Biomedical subjects

D P Nicolau

Publications and source records attributed to D P Nicolau.

At least 19 recordsLinked to original sources

PubMed2005

Intrapulmonary concentrations of telithromycin: clinical implications for respiratory tract infections due to Streptococcus pneumoniae.

BACKGROUND: Antimicrobial efficacy is dependent on the ability of the agent to reach the site of infection. To assess the bronchopulmonary drug disposition of a novel ketolide, telithromycin (TEL), the epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations were utilized as a surrogate marker for lung penetration. METHODS: Adult subjects scheduled for diagnostic bronchoscopy received oral TEL 800 mg once daily for 5 days. Plasma and bronchoalveolar lavage (BAL) samples were collected 2, 8, 12, or 24 h after the last TEL dose. TEL concentrations in the ELF and AM were determined using a validated HPLC assay. ELF drug concentrations were calculated using the urea dilution method. RESULTS: Seventeen subjects with a mean age 65 +/- 13 years and a mean weight of 81 +/- 25 kg completed this open-label study. The median (range) TEL concentrations in plasma and ELF, respectively, were 1.09 mg/l (1.00-4.81) and 3.91 mg/l (2.64-9.59) at 2 h (n = 6), 0.48 and 1.09 mg/l at 8 h (n = 1), 0.65 mg/l (0.18-1.55) and 1.81 mg/l (0.61-10.0) at 12 h (n = 5), and 0.11 mg/l (0.09-0.24) and 0.69 mg/l (0.15-1.58) at 24 h (n = 5). The median AM concentrations obtained from these subjects were 53.35 mg/l at 2 h, 32.55 mg/l at 8 h, 65.96 mg/l at 12 h, and 26.43 mg/l at 24 h. Overall TEL was well tolerated. No discontinuation was required due to an adverse event. CONCLUSIONS: TEL displayed high intrapulmonary penetration with ELF concentrations exceeding that of plasma at all time points. AM intracellular concentrations were multiple times higher than in the ELF and plasma. These data support the clinical efficacy of TEL against intracellular and extracellular pathogens, particularly with Streptococcus pneumoniae having an MIC(90 )well below achievable concentrations at the site of infection.

Aged↗

PubMed2004

The integration of pharmacokinetics and pathogen susceptibility data in the design of rational dosing regimens.

The integration of pharmacokinetic and pathogen susceptibility data has had an increasing impact on the design of dosage regimens. Pathogen susceptibility is often described by the minimum inhibitory concentration (MIC). While the MIC is an indicator of drug potency, it does not predict pharmacologic response in vivo when drug concentrations are fluctuating. To this end, three pharmacokinetic/pharmacodynamic (PK/PD) parameters that result from indexing pharmacokinetics to MIC have proven quite useful. A number of experimental models of infection have determined the magnitude of each parameter, AUC/MIC, Cmax/MIC and %T>MIC, required for the optimal treatment of specific pathogens. These measurements have proven to be predictive of clinical outcomes as well. As a result, PK/PD breakpoints have been determined based on the likelihood that the pharmacokinetic profile of a given dose will achieve a target PK/PD parameter value. These breakpoints correlate well with treatment success or failure, particularly evident in infections conducive to microbiologic sampling such as otitis media. Therefore, PK/PD assessments have fostered a much more targeted approach to the treatment of patients with infectious diseases, and have proven useful in the selection of antimicrobial therapy and the development of novel dosing strategies.

Anti-Infective Agents↗

PubMed2003

Beneficial pharmacokinetic interaction between cyclosporine and itraconazole in renal transplant recipients.

BACKGROUND: Itraconazole is often given for fungal prophylaxis to renal transplant recipients, who require concomitant cyclosporine in the immediate posttransplant period. We determined the extent of the pharmacokinetic interaction between cyclosporine and itraconazole oral solution in renal transplant recipients and the effect on daily drug costs. METHOD: This was a single-center, open-label, nonrandomized study. Posttransplantation, renal transplant recipients received itraconazole solution 200 mg twice daily and cyclosporine, dosed to achieve target concentrations. Once at steady state, blood samples were collected over 12 hours for pharmacokinetic evaluation of cyclosporine, itraconazole, and hydroxy-itraconazole. Itraconazole was discontinued after approximately a 3-month prophylaxis regimen. Cyclosporine doses were titrated to achieve target concentrations and cyclosporine concentrations were once again determined when steady state was achieved. A noncompartmental analysis was used to analyze cyclosporine pharmacokinetic parameters. The pharmacoeconomic impact was measured based on the percent change in dose of cyclosporine when administered with and without itraconazole. Drug costs were calculated using the average wholesale price. The cost per patient, as well as the average cost, was calculated for the cyclosporine/itraconazole combination, as well as the cyclosporine regimen alone. RESULTS: Eight renal transplant recipients completed the study. All were included for itraconazole analyses and seven for cyclosporine analyses. Mean peak and trough itraconazole levels were 1.64 +/- 0.82 and 1.23 +/- 0.90 microg/mL respectively. Mean peak and trough hydroxy-itraconazole levels were 2.37 +/- 1.55 and 2.20 +/- 1.48 microg/mL, respectively. While on itraconazole, a 48% reduction in the mean total daily dose of cyclosporine was necessary to maintain target concentrations (171 +/- 63.6 versus 329 +/- 103.5 mg, P =.003). This reduction in cyclosporine dose resulted in a discounted itraconazole daily drug cost of approximately 29.5%. CONCLUSION: Administering itraconazole with cyclosporine allows for a decrease in the cyclosporine dose, thus lowering daily drug costs and providing adequate antifungal coverage with itraconazole and hydroxy-itraconazole trough concentrations above the MIC(90) of Candida and Aspergillus spp.

Antifungal Agents↗

PubMed2002

Clearance of quinupristin-dalfopristin (Synercid) and their main metabolites during continuous veno-venous hemofiltration (CVVH) with or without dialysis.

BACKGROUND: Quinupristin-dalfopristin (Q/D) is often utilized in critically ill patients, some of whom require CVVH. This study was undertaken to determine the clearance of O/D and their main active metabolites (RPR 100391, RP 69012, RP 12536) via CVVH in the swine model. METHODS: Q/D 7.5 mg/kg was intravenously administered over 0.5 h to 12 swine after induction of acute renal failure by ligation of the renal arteries. At 0.5 h post injection, the CVVH procedure was initiated and continued for 8 hours at the following pump rates: (1)100 mL/min, (2)180 rnL/min, and (3)100 mL/min with dialysis (flow rate: 1 L/h). Blood and ultrafiltrate samples were collected at 1 h intervals and assessed by a validated HPLC method. RESULTS: Plasma analysis suggests rapid metabolism to the main active metabolites which are appreciably cleared as demonstrated by high clearance and sieving coefficient estimates. Mean clearance estimates for RP 69012, RP 100391, and RP 12536 are 729, 777, and 578 mL/h in the 100 mL/min CVVH group, 772, 785, 685 mL/min in the 180 mL/min CVVH group, and 753, 791, 616 mL/min in the 100 mL/min CVVH group with 1 L/h dialysis, respectively. CONCLUSION: These data reveal that Q/D is rapidly metabolized and the metabolites are cleared to a large extent via CVVH. Due to the considerable contribution of the metabolites to overall in vivo activities, additional studies are required to fully quantify their removal before final dosage modifications for patients undergoing CVVH can be recommended.

Animals↗

PubMed2002

Pharmacodynamic rationale for short-duration antibacterial therapy.

With the global spread of antibacterial resistance, selecting appropriate therapy for respiratory tract infections (RTIs) presents a major challenge. Current opinion favours short-duration chemotherapy, which can improve patient compliance, thereby reducing potential resistance, minimize toxicodynamic profiles and decrease treatment costs. Neither microbiological nor pharmacokinetic (PK) data alone can determine whether a drug is suitable for short-duration therapy. Pharmacodynamics (PD) seeks to integrate PK and microbiological data into models that can then be used to predict clinical outcomes and to guide rational dosing strategies. Telithromycin is the first ketolide antibacterial to undergo clinical development. Its novel structure provides enhanced microbiological activity, even against beta-lactam and macrolide-resistant pathogens, and the potential to minimize the selection of resistance. PK profiling of telithromycin reveals that once-daily oral administration of 800 mg achieves plasma concentrations that exceed the MICs of key respiratory pathogens throughout most of the dosing period. PK-PD modelling indicates that the AUC:MIC ratio is predictive of outcome for this antibacterial. Telithromycin achieves high AUC:MIC ratios, has a prolonged postantibiotic effect, shows excellent penetration into respiratory and inflammatory tissues and has a long elimination half-life from these tissues. These variables strongly suggest that telithromycin is suitable for short-duration therapy and a once-daily dosing regimen.

Anti-Bacterial Agents↗

PubMed2001

Pharmacodynamic profiling of levofloxacin and gatifloxacin using Monte Carlo simulation for community-acquired isolates of Streptococcus pneumoniae.

In vitro and in vivo models of infection suggest that the area under the concentration-time curve (AUC): minimum inhibitory concentration (MIC) ratio is the pharmacodynamic parameter that is most predictive of bactericidal activity for the fluoroquinolones. Additionally, this parameter has also been correlated with clinical outcomes in humans with respiratory tract infection. Despite these defined relationships, broad-scale application of these principles in the section of optimal therapy in the clinical arena has been restricted by the imprecise estimates of drug exposures (ie, AUC:MIC ratio) in the infected population. In an effort to best describe the known variability in the pharmacokinetic and susceptibility profile of agents of interest, Monte Carlo simulation has been employed to assess the probability of attaining the desired AUC:MIC ratio. In this report Monte Carlo simulation was used to estimate the probability of attaining various target AUC:MIC ratios using AUC values from patients treated with either gatifloxacin or levofloxacin and the in vitro potency of the compounds as assessed in 881 clinical isolates of Streptococcus pneumoniae isolated from outpatients. Using a simulated patient population of 5,000, the median AUC:MIC ratios were 144 and 50 for gatifloxacin and levofloxacin, respectively. The probability of attaining AUC:MIC ratios of 30, 40, 65, 100, and 125 for gatifloxacin were 99%, 95%, 85%, 68%, and 60%, respectively. For levofloxacin, similar dynamic hit rates were 82%, 61%, 35%, 17%, and 12% over the range of target values. Regardless of the optimal ratio selected, gatifloxacin had a higher probability of achieving the AUC:MIC target than did levofloxacin. Simulations of this type can assist in the decision process surrounding the choice of optimal therapies based on our current understanding of antimicrobial pharmacodynamic principles.

Adolescent↗

PubMed2001

Determination of BMS-284756, a new quinolone, in mouse serum by high-performance liquid chromatography with fluorescence detection.

A sensitive, simple, and accurate method for determination of BMS-284756, a novel des-F(6)-quinolone antimicrobial agent in mouse serum was developed by HPLC with fluorescence detection. Sample preparations were carried out by protein precipitation with the addition of acetonitrile, followed by evaporation of the acetonitrile to dryness. The resultant residual was then reconstituted in 0.01 M HCl and injected onto a Nucleosil 100 10 microm, C18 25 cm x 4.6 mm analytical column. The mobile phase consisted of acetonitrile-0.01 M NaH2PO4 (20:80, v/v) with 0.01 M tetrabutylammonium hydrogen sulfate. The fluorescence of the column effluent was monitored at an excitation wavelength of 290 nm and an emission wavelength of 418 nm. The assay was shown to be linear from 0.2 to 10.0 microg/ml (R2=0.998). Mean recovery was determined as 95.1%. Inter- and intra-assay precisions were <6% RSD. The HPLC method developed has been applied to determine the pharmacokinetics of BMS-284756 in a murine bacterial infection model.

Animals↗

PubMed2001

Adherence to highly active antiretroviral therapy predicts virologic outcome at an inner-city human immunodeficiency virus clinic.

This study's hypothesis is that human immunodeficiency virus-infected patients in the inner city (predominantly injection drug users and ethnic minorities) do not take highly active antiretroviral therapy (HAART) as prescribed and that nonadherence leads to virologic failure. A prospective, observational, 3-month study of adherence to HAART was undertaken at an inner-city clinic. There were 40 subjects [110 subject-months]; 30 were male, 10 were female, 75% were Hispanic, 23% were African American, 68% were injection drug users, and 68% were receiving triple therapy. At 3 months, adherence, which was determined by use of the Medication Event Monitoring System (Aprex) was significantly associated with virologic success: lower virus loads were associated with a rate of adherence of >80% (P<.05). Although nonadherence predicted virologic failure, virologic success was not always predicted by adherence: 11 (27.5%) of 40 subjects with suboptimal adherence rates (<90%) had complete virologic suppression.

Adult↗

PubMed2001

Pharmacodynamics of ceftriaxone and cefixime against community-acquired respiratory tract pathogens.

Over the last decade or so there has been a growing interest in routes of antimicrobial administration other than by the conventional intravenous route for institutionalized patients and for some outpatients. Both oral (PO) and intramuscular (IM) routes of administration are less costly than giving antimicrobial agents by vein (IV). In addition, fewer complications such as catheter-related sepsis and phlebitis are associated with non-IV routes of administration. Furthermore, a reduced-dosage, reduced-volume IM administration of ceftriaxone may provide a tolerable route of administration and equivalent bactericidal activities compared with higher dose IV ceftriaxone. The purpose of this study was to determine the time that the drug concentration remained in excess of the minimum inhibitory concentration (MIC) (T > MIC) and the duration of bactericidal activities of ceftriaxone one gram administered IV, ceftriaxone 250 mg given IM and cefixime 400 mg given orally against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in adult volunteers. Single doses of each agent were administered and serum concentrations were collected over the standard dosing period of 24 h for all study regimens. Ceftriaxone, regardless of route of administration and dose, resulted in bactericidal activities and T > MIC for 100% of the dosing period for S. pneumoniae, H. influenzae, and M. catarrhalis. Cefixime maintained at least 50% T > MIC and bactericidal activity against both isolates each of H. influenzae and M. catarrhalis. Against both isolates of S. pneumoniae, cefixime achieved T > MIC for at least 50% of the dosing period, but did not maintain bactericidal activity. Reduced dose ceftriaxone given IM seems to be a viable alternative to ceftriaxone IV if the pathogen, susceptibility and infection site are known. Based on T > MIC exceeding 50% of the dosing interval, cefixime would be considered an effective alternative to IV therapy against common respiratory tract pathogens. Clinical studies need to be conducted to confirm these findings.

Administration, Oral↗

PubMed2001

Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia.

A prospective, randomized pilot study was undertaken to compare the efficacy of continuous versus intermittent ceftazidime in ICU patients with nosocomial pneumonia. Ceftazidime was administered either as a 3 g/day continuous infusion (CI) or an intermittent infusion (II) of 2 g every 8 h. In addition, all patients received concomitant once-daily tobramycin. The demographics of the evaluable patients (n = 35) were similar between the groups: age (years), CI 46 +/- 16, II 56 +/- 20; Apache score, CI 14 +/- 4, II 16 +/- 6; time (days) from admission to diagnosis, CI 9 +/- 6, II 9 +/- 6. Clinical efficacy, defined as cure/improvement was similar between groups [n (%), CI 16/17 (94), II 15/18 (83)], while microbiological response was also comparable [n (%), CI 10/13 (76), II 12/15 (80)]. Minimal inhibitory concentrations (MICs) for all isolates were measured throughout the treatment course; there was no development of resistance during therapy for either regimen. While limited clinical data exist, our results suggest that the use of ceftazidime by CI administration maintains clinical efficacy, optimizes the pharmacodynamic profile and uses less antibiotic compared with the standard 2 g every 8 h intermittent dosing regimen.

Adult↗

PubMed2001

Pharmacokinetic and pharmacodynamic profile of high dose extended interval piperacillin-tazobactam.

A multiple-dose, open-labelled, randomized, two period crossover human volunteer study was performed (i) to describe the pharmacokinetic profile and safety profile of piperacillin and tazobactam (P/T) administered 6.0/0.75 g and 8.0/1.0 g q12h and (ii) to characterize the pharmacodynamic profile of these regimens against a variety of common targeted pathogens. Blood samples were collected after the third dose and concentrations of P/T were determined by a validated high-performance liquid chromatography assay. Pharmacokinetic profiles of P/T were determined by non-compartment analysis. Percentage time above the MIC (%T > MIC) of piperacillin was calculated for a range of MICs. In this study, no adverse events were attributed after multiple administrations of either 6.0/0.75 g or 8.0/1.0 g dose regimens. The peak concentration, half-life and area under the curve (AUC0-(0-tau)) of piperacillin were significantly different by a paired t-test (P < 0.05) between the two study regimens. The trough concentration, half-life and area under the curve (AUC0-(0-tau)) of tazobactam were substantially different from parameters reported previously for conventional regimens. The 8.0/1.0 g regimen provided 50% T > MIC for MICs < or =32 mg/L, while a similar value for the 6.0/0.75 g regimen was < or = 16 mg/L. High-dose P/T regimens with extended interval were well tolerated and provide adequate dynamic exposure for a variety of susceptible pathogens.

Adult↗

PubMed2001

Streptococcus pneumoniae response to repeated moxifloxacin or levofloxacin exposure in a rabbit tissue cage model.

The role of moxifloxacin and levofloxacin pharmacokinetics (PK) in antimicrobial efficacy and in the selection of fluoroquinolone-resistant Streptococcus pneumoniae strains was investigated using the rabbit tissue cage abscess model. A rabbit tissue cage was created by insertion of sterile Wiffle balls in the dorsal cervical area. Animals orally received a range of moxifloxacin or levofloxacin doses that simulate human PK for 7 days 48 h after the Wiffle balls were inoculated with fluoroquinolone-sensitive S. pneumoniae (10(7) CFU). Abscess fluid was collected on a daily basis over 14 days to measure bacterial density and MICs. Moxifloxacin regimens produced a range of area under the concentration-time curve (AUC)/MIC ratios ranging from 9.2 to 444 and peak/MIC ratios ranging from 1.3 to 102. Levofloxacin doses produced AUC/MIC ratios of 5.1 to 85.5 and peak/MIC ratio of 0.9 to 14.8. Moxifloxacin at 6.5, 26, and 42 mg/kg reduced the bacterial log CFU per milliliter in abscess fluid (percentage of that in a sterile animal) by 4.2 +/- 2.2 (20%), 5.8 +/- 0.4 (100%), and 5.4 +/- 0.4 (100%), respectively, over the dosing period. Levofloxacin at 5.5, 22, and 32 mg/kg reduced the log CFU per milliliter in abscess fluid (percentage of that in a sterile animal) by 2.8 +/- 0.7 (20%), 5.1 +/- 1.3 (80%), and 4.6 +/- 1.3 (60%), respectively. Moxifloxacin has a greater bactericidal rate as determined by regression of log CFU versus time data. The AUC/MIC and peak/MIC ratios correlated with the efficacy of both drugs (P < 0.05). Resistance to either drug did not develop with any of the doses as assessed by a change in the MIC. In conclusion, data derived from this study show that moxifloxacin and levofloxacin exhibit rapid bactericidal activity against S. pneumoniae in vivo, and moxifloxacin exhibits enhanced bactericidal activity compared to levofloxacin, with AUC/MIC and peak/MIC ratios correlated with antimicrobial efficacy for both drugs. The development of fluoroquinolone-resistant S. pneumoniae was not observed with either drug in this model.

Animals↗

PubMed2001

Pharmacodynamic assessment of gatifloxacin against Streptococcus pneumoniae.

The pharmacodynamic parameters of peak serum drug concentration/MIC (peak/MIC) ratio and the area under the curve (AUC)/MIC ratio have been used to characterize in vivo drug exposure and its relationship to bacterial killing for the fluoroquinolones. Our study objectives were to describe the pharmacodynamic relationship between gatifloxacin exposure and outcome as assessed by bacterial density and survival in an immunocompromised murine thigh model of pneumococcal infection and to assess the relationship between drug exposure and these outcomes in an immunocompetent host. ICR mice were rendered neutropenic, and thigh infection was induced by intramuscular administration of 0.1 ml of 10(5) to 10(7) CFU of Streptococcus pneumoniae/ml. Mice received 1 to 5 mg of uranyl nitrate/kg of body weight at day -3 and were randomized to receive 10 to 80 mg of gatifloxacin/kg every 6 to 24 h orally, starting at 2 h postinoculation. Bacterial density studies were completed 24 h after initiation of therapy, and survival was assessed after 4 days of treatment. MICs for clinical isolates (n = 8) ranged from 0.25 to 1.0 microg/ml. Correlations were assessed between the change in bacterial density, as well as survival, and the AUC/MIC ratio, peak/MIC ratio, and the duration of time that serum drug concentration remained above the MIC. The best predictor of bacterial response was the AUC/MIC ratio for both outcome measures. There was greater efficacy, as measured by a decrease in log change in CFU as well as by survival data, in the immunocompetent mice compared to the immunocompromised mice. These data demonstrate (i) the appropriateness of the AUC/MIC ratio as a dynamic predictor of response to pneumococcal infection for the fluoroquinolones, (ii) that gatifloxacin AUC/MIC ratios of 30 to 40 appear to optimize bactericidal activity and survival in this model, and (iii) that immunocompetency of the host plays a role in efficacy.

Animals↗

PubMed2001

Lack of interaction between levofloxacin and oxycodone: pharmacokinetics and drug disposition.

Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and levofloxacin. Eight healthy volunteers were randomized in an open-label, two-way crossover study to receive oxycodone, 5 mg p.o. Q4H, and levofloxacin, 500 mg p.o. 1 hour after starting the oxycodone or levofloxacin 500 mg p.o. alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours for Cmax, tmax, and AUC determinations. There was not a significant difference (p > 0.05) in AUC (48.59 +/- 8.52 vs. 49.9 +/- 9.93), Cmax (7.73 +/- 2.6 vs. 6.6 +/- 2.0), and tmax (1.1 +/- 0.6 vs. 1.6 +/- 1.1) for levofloxacin versus levofloxacin/oxycodone regimens. It was concluded that oral oxycodone and levofloxacin can be administered concomitantly without a significant decrease in AUC, Cmax, or tmax.

Adult↗

PubMed2001

Effects of adjunctive treatment with combined cytokines in a neutropenic mouse model of multidrug-resistant Enterococcus faecalis septicemia.

STUDY OBJECTIVE: To examine whether the antienterococcal efficacy of a regimen of gentamicin plus vancomycin combined with granulocyte colony-stimulating factor (G-CSF) is enhanced by concurrent therapy with interferon-gamma (IFN-gamma). SETTING: Hospital laboratory. INTERVENTION: Mice rendered neutropenic by cyclophosphamide were intraperitoneally inoculated with a gentamicin- and vancomycin-resistant Enterococcus faecalis isolate. MEASUREMENTS AND MAIN RESULTS: Infected animals were randomized into treatment groups that received G-CSF alone or in combination with various dosages of IFN-gamma. Additional groups of animals received vancomycin; G-CSF, G-CSF plus vancomycin, IFN-gamma, and G-CSF; or vancomycin with both cytokines. Addition of IFN-gamma to G-CSF regimen resulted in no significant change (p>0.05) in survival, compared with treatment with G-CSF alone. Also, the antienterococcal efficacy of antibiotic plus G-CSF was not modified by coadministration of IFN-gamma. CONCLUSION: This study suggests that adjunctive application of combined cytokines may not be more beneficial than only G-CSF in combination with an antibiotic to treat multidrug-resistant enterococcal infection.

Animals↗

PubMed2001

Cost-effectiveness of ceftazidime by continuous infusion versus intermittent infusion for nosocomial pneumonia.

STUDY OBJECTIVE: To determine if continuous-infusion ceftazidime is more cost-effective and efficacious than intermittent infusion in patients with nosocomial pneumonia. DESIGN: Prospective, open-label, randomized trial. SETTING: Large, community teaching hospital. PATIENTS: Intensive care unit (ICU) patients with nosocomial pneumonia. INTERVENTIONS: Ceftazidime 3 g/day was administered as a continuous infusion or as 2 g 3 times/day by intermittent infusion to treat nosocomial pneumonia in the ICU. Patients also received tobramycin 7 mg/kg once/day. MEASUREMENTS AND MAIN RESULTS: Thirty-five patients were evaluable; 17 received continuous infusion and 18 intermittent infusion. Clinical efficacy (94% and 83% successful outcomes with continuous and intermittent infusion, respectively), adverse events, and length of stay did not vary significantly between groups. Costs associated with continuous infusion, $627 +/- 388, were significantly lower (p < or = 0.001) than with intermittent infusion, $1007 +/- 430. CONCLUSIONS: Continuous infusion of ceftazidime is a cost-effective alternative to intermittent infusion for nosocomial pneumonia in the ICU.

Adult↗

PubMed2001

Antibacterials for the prophylaxis and treatment of bacterial endocarditis in children.

Although the overall incidence of infective endocarditis in the paediatric population is considered to be low, over the last 20 years a rising trend in infective endocarditis has been observed among children. This could be due to several reasons including the availability of improved diagnostic techniques, use of continuous central venous catheters and cardiac implants increasing the risk of infection, and the survival of a greater number of infants with congenital heart disease as a result of improved medical management. The predominant causative organisms of paediatric endocarditis include staphylococci and streptococci. There is increased concern surrounding the emergence of endocarditis in children caused by methicillin-resistant Staphylococcus aureus and drug resistant strains of Streptococcus pneumoniae. The treatment approach to paediatric endocarditis is similar to that for adult patients with endocarditis because of similarities in disease pathogenesis and aetiology. The therapeutic goal is to achieve sterilisation of the cardiac vegetations. The choice of antibacterial is dependent upon the susceptibility profile of the causative organism. Vancomycin or gentamicin is recommended for enterococcal endocarditis, according to guidelines from the American Heart Association. For staphylococcal endocarditis in patients with no prosthetic valve, oxacillin or nafcillin with or without gentamicin is the treatment of choice. In the case of endocarditis caused by methicillin-resistant S. aureus, vancomycin is commonly used in patients with no prosthetic valve and a combination of vancomycin, gentamicin and rifampicin (rifampin) for patients with prosthetic material. Cefazolin or ceftriaxone is the treatment of choice for penicillin allergic paediatric patients with endocarditis caused by viridans streptococci. While there have been no major changes in endocarditis therapy for the last decade, the current focus is on the recognition of multiple-drug resistant pathogens and the use of newer agents such as quinupristin/dalfopristin in the treatment of resistant bacterial endocarditis. Prophylactic antibacterial therapy is recommended for procedures thought to be associated with the occurrence of bacteraemia involving organisms commonly associated with endocarditis. These include dental extractions and oral, respiratory tract, genitourinary, gastrointestinal or oesophageal procedures. Prophylactic antibacterials recommended by the American Heart Association during genitourinary and gastrointestinal surgical procedures in high risk patients include ampicillin + gentamicin or vancomycin + gentamicin in high risk patients with penicillin allergy. Ampicillin has been recommended for prophylaxis of bacterial endocarditis in children undergoing oral, respiratory tract or oesophageal procedures. In the case of penicillin allergy in these patients, cephalosporins, clindamycin, azithromycin or clarithromycin have been recommended. The general consensus is that antibacterial prophylaxis during dental procedure is unnecessary, and in fact propagates bacterial resistance.

Anti-Bacterial Agents↗

PubMed2001

Predicting antibacterial response from pharmacodynamic and pharmacokinetic profiles.

The aim of antibacterial chemotherapy is to achieve sufficient drug concentrations at the site of infection for an adequate length of time to ensure bacterial eradication and optimize clinical success. Whether the desired outcome is achieved or not depends on a number of pathogen-, drug- and patient-related factors. Neither microbiologic activity nor antibacterial pharmacokinetic data alone can adequately describe the complex interaction between pathogen, host and antibacterial during the disease process. A relatively new discipline - pharmacodynamics - seeks to integrate both microbiologic and pharmacokinetic data. The particular model that best predicts clinical outcome depends on the pattern of microbial killing and the persistence of antibacterial effects after plasma concentrations have fallen below the minimum inhibitory concentration (MIC) for the target pathogen (post-antibiotic effect [PAE]). The beta-lactams, for example, exhibit time-dependent bacterial killing with minimal persistent effects. Time above MIC (T(MIC)) is therefore the parameter that best correlates with clinical efficacy for these agents and that, in turn, necessitates multiple daily dosing to optimize the duration of exposure. The macrolides erythromycinA and clarithromycin exhibit a similar pharmacokinetic/pharmacodynamic relationship to that of the beta-lactams, although for clarithromycin the area under the concentration-time curve (AUC) also correlates with clinical outcome (reflecting the more prolonged PAE of this agent). Azithromycin, ketolides, such as telithromycin (HMR 3647), streptogramins and fluoroquinolones exhibit concentration-dependent killing and have prolonged persistent effects, such that the AUC:MIC or Cmax:MIC ratio correlates most closely with clinical efficacy. For these agents the aim is to maximize drug concentrations to which the target pathogen is exposed and this may require higher doses and hence enable longer dosing intervals to be used. In summary, pharmacodynamic models provide a unique approach to determining likely in vivo activity of individual antibacterial agents and prediction of clinical outcomes.

Animals↗