subsequent interval adjustments are made by using a single concentration in serum and a nomogram designed for monitoring of ODA therapy. Since initiation of the program, 2,184 patients have received this ODA regimen. The median dose was 450 (range, 200 to 925) mg, while the median length of therapy was 3 (range, 1 to 26) days. The median age of the population was 46 (range, 13 to 97) years. Gentamicin accounted for 94% of the aminoglycoside use, and the majority (77%) of patients received the drug q24h. The 36-, 48-, and > 48-h intervals were used for 15, 6, and 2% of this population, respectively. Three patients exhibited clinically apparent ototoxicity. Twenty-seven patients (1.2%) developed nephrotoxicity (the Hartford Hospital historical rate is approximately 3 to 5%) after a median of 7 (range, 3 to 19) days of therapy. On the basis of a prospective evaluation of 58 patients and follow-up of additional patients via clinician reports, we have noted no apparent alterations in clinical response with our ODA program. This ODA program appears to be clinically effective, reduces the incidence of nephrotoxicity, and provides a cost-effective method for administration of aminoglycosides by reducing ancillary service time and serum aminoglycoside determinations.

Adolescent↗