Application of antimicrobial stewardship to optimise management of community acquired pneumonia.

The aim of this study was to review the application of antimicrobial stewardship principles to the management of community-acquired pneumonia (CAP). Data from 14 published clinical studies, meta-analyses and practice guidelines regarding the application of antimicrobial stewardship strategies to the management of CAP were identified and analysed. In the context of CAP, application of stewardship strategies (alone or in combination) has been shown to increase physician awareness of guidelines, improve appropriate antimicrobial use and reduce unnecessary antimicrobial prescribing. In addition, application has had a profound favourable impact on patient outcomes, including decreased 30-day mortality and in-hospital mortality rates, reduced length of hospital stay, reduced treatment failure rates and reduced healthcare costs. Antimicrobial stewardship programmes have been demonstrated to successfully increase the level of appropriate antibiotic prescribing, reduce pathogen resistance and improve clinical outcomes in the management of CAP within hospitals. Studies have also shown that adherence to evidence-based guidelines, even at the level of the individual clinician, can have a profound and positive impact on patient outcomes and healthcare costs. Adherence to evidence-based guidelines can have a profound and positive impact on patient outcomes and healthcare costs.

The association between antibiotic use and resistance: the role of secondary antibiotics.

Using susceptibility rates of Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae over time as markers, we assessed the significance of the change of susceptibility rates to imipenem, ceftriaxone, cefepime, piperacillin/tazobactam, and ciprofloxacin over time and the relationship to antibiotic use for the period 2000-2006. Antibiotic use-susceptibility relationships were assessed using longitudinal regression analysis. The variables "time" and define daily doses (DDD)/1,000 patient days for the specific drug related to the susceptibility rates of that particular model's dependent variable were considered as the main effects, with significance determined at the 0.05 level. Decreases in susceptibility of the target organisms were common over the period of observation. Decreasing susceptibility trends over time were not statistically associated with the primary drug (e.g., organism susceptibility rate to imipenem with imipenem usage). However, secondary drug use was associated with susceptibility rates (e.g., susceptibility of E. cloacae to cefepime with piperacillin/tazobactam usage). These results suggest that antibiotic use-resistance relationships are influenced by the use of secondary antibiotics. Thus, a resistance problem may not be adequately addressed by simply altering the utilization of the primary antibiotic.

Effect of probenecid on the formation and elimination of acyl glucuronides: studies with zomepirac.

When 100 mg oral zomepirac was taken with 500 mg b.i.d. oral probenecid by six healthy subjects, the disposition of zomepirac was markedly altered. Probenecid decreased total plasma clearance of zomepirac by 64%, which resulted in an increase in bioavailability from 0.55 without probenecid to 0.84 when given concurrently. The apparent metabolic clearance of zomepirac to form zomepirac acyl glucuronide was reduced 71% and zomepirac renal clearance, a minor elimination route, was reduced by 79%. When assayed by a method that prevents degradation of the labile acyl glucuronide, zomepirac glucuronide concentrations in plasma were comparable to those of zomepirac. Probenecid decreased the renal clearance of zomepirac glucuronide by 72%, which, together with the increased zomepirac levels, resulted in a 2.8-fold increase in the AUC of the conjugate. Urinary excretion of zomepirac glucuronide was reduced from 72% to 58% of the dose, but the excretion of free zomepirac was unchanged at 5% of the dose. The ratio of the total clearance/bioavailability of zomepirac in control subjects was 682 +/- 246 ml/min, which is double the value reported in previous studies of zomepirac disposition. We believe that this difference is due to degradation of the unstable zomepirac acyl glucuronide in the previous analytic methodologies used. Qualitatively, the effects of probenecid on zomepirac disposition are similar to those previously reported for other drugs of this class that are metabolized to acyl glucuronides. However, zomepirac appears unusual in that significant levels of its acyl glucuronide metabolite are found in vivo.

Use of ciprofloxacin in cystic fibrosis patients.

In order to evaluate the clinical efficacy and safety of oral ciprofloxacin in the treatment of acute pulmonary exacerbations of cystic fibrosis and trace the possible development of resistance over time, three trials were conducted. In an open-label, uncontrolled trial, 25 courses of ciprofloxacin were administered to 16 patients. Efficacy and safety were assessed based on changes in short-term clinical scores, white blood cell counts, Pseudomonas aeruginosa counts in sputum, pulmonary function tests, and standard serum chemistries and urinalysis that were performed before therapy, weekly during therapy, at the end of therapy, and at a seven-day follow-up visit after therapy. In an open-label, randomized, controlled study, the efficacy and tolerance of oral ciprofloxacin were compared with those of intravenous tobramycin and azlocillin. In another study, the rate of susceptibility of P. aeruginosa isolated from cystic fibrosis patients during more than two years of clinical use was determined. In the uncontrolled trial, ciprofloxacin therapy was associated with clinical improvement in most cases with changes in short-term clinical score and forced expiratory volume in one second being statistically significant (p less than 0.05). Twenty-five patients were entered in the controlled trial with 12 patients in each treatment group being evaluable. The groups were comparable based on admitting demographic and disease characteristics, and no differences in therapeutic response or side effects were noted between the two treatments (p greater than 0.5). Bacterial susceptibility to ciprofloxacin has remained relatively stable over time. Based on these results as well as those from similar evaluations, ciprofloxacin appears to be efficacious in the treatment of acute pulmonary exacerbations in adults with cystic fibrosis, producing responses similar to those observed with standard intravenous antibiotic therapy.

Ciprofloxacin versus tobramycin plus azlocillin in pulmonary exacerbations in adult patients with cystic fibrosis.

Twenty adult patients with cystic fibrosis who were experiencing acute pulmonary exacerbations were enrolled in a randomized, controlled trial comparing oral ciprofloxacin with intravenous tobramycin plus azlocillin. Efficacy of the two treatments was compared based upon changes in clinical status, pulmonary function tests, white blood cell counts, and quantitative bacteriology of sputum. No statistically significant differences were detected in these parameters of response between the two treatment groups (p greater than 0.05). Ciprofloxacin appears to be therapeutically equivalent to intravenous antibiotics in the treatment of adult patients with cystic fibrosis who are experiencing pulmonary exacerbations associated with susceptible bacteria.

Optimisation of antibiotic therapy in cystic fibrosis patients. Pharmacokinetic considerations.

Antibiotic therapy plays a central role in the medical management of patients with cystic fibrosis. While totally convincing efficacy data are lacking, antibiotics probably have a pronounced beneficial effect on both morbidity and mortality. Much has been learned in the past 20 years about antibiotic use in this population. At the same time, new antimicrobial agents with the potential to treat this condition have become available for use. The pharmacokinetics of a number of antibiotic classes, including beta-lactams, aminoglycosides and quinolones, are altered in this patient population. Increased total body clearance is a common occurrence but is not always changed enough to warrant altered dosages. Nonetheless, in light of altered pharmacokinetics in the cystic fibrosis population, appropriate dosage and monitoring parameters for a number of antibiotics have been determined.

Treatment options for the pharmacological therapy of neonatal meningitis.

Neonatal bacterial meningitis has a relatively low incidence in developed countries, but continues to cause morbidity and mortality despite advances in antimicrobial therapy. Bacterial pathogens commonly associated with neonatal meningitis include Group B streptococci, Escherichia coli K1 and other coliforms, Listeria monocytogenes and staphylococci. As it can be difficult to differentiate meningitis from septicaemia in neonates, empirical antibiotic therapy should be effective for both. Selection of an empirical antibiotic regimen should be based on: (a) bacterial prevalence and susceptibility; (b) drug characteristics; (c) postnatal age at the onset of disease; and (d) patient-specific factors. A penicillin in combination with an aminoglycoside or cefotaxime is commonly used in empirical therapies. The increased risk of staphylococcal infection in older neonates requires consideration of an antistaphylococcal antibiotic in the empirical therapy regimen. Once a causative organism has been identified, antimicrobial therapy should be directed towards that pathogen. Duration of therapy remains empirical, but should be at least 7 days for documented bacterial meningitis. Viral meningitis continues to have a high mortality despite the availability of antiviral agents. Adjunctive therapies may further reduce the morbidity and mortality of meningitis. While most of these therapeutic options have not been investigated in neonates, they may prove to be of benefit in the future. Anti-inflammatory agents, such as glucocorticoids, nonsteroidal anti-inflammatory agents and immunoglobulin, may modulate the inflammatory response of a meningeal infection. Other possible therapies in neonatal meningitis include cerebral blood flow modulators and disease prevention with maternal vaccines and perinatal antibiotics. Practical aspects of drug therapy such as route of administration and serum drug concentration monitoring can improve both drug therapy and patient outcome. While antibiotics have greatly improved the treatment outcome of neonatal meningitis, it is clear that additional intervention will be required to increase cure rates and reduce sequelae.

Controlled trial of aztreonam vs. tobramycin and azlocillin for acute pulmonary exacerbations of cystic fibrosis.

The efficacy of aztreonam was compared to that of standard therapy consisting of tobramycin and azlocillin in the treatment of acute pulmonary exacerbations of cystic fibrosis in a randomized, open trial. Fifteen patients were randomized to each treatment. Responses were assessed based on changes in pulmonary and clinical scores, white blood cell counts, pulmonary function tests and quantitative bacteriology of sputum which were performed before, every 5 to 7 days during and on the last day of therapy. Patients in both groups responded to therapy and there were no statistically significant differences in changes in the above indicators of response with therapy between the two groups (P greater than 0.05). The incidence of detection of Pseudomonas aeruginosa isolates resistant to all three study antibiotics increased with therapy. Side effects were limited to transient elevations of liver enzymes (both groups) and rash and fever in one patient treated with azlocillin. Aztreonam represents effective therapy for pulmonary exacerbations of cystic fibrosis associated with susceptible pathogens.

The use of aztreonam in the cystic fibrosis patient.

Eradication of pulmonary infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients has long presented a significant challenge to the medical community. Many antimicrobial agents have proved incompletely effective against this persistent pathogen, and even the aminoglycosides, which represent the traditional therapy for such infections, have been associated with considerable toxicity and resistance. The monobactam antibacterial agent aztreonam is used both as single-agent therapy and in combination with other drugs. Several controlled, clinical trials have demonstrated the efficacy of aztreonam in the treatment of CF patients with pulmonary exacerbations caused by P. aeruginosa. The only side effect of aztreonam therapy commonly encountered in these studies was elevation of hepatic transaminase concentrations; this effect was of uncertain significance. It was concluded that aztreonam may offer clinical efficacy comparable to that provided by the combination of tobramycin plus azlocillin. Further, there does not seem to be any appreciable difference in the development of resistance to aztreonam compared with traditional therapies.

Efficacy of aztreonam in pulmonary exacerbations of cystic fibrosis.

A noncomparative pilot study was conducted to assess the potential usefulness of aztreonam in pulmonary exacerbations of cystic fibrosis. Of 27 patients initially enrolled 25 received sufficient courses of aztreonam therapy to be evaluable. All patients received 200 mg/kg/day of aztreonam in 4 equally divided doses administered intravenously. Of 57 isolates of Pseudomonas aeruginosa from pretherapy sputum cultures, 48 were susceptible to aztreonam in vitro as were 11 of 18 strains isolated at the conclusion of therapy. With treatment colony counts of P. aeruginosa in sputum were reduced by 3 log10 or more in 15 patients. It was totally (but temporarily) eradicated in 11 of these patients. Clinical scores and white blood cell counts improved significantly (P less than 0.05). Side effects of aztreonam were limited to transient elevations of liver enzymes occurring in 16 patients. Aztreonam merits further evaluation in a randomized, comparative trial with standard antibiotic therapy for cystic fibrosis.

Absence of rapidly developing resistance during treatment of cystic fibrosis patients with aztreonam.

The in vitro activity of aztreonam and 10 other antibiotics was determined for clinical isolates of Pseudomonas aeruginosa from 18 cystic fibrosis patients obtained before, at the end of, and 7-14 days after the completion of therapy with aztreonam. The percent of isolates susceptible to aztreonam at each sampling period were 79%, 78%, and 81% respectively.

Evaluation of antibiotic synergy against Acinetobacter baumannii: a comparison with Etest, time-kill, and checkerboard methods.

Acinetobacter baumannii is becoming increasingly resistant to antibiotics, often requiring combination therapy. Numerous methods exist to detect the presence of in vitro synergy with the time-kill and checkerboard tests being widely used. The Epsilometer test (E test) is a new method that is less labor intensive, but has not been evaluated using a wide range of antimicrobials and organisms. We assessed synergy using the time-kill and checkerboard tests and compared the results to the E test method using 10 clinical isolates of A. baumannii. Antimicrobial combinations evaluated consisted of trovafloxacin or tobramycin in combination with cefepime or piperacillin. Synergy was detected with all combinations by either the checkerboard or time-kill method. Synergy was not detected by the Etest method. The agreement between the time-kill test and Etest method was 72% (range 42-97%); for the time-kill and checkerboard tests, agreement was 51% (range 30-67%). The Etest method appears promising although further testing should be performed with additional antimicrobial agents and organisms.

Comparative in vitro pharmacodynamics of imipenem and meropenem against ATCC strains of Escherichia coli, Staphylococcus aureus and Bacteroides fragilis.

We evaluated the pharmacodynamics of imipenem and meropenem, utilizing time-kill studies over a concentration/MIC (C/MIC) range of 0.0625-1024 for E. coli ATCC 35218 (EC) and S. aureus ATCC 29213 (SA) and from 0.125-512 for B. fragilis ATCC 25285 (BF). Area under the time-kill curves were converted to percent response (%R). AUCs were calculated from drug concentrations corrected for degradation and %R vs. C/MIC and AUC/MIC were fit to a sigmoidal Emax model. Emax was similar for both agents for all organisms. Meropenem was 4x more potent than imipenem against EC based on the MIC and required 7 and 13.5-fold lower AUCs to achieve E50 and E90, (50% and 90% of the maximal response, respectively) respectively, whereas imipenem was 8x more potent than meropenem against SA based on the MIC and required 8 and 13-fold lower AUCs to achieve E50 and E90, respectively. The C/MIC and AUC/MIC to achieve E50 and E90 with imipenem were 2- and fourfold higher, respectively than meropenem against EC. There was less than a twofold difference in C/MICs and AUC/MIC between imipenem and meropenem for both E50 and E90 against SA. Against BF, concentrations and AUCs at E50 were similar for both agents; however, imipenem required 4 to 6-fold higher concentrations and AUC to achieve E90. Although there are differences in the potency of these agents as assessed by the MIC or AUC vs. response, when normalized by the MIC and corrected for drug degradation, these agents displayed similar pharmacodynamic parameter-response relationships.

Tolerance and percutaneous absorption of topically applied arildone.

Arildone, an investigational antiviral agent, was compared to both its vanishing cream and 90% dimethyl sulfoxide (DMSO) solution vehicles to determine cutaneous and systemic tolerance as well as percutaneous absorption. In separate studies, immunosuppressed patients randomly received either arildone in vanishing cream (study 1), arildone in DMSO solution (study 2), or the vehicles without arildone. Test formulations were applied to the same area of one forearm four times daily for seven days. Blood, urine, and fecal samples were collected on days 1, 4, and 7, and patients were observed daily. Arildone was sporadically detected in biologic specimens suggesting limited percutaneous absorption. Unexpectedly, DMSO did not appear to enhance absorption of the drug. No clinical or laboratory evidence of systemic intolerance was observed for any preparation. While cutaneous tolerance was excellent for the vanishing cream preparations, the DMSO preparations were associated with a high (90%) incidence of erythematous reactions.

The comparative in vitro activity of ofloxacin and selected ophthalmic antimicrobial agents against ocular bacterial isolates.

The in vitro activity of ofloxacin, a new fluoroquinolone anti-infective agent, was evaluated against 419 ocular bacterial isolates of 55 species to determine its potential as a topical agent for the treatment of ocular infections. Other agents tested in this study, in which a modified tube-dilution procedure was used, include norfloxacin, gentamicin, tobramycin, chloramphenicol, and polymyxin B. Ofloxacin demonstrated good to excellent activity against a variety of gram-positive and gram-negative pathogens. The minimum inhibitory concentration against 90% of all bacterial strains tested (MIC90) of ofloxacin was 0.5 microgram/ml for Staphylococcus aureus and S. epidermidis, 2 micrograms/ml for Streptococcus pneumoniae, and 4 micrograms/ml for Pseudomonas aeruginosa. These species were more susceptible to ofloxacin than to any of the nonquinolones tested. The MIC90 of ofloxacin was lower than that of norfloxacin, another quinolone, against S. aureus, S. epidermidis, and St. pneumoniae and equal to that of norfloxacin against P. aeruginosa. Because of its broad spectrum of activity and excellent in vitro activity, we concluded that ofloxacin has the potential for development into a superior topical treatment for ocular infection.

The use of aztreonam in pediatric patients: a review.

Aztreonam is the first monobactam available for use in this country. A parenteral antibiotic, its antibacterial spectrum is limited to gram-negative aerobic pathogens. The drug's pharmacologic, pharmacokinetic, and toxicologic properties are reviewed. Based on early experience in pediatric patients, certain recommendations can be made for the use of aztreonam.

CYP2D6, N-acetylation, and xanthine oxidase activity in cystic fibrosis.

STUDY OBJECTIVE: To determine the activity of CYP2D6, N-acetylation, and xanthine oxidase, three drug-metabolizing enzyme systems, in patients with cystic fibrosis and compare the findings with those in individuals without the disease. DESIGN: Prospective cohort study. SETTING: General pediatrics service. PATIENTS: Fifty-nine patients with cystic fibrosis and 480 healthy Caucasian volunteers. INTERVENTIONS: Enzyme activity was determined based on urinary molar metabolite ratios of caffeine and dextromethorphan probes. MEASUREMENTS AND MAIN RESULTS: The percentage of poor metabolizers of CYP2D6 in patients with cystic fibrosis was not different from that in the control group (p = 0.45). N-Acetylation activity was significantly lower in the patients (p = 0.007), but no statistically significant difference was found in xanthine oxidase activity (p = 0.12). CONCLUSION: The activity of these drug-metabolic pathways does not appear to be increased in cystic fibrosis. Whether the activity of other pathways is increased, thus providing a partial explanation for the generally increased drug clearance in this disease, remains to be determined.

A pilot study of the efficacy of constant-infusion ceftazidime in the treatment of endobronchial infections in adults with cystic fibrosis.

STUDY OBJECTIVE: To compare the efficacy of constant-infusion ceftazidime (CTZ) with that of traditional intermittent dosing in a pilot trial. DESIGN: Prospective, crossover trial. SUBJECTS: Five adults with cystic fibrosis requiring intravenous antibiotic therapy for pulmonary exacerbations of the disease. INTERVENTIONS: Patients were initially treated with standard CTZ 2 g 3 times/day for 10 days. At the next hospitalization patients were crossed over and CTZ was administered as a constant infusion at a rate determined to achieve a serum concentration 6.6 times the minimum inhibitory concentration (MIC) of the least susceptible Pseudomonas aeruginosa isolate. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of CTZ were determined, as were MICs for all P. aeruginosa isolates. Outcome parameters of interest were changes with therapy in white blood cell count, P aeruginosa density in sputum, and pulmonary function test results. Differences in these parameters for the two forms of administration were not significant. With the exception of one patient who received 6 g/day with both regimens, the average reduction in dosage with the constant infusion was 50%. CONCLUSION: These preliminary data suggest that constant-infusion CTZ may be as safe and efficacious as intermittent dosing.

Compatibility of filgrastim with selected antimicrobial drugs during simulated Y-site administration.

The compatibility of filgrastim with imipenem-cilastatin, ceftazidime, fluconazole, gentamicin, tobramycin, and amikacin was studied. Filgrastim 40 micrograms/mL or filgrastim 10 micrograms/mL (with human albumin) was combined with (1) imipenem-cilastatin 5 mg/mL (in terms of imipenem content), (2) ceftazidime 10 mg/mL (as the sodium salt), (3) fluconazole 2 mg/ mL, (4) gentamicin 1.6 mg/ mL (as the sulfate), (5) tobramycin 1.6 mg/mL (as the sulfate), or (6) amikacin 5 mg/ mL (as the sulfate). Equal volumes (5 mL) of the test-agent solutions were added in pairs to glass containers (simulating Y-site administration) in triplicate. Samples were analyzed for filgrastim activity, drug concentration, pH, and visible physical changes during storage at approximately 25 degrees C for up to four hours. Filgrastim activity was measured by the in vitro bioassay, and antimicrobial drug concentrations were measured by stability-indicating high-performance liquid chromatography or fluorescence polarization immunoassay. Filgrastim retained its activity, except for the combination of filgrastim at the lower concentration with gentamicin or at the higher concentration with imipenem-cilastatin. Antimicrobial drug concentrations did not change significantly during the study. No precipitation, color change, or haze was noted in any mixture. Changes in pH were negligible except for an increase in the mixture of filgrastim at either concentration with ceftazidime. In most cases, filgrastim retained its activity in the presence of a variety of antimicrobial drugs for up to four hours; in all cases, the antimicrobial drugs remained stable.

Stability of ceftazidime sodium and teicoplanin sodium in a peritoneal dialysis solution.

The stability of ceftazidime sodium and teicoplanin sodium separately and in combination in a peritoneal dialysis (PD) solution was studied. PD solutions containing ceftazidime 100 micrograms/mL (as the sodium salt), teicoplanin 25 micrograms/mL (as the sodium salt), or ceftazidime 100 micrograms/mL plus teicoplanin 24 micrograms/mL were prepared in triplicate for each of two conditions: condition A, storage at 25 degrees C (room temperature) for 24 hours, then at 37 degrees C for eight hours; and condition B, storage for seven days at 4 degrees C, followed by 16 hours at 25 degrees C and 8 hours at 37 degrees C. The dialysis solution used was Dianeal PD-2 with 1.5% dextrose. Samples were removed at intervals and analyzed by stability-indicating high-performance liquid chromatography. Under condition A, ceftazidime sodium alone was stable for 24 hours at 25 degrees C but only 2 hours when then heated to 37 degrees C. Under condition B, ceftazidime sodium alone was stable throughout the observation period. Teicoplanin sodium alone was stable throughout the observation periods under both conditions. In combination, the drugs were stable if initially refrigerated and then brought to room temperature one week later, but were unstable when initially stored at 25 degrees C. No visual changes were noted, and pH did not vary substantially. Ceftazidime 100 micrograms/mL (as the sodium salt) and teicoplanin 25 micrograms/mL (as the sodium salt) combined in a PD solution were unstable when first kept at 25 degrees C before storage at 37 degrees C. The drugs in the combination remained stable when the solution was kept at 4 degrees C before storage at 37 degrees C.