Impact of organism species on microbial eradication and development of resistance in severe gram-negative pneumonia.

This study evaluated the species differences in microbiological outcomes of Gram-negative bacteria (GNB) causing severe pneumonia from the viewpoint of area under the concentration-time curve/MIC ratio (AUC/MIC). In total, 111 strains of GNb from 74 patients were analyzed. Overall, microbiological eradication was achieved in 88% of the cases with initial AUC/MIC>119. However, relapse often occurred when resistance developed or AUC/miC was <176. Pseudomonas aeruginosa and Enterobacter spp. were commonly involved in failed microbiological eradication and development of resistance. The AUC/MIC required for initial eradication of P. aeruginosa was much higher (478) and antibiotic resistance in P. aeruginosa and Enterobacter spp. occurred less frequently with combination therapy (10.0% vs. 67.7%). These data argue that target magnitudes of AUC/MIC to eradicate GNB differ by species. Since antibiotic resistance developed in some species of GNB despite high AUC/MIC, strategies to minimize development of resistance, including combination therapy, must be considered.

A case series of macrolide treatment failures in community acquired pneumonia.

This was a retrospective, multi-center study of patients admitted to hospital with community-acquired pneumonia, caused by Streptococcus pneumoniae, after failing to respond to >2 days of outpatient macrolide therapy. 122 cases, treated between 2000-2004, were enrolled from 31 North American sites between January 2004 - March 2005. Non-susceptible isolates (predominately low-level resistance: erythromycin MICs of 1-16 mcg/ml) were recovered from 87 patients (71%). Bacteremia was present in 63 patients (52%). The in-hospital mortality rate was 5.7 %; all 7 patients who died were bacteremic, 6 had a non-susceptible isolate. We report here the largest series of macrolide failures published to date. The patients were notable for their high rates of macrolide resistance, bacteremia, and mortality. High-level macrolide resistance remains rare among US patients failing outpatient macrolides. The majority of cases and virtually all of the mortality occurred in patients with low-level resistant strains.

Linezolid in the treatment of osteomyelitis: results of compassionate use experience.

BACKGROUND: This case series examines osteomyelitis patients enrolled into a prospective, open label, noncomparative, non-randomized compassionate use program. Patients received 600 mg bid iv or po linezolid. PATIENTS AND METHODS: 89 patients were enrolled into the compassionate use program with the diagnosis of osteomyelitis and were evaluated for clinical efficacy, safety and tolerability. Informed consent was obtained from the patients or their guardians and guidelines for human experimentation of the US Department of Health and Human Services and/or those of the investigators' institutions were followed in the conduct of this clinical research. RESULTS: 55 cases of osteomyelitis met the inclusion criteria for clinical assessment. The 55 courses included long bone (53%), diabetic foot (18%), sternal wound (14.5%) and vertebral osteomyelitis (15%). Clinical assessment at longterm follow-up occurred at a median of 195 days after the last dose, and the clinical cure rate in 22 evaluable cases was 81.8% and failure rate 18.2%. The most common clinical adverse drug events (ADEs) were gastrointestinal disturbances. Reduction in hemoglobin/hematocrit and in platelet counts were the most common laboratory ADEs. CONCLUSION: Linezolid iv or po was successful in treating patients with osteomyelitis caused by resistant grampositive organisms or those with intolerance or nonresponsiveness to other potentially effective treatments. Larger comparator controlled studies should be performed to confirm these findings.

Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia.

BACKGROUND: Linezolid is a recently approved oxazalidinone with extended activity against Gram-positive bacteria. We evaluated the results of linezolid therapy in neutropenic cancer patients with Gram-positive bacterial infections from a compassionate-use program. PATIENTS AND METHODS: This was a prospective, multicenter, open-label, non-comparative, non-randomized compassionate-use treatment program in patients with serious Gram-positive infections. To qualify for enrollment patients were required to have an infection resistant to available antimicrobial agents, or in whom available agents had failed or to which they were intolerant. Patients with absolute neutrophil counts (ANC) <500 cells/mm(3) or <1000 cells/mm(3) and expected to decrease to <500 cells/mm(3), and who received linezolid 600 mg twice daily were included. Plasma samples for population pharmacokinetic analysis were collected. Clinical and microbiological assessments of outcomes were made at the end of therapy and at short-term follow-up. RESULTS: Of the patients in the compassionate-use trial, 103 were neutropenic. The mean [standard deviation (SD)] age was 50.1 (17.5) years, 47% were female, and 47.6% had a baseline ANC

Pharmacokinetic and pharmacodynamic predictors of antimicrobial efficacy: moxifloxacin and Streptococcus pneumoniae.

Infections caused by Streptococcus pneumoniae place a considerable personal and economic burden on both patients and healthcare systems. As the resistance of S. pneumoniae to older antimicrobial agents such as penicillin, cephalosporins, and macrolides has increased, new antimicrobials with good activity against S. pneumoniae have been developed. The newer fluoroquinolones, including levofloxacin, gatifloxacin and moxifloxacin provide a safe and easy tool in the treatment of S. pneumoniae infections. However, there have been recent reports of levofloxacin-resistant strains of S. pneumoniae. Pharmacokinetics and pharmacodynamics can be used to determine which fluoroquinolone delivers the best coverage against S. pneumoniae, and also the 24-h AUC/MIC ratio (the AUIC) required to impede the emergence of bacterial resistance. Monte Carlo analysis suggests that moxifloxacin, with 4-8-fold greater activity and higher AUIC against S. pneumoniae than levofloxacin or gatifloxacin, provides the best coverage in terms of probability of cure and probability of minimizing emergence of resistance.

Effects of the concomitant administration of tamsulosin (0.8 mg/day) on the pharmacokinetic and safety profile of theophylline (5 mg/kg): a placebo-controlled evaluation.

We performed a single-blind, sequential-design study to investigate the effects of concomitant oral tamsulosin 0.8 mg/day on the pharmacokinetics and safety of intravenous theophylline 5 mg/kg in healthy subjects. Ten healthy volunteers aged 19-39 years received placebo on study days 0, 1, 2 and 10 and tamsulosin on days 3-9. Theophylline was administered intravenously on days 1 and 9. Theophylline and tamsulosin pharmacokinetic data were determined following administration of the drugs on days 1 and 9 and day 9, respectively. No differences were observed in theophylline pharmacokinetic parameters with and without concomitant tamsulosin, and there were no abnormalities in tamsulosin pharmacokinetic data. Some significant changes in vital signs and a number of mild adverse reactions were reported, but the overall safety profile of tamsulosin and theophylline was acceptable. The results of the study suggest that no dose adjustment in tamsulosin is necessary when it is administered concomitantly with theophylline.

Effects of the concomitant administration of tamsulosin (0.8 mg) on the pharmacokinetic and safety profile of intravenous digoxin (Lanoxin) in normal healthy subjects: a placebo-controlled evaluation.

A 20-day, nonrandomized, open-label, placebo-controlled study was performed to investigate whether concomitant administration of tamsulosin (0.8 mg) affects the pharmacokinetic and safety profile of intravenous digoxin (0.5 mg) in healthy subjects. Ten healthy subjects aged 21-39 years received a single oral dose of placebo on study days 1-8 and tamsulosin on days 9-18. Tamsulosin was initiated at 0.4 mg/day and the dose was increased to 0.8 mg/day from day 11. On days 2 and 15, subjects received a single intravenous dose of digoxin (0.5 mg). Safety monitoring was carried out throughout the study. Following digoxin administration, blood was drawn and urine collected over a 96-h period for pharmacokinetic determinations. Plasma tamsulosin concentrations were measured at regular intervals after dosing on day 15. The digoxin pharmacokinetic parameters with and without concomitant tamsulosin were compared. No significant difference was observed, and no irregularity was found in the plasma tamsulosin concentration data. Six subjects experienced adverse events while receiving placebo and seven while on tamsulosin. The most frequent adverse event was mild dizziness reported by four subjects. Moderate chest pain was reported in two subjects, but this was not considered to be related to the administration of the study medications. Some significant changes in vital signs were observed; however, none was accompanied by symptoms of medical concern. These changes were not temporally related to the administration of study drugs. Thus, concurrent administration of digoxin with tamsulosin did not produce any change in the pharmacokinetics of digoxin and the safety profile was acceptable. As reflected in the prescribing information for tamsulosin, no adjustment in tamsulosin dosing is required when it is administered concomitantly with digoxin.

Clinical use of ceftriaxone: a pharmacokinetic-pharmacodynamic perspective on the impact of minimum inhibitory concentration and serum protein binding.

Ceftriaxone is a third-generation cephalosporin that is used for a variety of infections such as meningitis, gonorrhoea and community-acquired pneumonia. The most important aspects of its pharmacokinetics include a long half-life, excellent tissue penetration and saturable (dose-dependent) serum protein binding of the drug. A pharmacodynamic analysis [total area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC)] was performed in several populations (healthy volunteers, children, the elderly, and patients with renal and hepatic impairment) against various bacterial species (Streptococcus pneumoniae, the Enterobacteriacieae, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa). AUC/MIC [area under the inhibitory time curve (AUIC)] was chosen as the pharmacodynamic parameter for this analysis since ceftriaxone is a time-dependent killer and high peak concentrations are not needed. In addition, there is a significant correlation between AUIC, time when concentration exceeds the MIC (t > MIC) and time to eradication. Total and free AUICs (assuming a free fraction = 10%) were calculated since it is highly protein bound. It was postulated that a free AUIC of at least 125 would be required to achieve efficacy. From our analysis of these various populations, we were able to conclude that the free AUIC values support the use of Ig daily in infections where MIC values are below 2 mg/L. In addition, consistent with its reported good activity against CSF organisms with MICs < or =1.0 mg/L and marginal activity against organisms with MICs > or =2.0 mg/L, we also recommend the target free AUIC values of at least 125 for patients with severe infections such as meningitis. Patients with mild infections may recover with values below 125 but they may remain at risk of the development of resistant organisms. Furthermore, it is essential to further validate these findings in patients who have received treatment, calculate AUICs and correlate these parameters with both clinical and microbiological outcomes.

Pharmacokinetics and pharmacodynamics of aztreonam and tobramycin in hospitalized patients.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) optimization of antibiotic therapy has been shown to improve outcomes in several antibiotic classes. Despite the frequent use of beta-lactams, clinical data in humans remain limited. OBJECTIVE: This study evaluated the relationship between serum pharmacokinetics, pharmacodynamics, pathogen susceptibility, and clinical outcomes in patients receiving aztreonam or tobramycin monotherapy. METHODS: The case-report forms of hospitalized patients who received either aztreonam or tobramycin for a bacterial infection in 3 clinical trials conducted between 1982 and 1984 were reviewed for the present study. A pathogen was identified for all included patients, and susceptibility testing was performed to determine the minimum inhibitory concentration (MIC) for each agent. Pharmacokinetic parameters for each antibiotic were determined using population modeling, and variables potentially related to outcomes were evaluated using tree-based modeling, logistic regression, and nonlinear regression methods. RESULTS: Data from 91 patients were analyzed, 68 treated with aztreonam monotherapy and 23 treated with tobramycin monotherapy. Of the types of infections treated, 39 were intra-abdominal, 42 involved the lower respiratory tract, and 10 involved the skin and skin structures. The pharmacodynamic ratio of the 24-hour area under the curve (AUC24) to the MIC was associated with clinical outcome for both antibiotics: aztreonam and to-bramycin patients with ratios meeting or exceeding the respective 24-hour inverse serum inhibitory titer breakpoints of 184 and 110 were significantly more likely to achieve a successful outcome than were those with ratios not meeting these values (P < 0.01). The probabilities of clinical success in patients at or above and below the AUC24/MIC breakpoints were a respective 85% and 53% for aztreonam and 80% and 47% for tobramycin (both, P < 0.01). When all patients were considered, the likelihood of achieving cure was 5.1 times greater in patients exceeding the target ratios (P < 0.01). CONCLUSION: PK/PD optimization of both aztreonam and tobramycin is associated with improved patient outcomes.

Factors associated with postoperative infection.

OBJECTIVE: We have developed and analyzed a large surgical prophylaxis database and now report the factors significantly associated with early infection, readmission due to infection, and death within 28 days of surgery. This study is intended to be a stepping-stone for further studies using our clinical database. DESIGN AND SETTING: A computerized database of 9,016 surgical patients from a 400-bed community hospital was examined. Multivariate logistic regression and tree-based modeling were used to identify factors associated with the outcomes. Factors considered included surgical procedure, prophylactic antibiotic, age, gender, serum creatinine, and albumin. RESULTS: 12.6% had an early infection, 2.5% were readmitted due to infection, and 2.5% died within 28 days. Most combination prophylactic antibiotics were associated with an increased probability of an early infection. Decreased albumin and increased age were associated with an increased probability of an early infection. Tracheostomy and amputations were associated with an increased probability of an early infection, whereas gallbladder and orthopedic procedures involving the arm were associated with a decreased probability. Factors associated with readmission due to infection included dialysis shunt, vascular repair, and an early infection. Factors associated with increased probability of death within 28 days included age, albumin, serum creatinine, and an early infection. Gallbladder procedures and obstetric-gynecologic procedures were associated with a decreased probability of death within 28 days. DISCUSSION: Older patients and those with a decreased albumin were most likely to have an early infection. To the extent that an early infection was a significant risk factor for readmission due to infection, the impact of age and albumin on the probability of readmission due to infection is demonstrated by their effects on early infections. Interestingly, albumin and age were significantly associated with death within 28 days, in addition to early infection, showing the predictive association between these factors and early death.

Antimicrobial management strategies for Gram-positive bacterial resistance in the intensive care unit.

This article summarizes the current situation with Gram-positive infections, including the two primary consequences-failure to cure and resistance-relevant to the intensive care unit. The past few years have seen Enterococcus faecium resistance to vancomycin increase from 10% of strains to approaching 60% of strains in some centers. Failure is now so frequent that vancomycin can no longer be safely used. This has lead to use of two new antibiotics, quinupristin/dalfopristin (Synercid), first marketed in the United States in September 1999, and linezolid (Zyvox), which reached the U.S. market in May 2000. Both of these agents are being used to treat culture-proven vancomycin-resistant E. faecium. The calculated areas under the inhibitory curve (AUIC) values of vancomycin, even when its minimal inhibitory concentration (MIC) is 4.0 microg/mL, show almost all vancomycin-resistant E. faecium have AUICs <125. This explains failure, as well as the further selection of this bacteria into subpopulations with progressively higher MICs. Less well defined, but potentially an even greater problem, is the poor efficacy of vancomycin against multiresistant Staphylococcus aureus. Here, there is evidence of clinical failure in lower respiratory tract infection patients, but in most cases the MIC values of the organism have not risen to the point where AUICs are <125. However, the minimum bactericidal concentration of this organism may be considerably higher than its MIC, and in other cases there may be a high inoculum effect or a protein-binding effect to explain the failure of vancomycin to kill multiresistant S. aureus. Besides the increasing use of the new agents, strategies to manage these two increasingly resistant Gram-positive infections include cephalosporin restriction, switch and streamlining when cultures come back from the lab, combination regimens, and cycling in selected intensive care units.

What have we learned from pharmacokinetic and pharmacodynamic theories?

Pharmacokinetic characteristics and pharmacodynamic properties dictate antimicrobial response and, along with natural immune responses, clinical outcomes. As new agents are developed with long half-lives, we will lose the ability to differentiate between concentration-dependent and time-dependent properties. The area under the inhibitory concentration curve (AUIC) defines drug regimens as a ratio of drug exposure to minimum inhibitory concentration (MIC) and allows them to be compared with each other. With AUIC and agents with long half-lives, these comparisons are possible regardless of chemical classification or concentration or time-dependent activity. Historical examples of reduced drug exposure from decreased doses (i.e., cefaclor, clarithromycin, and ciprofloxacin), and thus low AUIC values, directly correlate with drug resistance. In the face of rising MICs (as is occurring worldwide with Streptococcus pneumoniae), close attention to appropriate dosing and concentration above the MIC may delay and potentially even prevent antibiotic resistance. Creating selective pressure on reliable antibiotics by inappropriately reducing their doses will undoubtedly challenge these agents and may destroy entire drug classes with similar mechanisms of action or resistance.

Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus.

Treatment factors predictive of clinical and microbiological outcomes and the relationship between a pneumonia scoring system and clinical outcomes in vancomycin-treated patients with a Staphylococcus aureus-associated lower-respiratory-tract infection (LRTI) were studied. A computer database review identified patients for whom S. aureus was isolated from a respiratory-tract specimen between January 1 and December 31, 1998, and who had antimicrobials ordered within 72 hours of isolation of that organism. Through further review of individual patient charts, this group was restricted to those treated with vancomycin for a documented S. aureus-associated LRTI. Classification-and-regression-tree (CART) modeling was performed to determine which clinical variables were correlated with clinical outcomes and microbiological outcomes. Median changes in clinical pneumonia scores from baseline in two patient groups (those with clinical success and those with clinical failure) were compared. Seventy patients met the study criteria. CART modeling found that both outcomes were associated with area under the inhibitory curve (AUIC). The pneumonia scoring system was predictive of eventual clinical success as early as day 3 of treatment; having at least a 4-point decrease in the pneumonia score by day 3 was correlated with an 87% clinical success rate. Both AUIC and a pneumonia scoring system were useful for predicting clinical and microbiological outcomes of vancomycin therapy in patients with LRTIs caused by S. aureus.

Pharmacokinetic/pharmacodynamic predictors of time to clinical resolution in patients with acute bacterial exacerbations of chronic bronchitis treated with a fluoroquinolone.

Forty nine subjects with acute bacterial exacerbations of chronic bronchitis (ABECB) treated with grepafloxacin were evaluated for parameters predictive of clinical outcome. Signs and symptoms associated with ABECB were serially collected and evaluated for changes. Coughs per day, sputum volume and the percentage of sputum neutrophils were associated with clinical outcome. A by groups analysis, based on clinical success was performed using Cox regression analysis to determine factors associated with time to clinical success and time to reduction in sputum volume, coughs per day and sputum neutrophil percent. Factors evaluated included AUIC (AUC/MIC), isolate species, years and type of underlying lung disease, alcohol use, smoking history and number of ABECB within the previous 12 months. AUIC<276 (mg h/l)/mg/l (P<0.03) and or the presence of mild bronchiectasis (P<0.01) were associated with longer time to clinical success. In addition a relationship was found between AUIC>212 (mg h/l)/mg/l (P<0.01) and AUIC>576 (mg h/l)/mg/l (P<0.02) and decreasing days to sputum volume reduction and coughs per day, respectively. A diagnosis of mild bronchiectasis prolonged the time to reduce coughs per day (P<0.03) and neutrophil percentage (P<0.01). Patients with mild bronchiectasis were found to have an increase in the time to clinical success, coughs per day improvement and sputum neutrophil percent improvement. AUIC is an important PK/PD parameter predictive of successful outcome in ABECB, even in subjects with mild bronchiectasis. Grepafloxicin has been withdrawn from sale since these studies were carried out. This work is published to illustrate the relationship between pharmacodynamics and clinical efficacy and the use of AUIC as a valuable predictive parameter for fluoroquinolones.

Containment of heart failure hospitalizations and cost by angiotensin-converting enzyme inhibitor dosage optimization.

Using our model relating angiotensin-converting enzyme (ACE) inhibitor dosing and outcomes in heart failure (HF), we designed a prospective intervention trial for patients with systolic dysfunction. A clinical pharmacist initiated or titrated ACE inhibitor therapy or adjusted other medications within an HF management program based on Agency for Healthcare Policy and Research guidelines. Entry into the protocol required the approval of the attending physician. All patients received dietary, nursing, rehabilitation, social service, and clinical pharmacy consultations. Treatment conformed to Agency for Healthcare Policy and Research guidelines in 25% of patients (group A). Suboptimal therapy (75% of patients) was usually due to failure to administer an ACE inhibitor (48%) or inadequate dosing of an ACE inhibitor (46%). In 62% of suboptimal cases, the attending physician agreed to follow the clinical pharmacist's recommendations (group B). Patients of physicians who declined pharmacist intervention served as a negative control (group C). On admission, mean enalapril-equivalent daily doses in groups A, B, and C were 30, 4, and 6 mg, respectively, and at discharge, 36, 18, and 6 mg, respectively. At 180 days, rehospitalization frequency and total charges were lower in groups A (31% and $5,600) and B (35% and $3,800) than in group C (63% [p <0.004] and $9,800 [p <0.04]). Thus, optimization of ACE inhibitor doses by a clinical pharmacist can greatly improve rehospitalization rates and significantly lower cost of care in an HF management program.

Clinical pharmacology of the fluoroquinolones: studies in human dynamic/kinetic models.

Traditional antibiotic dosage adjustments, compensate only for disease-induced changes in the serum concentration profile. Dosage adjustments tend to be effective when a well-defined range of concentration is associated with efficacy. However, the bacterial target of antibiotic action-minimum inhibitory concentration (MIC) is variable, because even susceptible bacteria may differ greatly in their antibiotic susceptibility. Newly developed computerized methods for the quantitation of susceptibility allow for testing of integrated kinetic-susceptibility models in patients. Our attention has focused on fluoroquinolones, since they are relatively nontoxic and provide the necessary dosage range needed to elucidate correlations between concentration and response. Studies of patients with nosocomial gram-negative pneumonia reveal that the best correlation parameters of favorable outcome are approximately 80% of time over MIC and 24-h area under the time-concentration curve (AUC)-to-MIC values >125.

Sparfloxacin: a review.

BACKGROUND: The continuing increase in the rate of penicillin and cephalosporin resistance among respiratory pathogens and of cross-resistance to macrolide antibiotics has led to the recommendation that fluoroquinolone antibiotics be used to treat high-risk patients with community-acquired pneumonia (CAP) and acute bacterial exacerbations of chronic bronchitis (ABECB). OBJECTIVE: This review focuses on sparfloxacin, an oral fluoroquinolone, discussing its mechanism of action, activity, pharmacokinetic characteristics, safety, and efficacy in CAP and ABECB. METHODS: Studies were identified by a MEDLINE search of the literature from 1990 to 1999, supplemented by educational materials from conferences and symposia. RESULTS: Sparfloxacin is active against the major respiratory pathogens and against the atypical pathogens in pneumonia that are being reported with increasing frequency. Its long half-life permits once-daily dosing. In large trials in CAP and ABECB in which all isolates were susceptible to both comparators, sparfloxacin was found to have similar efficacy to erythromycin, cefaclor, amoxicillin, ofloxacin, and clarithromycin. Its safety profile is similar to that of the macrolides and other quinolone antimicrobial agents. Photosensitivity, nausea, and diarrhea are the most common adverse events reported in clinical trials of sparfloxacin. Its use is contraindicated in patients with QTc-interval prolongation. CONCLUSION: The increasing prevalence of beta-lactam- and macrolide-resistant bacteria in respiratory infections emphasizes the need for newer agents such as the fluoroquinolones. The choice between agents should be based on activity against the relevant respiratory pathogens in high-risk patients.

Comparison of the fluoroquinolones based on pharmacokinetic and pharmacodynamic parameters.

Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory concentrations (MICs) alone is insufficient to predict in vivo potency. Achievable serum and tissue concentrations as well as pharmacokinetic characteristics must be considered. When pharmacokinetic and pharmacodynamic values are combined, the area under the inhibitory curve (AUIC) and peak concentration:MIC ratio predict clinical cure for fluoroquinolones. Clinical data and animal models indicate that a peak:MIC of 10:1 and above and an AUIC of 125 and above are predictive of a clinical cure for this class of antimicrobials against gram-negative organisms. The values may be used to compare and contrast fluoroquinolones to determine which would be best for treating a specific microorganism. Pharmacodynamic data also can be used to design regimens that minimize the risk of suboptimal drug levels. Ensuring the optimal fluoroquinolone dosage based on pharmacodynamic principles would diminish the emergence of resistant organisms and prevent treatment failures.

Comparison of the abilities of grepafloxacin and clarithromycin to eradicate potential bacterial pathogens from the sputa of patients with chronic bronchitis: influence of pharmacokinetic and pharmacodynamic variables.

A randomized open-label study was conducted to compare the pharmacokinetics and pharmacodynamics of grepafloxacin with those of clarithromycin in patients with chronic bronchitis whose sputa were colonized with potential bacterial pathogens. Patients received oral grepafloxacin 400 mg od for 10 days (n = 15) or oral clarithromycin 500 mg bd for 10 days (n = 10). Sputum samples were collected before the first dose, 1, 4 and 8 h after a dose on day 1 and then before a dose on days 2, 3, 5, 7 and 10 to determine the time to eradication (T(erad)) of the potential bacterial pathogens. Blood samples for measurement of grepafloxacin or clarithromycin and 14-hydroxyclarithromycin concentrations were obtained before a dose and 1, 2, 4, 8 and 12 h after doses on days 1 and 5. The area under the inhibitory serum concentration-time curve over 24 h (AUIC(24)), peak serum concentration:MIC ratio (C(max):MIC) and the percentage of the dosing interval during which the serum concentration exceeded the MIC (%tau >MIC) were calculated and serum inhibitory titres (SITs) were determined. Haemophilus spp. were the predominant potential bacterial pathogens and were recovered from the sputa of 24 patients. Strains of Streptococcus pneumoniae were isolated from two patients in the grepafloxacin group and a strain of Moraxella catarrhalis was isolated from one patient in the clarithromycin group. Haemophilus spp. isolates were eradicated from the sputa of 13 of 14 (93%) patients given grepafloxacin, but from only two of 10 (20%) patients given clarithromycin (P < 0.05). In the other eight (80%) patients who received clarithromycin, the sputum cultures remained positive throughout the 10 day course. Grepafloxacin eliminated potential bacterial pathogens more quickly than clarithromycin (median T(erad) 4 h versus 76 h). The S. pneumoniae strains were eradicated by grepafloxacin within 4 h and the single M. catarrhalis strain was eradicated by clarithromycin within 1 h. The greater efficacy of grepafloxacin, compared with that of clarithromycin, in terms of the incidence and speed of eradication of the Haemophilus spp. isolates, was associated with higher median values of AUIC(24) (169 SIT(-1)*h versus 8.1 SIT(-1)*h), C(max):MIC ratio (23.6 versus 0.7) and %tau >MIC (100% versus 0%). A Hill-type model adequately described the relationship between the percentage probability of eradicating potential bacterial pathogens from sputa and the plasma grepafloxacin concentration.

Pharmacodynamic modeling of risk factors for ciprofloxacin resistance in Pseudomonas aeruginosa.

OBJECTIVE: To determine risk factors for ciprofloxacin resistance in Pseudomonas aeruginosa. METHODS: Patients with cultures (any site) positive for P aeruginosa, susceptible to ciprofloxacin, between January 1993 and December 1996 were identified using a computerized database. Factors predictive of emergence of ciprofloxacin resistance in P aeruginosa strains isolated from the same cultured site, within 21 days of the initial culture, were determined. Factors considered included length of stay prior to initial P aeruginosa culture, isolation site, initial minimum inhibitory concentration (MIC), antibiotic area under the 24-hour concentration curve (AUC24), total area under the 24-hour inhibitory concentration curve ([AUIC24] AUC24/MIC summed for all active drugs), antibiotic(s) used as dichotomous variables (yes/no), and use of monotherapy or combination therapy. RESULTS: Of 635 patients, 43 (7%) subsequently had ciprofloxacin-resistant P aeruginosa isolated. Four significantly differing patient groups were identified: group 1, P aeruginosa isolates from all sites other than the respiratory tract, treated with any drugs; group 2, respiratory tract isolates treated with drugs other than ciprofloxacin; group 3, respiratory tract isolates treated with ciprofloxacin at AUIC24 >110 (microg x h/mL)/microg/mL; and group 4, respiratory tract isolates treated with ciprofloxacin at AUIC24 < or =110 (microg x h/mL)/microg/mL. The observed percentage resistant was a continuous function of prior length of stay in all four groups. Respiratory tract isolates had higher rates of ciprofloxacin resistance (12%) than isolates from other infection sites (4%). Respiratory tract isolates exposed to ciprofloxacin at AUIC24 < or =110 (microg x h/mL)/microg/mL had the highest resistance (17%). At AUIC24 >110 (microg x h/mL)/microg/mL, resistance was decreased to 11%, a rate similar to that seen in respiratory isolates not exposed to ciprofloxacin (7%). CONCLUSIONS: Application of pharmacokinetic and pharmacodynamic principles to dosing of ciprofloxacin may reduce the risk of ciprofloxacin resistance to the level seen in isolates exposed to other agents.