Multicentre assessment of linezolid antimicrobial activity and spectrum in Europe: report from the Zyvox antimicrobial potency study (ZAPS-Europe).

OBJECTIVE: To evaluate the in vitro spectrum and activity of linezolid, a recent oxazolidinone, according to well-controlled surveillance data from 42 medical centers in 13 countries throughout Europe. METHODS: Participants tested the susceptibility of 125 clinical strains of enterococcal and staphylococcal species against 13 drugs using reference broth microdilution trays or the standardized disk diffusion method of the National Committee for Clinical Laboratory Standards (NCCLS). Streptococcal species (n = 25 at each center) were tested against six drugs using E test (AB BIODISK, Solna, Sweden). Quality assurance testing was conducted using NCCLS-recommended strains and verification of resistance to linezolid and other selected agents was performed by retesting strains at the regional (Europe) and international (USA) monitor sites. RESULTS: A total of 5598 strains from throughout Europe (91% compliance) were tested. Vancomycin resistance was reported in only 0.6 and 3.0% of Enterococcus faecalis and E. faecium, respectively. Penicillin resistance occurred in 25.1% of Streptococcus pneumoniae; 4.9% at the high-level (> or =2 mg/L). The MIC90 for linezolid was 1 mg/L for streptococci and 2 mg/L for enterococci and staphylococci. Using the US FDA- and EUCAST-recommended susceptible breakpoints for linezolid, there were no confirmed reports of linezolid resistance [minimum inhibitory concentration (MIC), > or =8 mg/L]. The distribution of linezolid MIC values was unimodal and varied between 0.25 and 1 mg/L for streptococci (>90% of isolates), and between 1 and 2 mg/L for staphylococci (>90%) and enterococci (>95%). There were no differences in linezolid susceptibility in the vancomycin-, oxacillin-, or penicillin-resistant subsets of strains when compared to susceptible organism populations. CONCLUSIONS: Compared to the North American component of this study, there was substantially less vancomycin resistance among E. faecium isolates (Europe 3.0% vs. North America 63.4%). While the occurrence of penicillin-resistant S. pneumoniae in Europe and North America was similar (25.1% vs. 29.7%), the recovery of high-level penicillin-resistant strains was nearly three-fold higher in North America (4.9% vs. 13.2%). Only linezolid was universally active against all the tested Gram-positive isolates at

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.

Multi-laboratory assessment of the linezolid spectrum of activity using the Kirby-Bauer disk diffusion method: Report of the Zyvox Antimicrobial Potency Study (ZAPS) in the United States.

The in vitro activity of linezolid against common Gram-positive pathogens was compared to that of penicillin or ampicillin or oxacillin (depending upon genus), cefazolin, erythromycin, clindamycin, quinupristin/dalfopristin, levofloxacin, nitrofurantoin and vancomycin by disk diffusion methods. One hundred and six centers (31 states in US) tested recent clinical isolates of Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecium, E. faecalis, Streptococcus pneumoniae, and other streptococci. Testing was conducted using the standardized disk diffusion method and concurrent quality control testing was performed. Strains with linezolid zone diameters of < or = 20 mm were requested for referral to the microbiology monitor for confirmation. A total of 3,100 isolates (97% compliance) were tested. Susceptibility (zone diameters, > or = 21 mm) of staphylococci and streptococci to linezolid was reported in 100% and 99.4% of staphylococci and streptococci, respectively. Susceptibility (zone diameters, > or = 23 mm) of enterococci to linezolid was 96.0% with only three isolates (0.4%) reported as resistant (zone diameters, < or = 20 mm; unconfirmed). Among a total of nine isolates (0.3%) reported to have zone diameters 20 mm, six were not submitted for further testing, two were contaminated with Gram-negative bacilli and one was determined to be linezolid-susceptible. There were no differences in linezolid susceptibility in the vancomycin- or oxacillin- or penicillin-resistant subsets of strains. This susceptibility pattern for US medical centers is indicative of the excellent and nearly complete in vitro activity against the key Gram-positive pathogens for which linezolid has received US Food and Drug Administration indications for clinical use.

Antimicrobial susceptibility of quinupristin/dalfopristin tested against gram-positive cocci from Latin America: results from the global SMART (GSMART) surveillance study.

Gram-positive cocci are important causes of both nosocomial and community-acquired infections, and antimicrobial resistance among these pathogens has become an important problem worldwide. Since resistance among these organisms can vary substantially by geographic location, we conducted a multicenter surveillance study with isolates from five Latin American countries (15 medical centers). Quinupristin/dalfopristin (formerly RP-59500) is a novel streptogramin combination with focused activity against Gram-positive cocci, many exhibiting emerging resistance. The in vitro activity of quinupristin/dalfopristin and 12 other antimicrobial agents were evaluated against 1,948 strains including Staphylococcus aureus (747 strains), coagulase-negative staphylococci (CoNS;446 strains), enterococci (429 strains), and various Streptococcus spp. (326 strains). Oxacillin resistance was observed in 41% of S. aureus (MIC, e; 13 mm) and 40% of CoNS (MIC, e; 18 mm). Vancomycin, teicoplanin, and quinupristin/dalfopristin (MIC(90), 0.25 - 1 mg/ml) remained effective against all strains, but cross-resistance was high among other tested drugs. The quinupristin/dalfopristin MIC(50) for Streptococcus pneumoniae and other streptococci was only 0.5 mg/ml (13% to 28% were penicillin-resistant; 12% to 22% were macrolide-resistant). Enterococci demonstrated variable inhibition by quinupristin/dalfopristin depending upon identification and the susceptibility testing method used. The demonstrated quinupristin/dalfopristin activity against Enterococcus faecium was confirmed, but potential species identification errors with various commercial systems continue to confuse susceptibility statistics, even though some strains of E. faecium confirmed by PCR-based or other molecular identification techniques did have quinupristin/dalfopristin MICs of >e; 4 microg/ml. Most important, glycopeptide-resistant enterococci are rapidly emerging in Latin America, and quinupristin/dalfopristin appears active against many of these isolates as well as having potency against nearly all staphylococci and streptococci tested at e; 16 mm. Comparisons to GSMART results from other continents show nearly identical quinupristin/dalfopristin activity for each Gram-positive species tested. These results define the role of quinupristin/dalfopristin in Latin American medical centers and provide a benchmark for future in vitro comparisons.

New agents for Gram-positive bacteria.

Infections caused by multiple-resistant Gram-positive organisms continue to occur at an alarming rate worldwide. Two new and unique antimicrobial agents targeted specifically against such organisms, quinupristin/dalfopristin and linezolid, have been approved for use in the USA in the past year and will play an important role in the treatment of life-threatening infections. In addition, several new fluoroquinolones have been approved recently or will be available in the near future to aid in the treatment of infections caused by resistant strains of Streptococcus pneumoniae.

Safety, tolerability, and pharmacokinetics of single oral doses of BCH-10652 in healthy adult males.

Racemic dOTC (BCH-10652) is a novel nucleoside reverse transcriptase inhibitor consisting of two enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine, (-)dOTC and (+)dOTC, that have both shown activity against human immunodeficiency virus type 1. The objectives of this study were to characterize the safety, tolerability, and stereospecific pharmacokinetics of single oral doses of racemic dOTC in healthy, nonsmoking adult male volunteers. Subjects received single oral doses of 100, 200, 400, 800, and 1,600 mg of racemic dOTC in a placebo-controlled, dose-rising, incomplete crossover study design, and the pharmacokinetics of both (+)dOTC and (-)dOTC were determined. At least six subjects were studied at each dose level, with each subject studied in three of five periods, receiving two different doses of racemic dOTC and one placebo dose. Plasma and urine drug concentrations were measured for 24 to 48 h after each dose. Pharmacokinetic models were fitted to the plasma concentrations of (+)dOTC and (-)dOTC using maximum likelihood and maximum a posteriori Bayesian procedures. Statistical hypothesis testing was by nonparametric analysis of variance (where possible) and, when tests with dose as a covariate were performed, by linear mixed-effects modeling. The mean terminal elimination half-lives for (+)dOTC and (-)dOTC were 15.3 h (coefficient of variation [CV], 28%) and 11.3 h (CV, 43%), respectively (P<0.05). The mean CV for total oral clearance (liter/h/65 kg) was 17.5 (25%) for (+)dOTC and 21.5 (24%) for (-)dOTC; for oral steady-state volume of distribution (liter/65 kg), values were 61.8 (24%) for (+)dOTC and 34.1 (33%) for (-)dOTC (P<0.05). The mean CV for renal clearance (liter/h/65 kg) of (+)dOTC was 10.4 (19%) and for (-)dOTC was 13.6 (20%) (P<0.05). There was no significant effect of dose size on the pharmacokinetics of racemic dOTC. All doses were well tolerated, and no serious adverse events or laboratory abnormalities were observed.

Absolute bioavailability and disposition of (-) and (+) 2'-deoxy- 3'-oxa-4'-thiocytidine (dOTC) following single intravenous and oral doses of racemic dOTC in humans.

The purpose of this study was to characterize the pharmacokinetics and determine the absolute bioavailability of 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) (BCH-10652), a novel nucleoside analogue reverse transcriptase inhibitor, in humans. dOTC belongs to the 4'-thio heterosubstituted class of compounds and is a 1:1 mixture of its two enantiomers, (-) and (+) dOTC. Twelve healthy adult male volunteers each received oral (800-mg) and intravenous (100-mg) doses of dOTC in two study periods separated by at least 7 days. Sixteen plasma samples were obtained over 72 h and assayed for (-) and (+) dOTC, and the resultant data fit by candidate pharmacokinetic models. Data were weighted by the fitted inverse of the observation variance; model discrimination was by AIC. The pharmacokinetic model was a linear, three compartment model, with absorption occurring during one to three first-order input phases, each following a fitted lag time. The model goodness-of-fit was excellent; r(2) ranged from 0.995 to 1.0. The mean absolute bioavailabilities of (+) and (-) dOTC were 77.2% (coefficient of variation [given as a percentage] [CV%], 14) and 80.7% (CV%, 15), respectively. The median steady-state volume of distribution for (+) dOTC, 74.7 (CV%, 19.2) liters/65 kg, was greater than that for (-) dOTC, 51.7 (CV%, 16.7) liters/65 kg (P<0.05). The median total clearance of (+) dOTC was less than that of (-) dOTC, 11.7 (CV%, 17.3) versus 15.4 (CV%, 18.6) liters/h/65 kg, respectively (P< 0.05). The intersubject variability of these parameters was very low. The median terminal half-life of (+) dOTC was 18.0 (CV%, 31.5) h, significantly longer than the 6.8 (CV%, 69.9) h observed for (-) dOTC (P<0.01). No serious adverse events were reported during the study. These results suggest that dOTC is well absorbed, widely distributed, and well tolerated. The terminal half-lives indicate that dosing intervals of 12 to 24 h would be reasonable.

A nationwide, multicenter, case-control study comparing risk factors, treatment, and outcome for vancomycin-resistant and -susceptible enterococcal bacteremia.

National Nosocomial Resistance Surveillance Group participants from 22 hospitals across the United States reviewed medical records for hospitalized patients with vancomycin-resistant enterococcal (VRE) or vancomycin-susceptible enterococcal (VSE) bacteremia to identify risk factors associated with the acquisition of VRE bacteremia, describe genetic traits of VRE strains, and identify factors predictive of clinical outcome. VRE cases were matched to VSE controls within each institution. Multiple logistic regression (LR) and classification and regression tree (CART) analysis were used to probe for factors associated with VRE bacteremia and clinical outcome. A total of 150 matched-pairs of VRE cases and VSE controls were collected from 1995 to 1997. Using LR, the following were found to be highly associated with VRE bacteremia: history of AIDS, positive HIV status, or drug abuse (OR 9.58); prior exposure with parenteral vancomycin (OR 8.37); and liver transplant history (OR 6. 75). CART analysis revealed that isolation of Enterococcus faecium, prior vancomycin exposure, and serum creatinine values > or = 1.1 mg/dl were predictors of VRE bacteremia. Greater proportions of clinical failure (60% versus 40%, P < 0.001) and all-cause mortality (52% versus 27%, P < 0.001) were seen in patients with VRE versus VSE bacteremia. Results from both LR and CART indicated that patients with persisting enterococcal bacteremia, intubation at baseline, higher APACHE II scores, and VRE bacteremia were at greater risk for poor outcome.

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.

Antibiotic dosing issues in lower respiratory tract infection: population-derived area under inhibitory curve is predictive of efficacy.

Several lower respiratory tract infection (LRTI) trials have documented a correlation between clinical response and area under the inhibitory curve (24 h AUC/MIC; AUIC). The AUIC values in these studies were based on measured MICs and measured serum concentrations. This study evaluates AUIC estimates made using population pharmacokinetic parameters, and MICs from an automated microbiological susceptibility testing system. A computer database review over 2 years yielded 81 patients at Millard Fillmore Hospital with a culture-documented gram-negative LRTI who had been treated with piperacillin and an aminoglycoside, ceftazidime, ciprofloxacin or imipenem. Their AUIC values were estimated using renal function, drug dosages and MIC values. Outcome groups (clinical and microbiological cures and failures) were related to the AUIC values using Kruskal-Wallis ANOVA, linear regression and classification and regression tree (CART) analysis. A significant breakpoint for clinical cures was an AUIC value at least 72 SIT(-1) x 24 h (inverse serum inhibitory titre integrated over time). All antibiotics performed significantly better above this value than below it. Clinical cure was well described by a Hill-type equation. Within the piperacillin/aminoglycoside regimen, most of the activity came from the piperacillin, which had a higher overall AUIC value than the aminoglycoside. AUIC estimations based upon MIC values derived from the automated susceptibility testing method differed from NCCLS breakpoint data and from tube dilution derived values in this hospital by as much as three tube dilutions. These automated methods probably overestimated the MIC values of extremely susceptible organisms. The lack of precise MIC estimates in automated clinical microbiology methods impairs the use of AUIC to prospectively optimize microbiological outcome. Even ignoring this limitation and using the values as they are reported, the results of this analysis suggest that AUIC targets between 72 and 275 SIT(-1) x 24 h are useful in predicting clinical outcome.

Antimicrobial activity of quinupristin-dalfopristin (RP 59500, Synercid) tested against over 28,000 recent clinical isolates from 200 medical centers in the United States and Canada.

A total of 200 medical center laboratories in the USA and Canada contributed results of testing quinupristin-dalfopristin, a streptogramin combination (formerly RP 59500 or Synercid), against 28,029 Gram-positive cocci. Standardized tests [disk diffusion, broth microdilution, Etest (AB BIODISK, Solna, Sweden)] were utilized and validated by concurrent quality control tests. Remarkable agreement was obtained between test method results for characterizing the collection by the important emerging resistances: 1) oxacillin resistance among Staphylococcus aureus (41.0 to 43.7%); 2) vancomycin resistance among Enterococcus faecium (50.0 to 52.0%); and 3) the penicillin nonsusceptible rate for pneumococci (31.1% overall, with 10.6% at MICs of > or = 2 micrograms/mL). The quinupristin-dalfopristin MIC90 for oxacillin-susceptible and -resistant S. aureus was 0.5 microgram/mL and 1 microgram/mL, respectively. The quinupristin-dalfopristin MIC90 for vancomycin-resistant E. faecium was 1 microgram/mL, and only 0.2% of isolates were resistant. Other Enterococcus species were generally not susceptible to the streptogramin combination but were usually inhibited by ampicillin (86 to 97% susceptible; MIC50, 1.0 microgram/mL) or vancomycin (86 to 95%; MIC50, 1.0 microgram/mL). Among all tested enterococci, the rate of vancomycin resistance was 16.2%. The quinupristin-dalfopristin MIC90 (0.75 microgram/mL) for 4,626 tested Streptococcus pneumoniae strains was not influenced by the penicillin or macrolide susceptibility patterns. When five regions in the USA and Canada were analyzed for significant streptogramin and other antimicrobial spectrum differences, only the Farwest region had lower numbers of streptogramin-susceptible E. faecium. Canadian strains were generally more susceptible to all drugs except chloramphenicol and doxycycline when tested against E. faecalis (73% and 89% susceptible, respectively). The U.S. Southeast region had S. pneumoniae strains less susceptible to macrolides (73%) but had more susceptibility among E. faecium isolates tested against vancomycin and ampicillin. The Northeast region of the USA had the greatest rate of vancomycin resistance among enterococci. Strains retested by the monitor because of quinupristin-dalfopristin resistance (MICs, > or = 4 micrograms/mL) were generally not confirmed (2.2% validation), and only 0.2% of E. faecium isolates were identified as truly resistant. The most common errors were: 1) species misidentification (28.0%); 2) incorrect susceptibility results (65.6%); and 3) mixed cultures (4.3%) tested by participants. Overall, quinupristin-dalfopristin was consistently active (> or = 90% susceptible) against major Gram-positive pathogens in North America, regardless of resistance patterns to other drug classes and geographic location of their isolation.

In vitro evaluation of sparfloxacin activity and spectrum against 24,940 pathogens isolated in the United States and Canada, the final analysis.

Sparfloxacin, a recently marketed oral fluoroquinolone, was tested against 24,940 recent clinical strains isolated from blood stream and respiratory tract cultures at 187 hospitals in the USA and Canada. Sparfloxacin activity was compared with 5 to 13 antimicrobial agents using either Etest (AB BIODISK, Solna, Sweden) and a reference broth microdilution or a standardized disk diffusion method. When applying recommended MIC breakpoint criteria of sparfloxacin susceptibility (< or = 0.5 microgram/mL) for Streptococcus pneumoniae (4,410 strains) and other Streptococcus spp. (554 isolates), 93% and 88% were inhibited, respectively. Furthermore, at < or = 1 microgram/mL sparfloxacin susceptibility rates for streptococci increased to 98% overall and 99.3% for S. pneumoniae. In contrast, only 46% and 68% of pneumococci were susceptible to ciprofloxacin (MIC90, 3 micrograms/mL; susceptible at < or = 1 microgram/mL) and penicillin (MIC90, 1.5 microgram/mL; susceptible at < or = 0.06 microgram/mL), respectively. Differences between regions in the USA for rates of penicillin-resistant pneumococcal strains were observed (greatest resistances in southeast and midwest), but results indicate that the sparfloxacin potency was not adversely influenced (MIC90, 0.5 microgram/mL). Also pneumococcal isolates from the lower respiratory tract were more resistant to penicillin and other beta-lactams. Nearly all Haemophilus species and Moraxella catarrhalis strains, including those harboring beta-lactamases, were susceptible to tested fluoroquinolones (sparfloxacin, ciprofloxacin), amoxicillin/clavulanic acid, and newer oral cephalosporins. Sparfloxacin was very active against oxacillin-susceptible Staphylococcus aureus (MIC90, 0.12 microgram/mL; 96-97% susceptible), Klebsiella spp. (MIC90 0.12 microgram/mL), and other tested enteric bacilli (92-95% susceptible). Comparisons between the broth microdilution MIC and disk diffusion interpretive results demonstrated excellent intermethod susceptibility category agreement (> 95%) using current sparfloxacin breakpoints, but some compounds (cefpodoxime disk diffusion tests for S. aureus) may require modifications. These results demonstrate that new Gram-positive focused fluoroquinolones (sparfloxacin) possess an excellent in vitro activity and spectrum against pathogens that cause respiratory tract infections. This spectrum of activity includes strains resistant to other antimicrobial classes, including the oral cephalosporins, macrolides, amoxicillin/clavulanic acid, and earlier fluoroquinolones (ciprofloxacin, ofloxacin). Overall, sparfloxacin inhibited 89% to nearly 100% of the isolates (species variable) tested against those species against which it has Food and Drug Administration indications for clinical use.

Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy.

The selection of bacterial resistance was examined in relationship to antibiotic pharmacokinetics (PK) and organism MICs in the patients from four nosocomial lower respiratory tract infection clinical trials. The evaluable database included 107 acutely ill patients, 128 pathogens, and five antimicrobial regimens. Antimicrobial pharmacokinetics were characterized by using serum concentrations, and culture and sensitivity tests were performed daily on tracheal aspirates to examine resistance. Pharmacodynamic (PD) models were developed to identify factors associated with the probability of developing bacterial resistance. Overall, in 32 of 128 (25%) initially susceptible cases resistance developed during therapy. An initial univariate screen and a classification and regression tree analysis identified the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC[0-24]/MIC) as a significant predictor of the development of resistance (P < 0.001). The final PK/PD model, a variant of the Hill equation, demonstrated that the probability of developing resistance during therapy increased significantly when antimicrobial exposure was at an AUC[0-24]/MIC ratio of less than 100. This relationship was observed across all treatments and within all organism groupings, with the exception of beta-lactamase-producing gram-negative organisms (consistent with type I beta-lactamase producers) treated with beta-lactam monotherapy. Combination therapy resulted in much lower rates of resistance than monotherapy, probably because all of the combination regimens examined had an AUC[0-24]/MIC ratio in excess of 100. In summary, the selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUC[0-24]MIC ratio of less than 100.

Pharmacokinetics of Oral Azithromycin in Serum, Urine, Polymorphonuclear Leucocytes and Inflammatory vs Non-Inflammatory Skin Blisters in Healthy Volunteers.

Two open-label studies were conducted to assess the serum, urine, polymorphonuclear (PMN) and red blood cell (RBC) pharmacokinetics of a 5-day course (1500mg total) of oral azithromycin. Inflammatory and non-inflammatory blisters were also induced to study the propensity of azithromycin to preferentially concentrate at a model infection site. 14 subjects participated in the two studies and tolerated azithromycin and the study methods well. Comodelling of the serum and urine data demonstrated very extensive distribution into peripheral compartments, low renal clearance (7% of total oral clearance) and an extended terminal half-life (79 hours). PMN leucocyte concentrations peaked at 119 mg/L following the final dose and remained above 60 mg/L 7 days after the final dose. The ratio of blister to serum AUCs was significantly higher in inflammatory (2.2) vs non-inflammatory (1.2) blisters (p < 0.02). The extensive uptake of azithromycin into PMNs coupled with the accumulation of azithromycin into an inflammatory compartment (e.g. infection site) support the hypothesis that PMN leucocytes laden with azithromycin migrate to sites of inflammation, thereby enhancing local concentrations. These studies further demonstrate the unique pharmacokinetic properties of azithromycin and its preferential delivery by phagocytes to the site of infection.

Comparative in vitro assessment of sparfloxacin activity and spectrum using results from over 14,000 pathogens isolated at 190 medical centers in the USA. SPAR Study Group.

Sparfloxacin, a new orally administered fluoroquinolone, was tested against 14,182 clinical strains isolated (generally blood stream and respiratory tract cultures) at nearly 200 hospitals in the United States (USA) and Canada. Sparfloxacin activity was compared with 13 other compounds by Etest (AB BIODISK, Solna, Sweden), broth microdilution, or a standardized disk diffusion method. Using the Food and Drug Administration/product package insert MIC breakpoint for sparfloxacin susceptibility (< or = 0.5 microgram/ml), 94% of Streptococcus pneumoniae (2666 isolates) and 89% of the other streptococci (554 isolates) were susceptible. However, at < or = 1 microgram/ml (the breakpoint for all nonstreptococcal species) sparfloxacin susceptibility rates increased to 100% and 98%, respectively, for the two groups of streptococci. Only 50% and 65% of pneumococci were susceptible to ciprofloxacin (MIC90, 3 micrograms/ml) and penicillin (MIC90, 1.5 micrograms/ml), respectively. Although there were significant differences between regions in the USA in the frequency of penicillin-resistant pneumococcal strains, results indicate that the overall sparfloxacin MIC90 was uniformly at 0.5 microgram/ml. Nearly all (> or = 99%) Haemophilus species and Moraxella catarrhalis, including those harboring beta-lactamases, were susceptible to sparfloxacin, ciprofloxacin, and amoxicillin/clavulanic acid. Only cefprozil and macrolides demonstrated lower potency and spectrum against these two species. Sparfloxacin was active against oxacillin-susceptible Staphylococcus aureus (96 to 97%), Klebsiella spp. (95%), and other tested enteric bacilli (93%). Comparison between broth microdilution MIC and disk diffusion interpretive results for M. catarrhalis, Staphylococcus aureus, and the Enterobacteriaceae showed an absolute intermethod categorical agreement of > 95% using current sparfloxacin breakpoints, in contrast to those of cefpodoxime for S. aureus where a conspicuous discord (98% versus 59%) between methods was discovered. These results demonstrate that sparfloxacin possesses sufficient in vitro activity and spectrum versus pathogens that cause respiratory tract infections (indications), especially strains resistant to other drug classes such as the earlier fluoroquinolones, oral cephalosporins, macrolides, and amoxicillin/clavulanic acid. The sparfloxacin susceptibility breakpoint for streptococci may require modification (< or = 1 microgram/ml) based on the MIC population analysis presented here. A modal MIC (0.38 to 0.5 microgram/ml) was observed at the current breakpoint. Regardless, sparfloxacin inhibited 89% (nonpneumococcal Streptococcus spp.) to 100% (Haemophilus spp., M. catarrhalis) of the isolates tested with a median activity of 97% against indicated species.

Modeling the response of pneumonia to antimicrobial therapy.

The response to antimicrobial therapy in patients with pneumonia was assessed by using a previously developed pneumonia scoring system. Patients from two different clinical trials were evaluated. The first group (n = 22) was treated with cefmenoxime. For these patients, doses were adjusted to achieve an area under the plasma concentration-versus-time curve (AUC) above the MIC of 140 microg x h/ml and pneumonia response scores were evaluated retrospectively. The second group (n = 21) were treated with either ciprofloxacin (CIP) or ceftazidime (TAZ) in a randomized clinical trial. Here, doses were adjusted to achieve AUC from 0 to 24 h/MIC values that were > 250 SIT(-1) x h (estimate of the area under the curve of inverse serum inhibitory titer versus time) and pneumonia response scoring was concurrent. In both studies eradication of the pathogen was determined by serial endotracheal cultures and clinical parameters were scored daily. A decrease in total score was indicative of an improving clinical condition. The percent change in clinical daily score was determined for each day of treatment. The rate of clinical response was determined by linear regression of the percent change in daily clinical score versus time during the course of antimicrobial therapy. Factors predictive of time to eradication were explored by interval analysis. Logistic regression was used to determine the earliest time point in therapy at which treatment scores predicted outcome. Kruskal-Wallis analysis of variance was used for statistical analysis, and significance was accepted at P < 0.05. There were no differences in baseline scores at day one for the patients treated with different antibiotics (P = 0.58). For patients with pathogen eradication, a significant difference between the two studies in time to eradication was found: 4.8 days for cefmenoxime-treated patients and 1.4 days for CIP- or TAZ-treated patients (P < 0.001). For patients experiencing bacterial eradication, the rates of clinical change for cefmenoxime and CIP or TAZ treatment were similar (P = 0.77). For patients with organisms that were not eradicated, the rates of change were similar (P = 0.14). There was a significant difference in the rate of change for patients experiencing eradication compared with that for patients in which the organism persisted (P << 0.01). Both treatment group and rate were found to be predictive of days to eradication. There was a significant difference in the percent change in clinical score on day 3 of therapy for patients with bacteria that were eradicated versus those with persistent organisms (P < 0.01). The percent change was more predictive of outcome with each subsequent day. Patients who demonstrated a > or = 10% reduction in clinical score after 72 h of treatment had an 88% probability of bacterial eradication. The clinical scoring system is a useful tool for modeling the response of pneumonia to antimicrobial therapy. The ability to predict outcome relatively early in therapy, by using a scoring system of clinical parameters which can be routinely monitored, will aid in assessing the response to antimicrobial therapy in clinical as well as in research settings.

Prospective validation of an optimal sparse plasma-sampling strategy for estimating ciprofloxacin pharmacokinetics.

Data obtained from 23 critically ill patients treated with intravenous ciprofloxacin in two clinical trials were used to validate prospectively a previously developed maximum a posteriori (MAP)-Bayesian estimator and optimal plasma-sampling strategy (OSS). Dosages ranged from 200 mg every 12 hours to 400 mg every 8 hours. Each patient had 8-16 samples taken, either as large gold standard sampling sets or as a mix of gold standard sets and OSSs. The MAP-Bayesian estimator used a two-compartment model and identified apparent volumes of distribution of the central and peripheral compartments, distributional clearance, and the slope and intercept of the relationship between creatinine clearance and total body clearance. Fit parameters were used to derive the apparent volume of distribution at steady state and the 24-hour area under the curve. All parameters derived from the OSS using the MAP-Bayesian estimates matched up almost identically to those obtained from modeling the gold standard sets. There was no systematic bias, and good precision was seen among all the parameters. These data demonstrate the usefulness and validity of the current OSS and MAP-Bayesian estimator, and provide further evidence of the utility of optimal sampling theory.

Development and evaluation of a Bayesian pharmacokinetic estimator and optimal, sparse sampling strategies for ceftazidime.

Data were gathered during an activity-controlled trial in which seriously ill, elderly patients were randomized to receive intravenous ceftazidime or ciprofloxacin and for which adaptive feedback control of drug concentrations in plasma and activity profiles was prospectively performed. The adaptive feedback control algorithm for ceftazidime used an initial population model, a maximum a posteriori (MAP)-Bayesian pharmacokinetic parameter value estimator, and an optimal, sparse sampling strategy for ceftazidime that had been derived from data in the literature obtained from volunteers. Iterative two-stage population pharmacokinetic analysis was performed to develop an unbiased MAP-Bayesian estimator and updated optimal, sparse sampling strategies. The final median values of the population parameters were follows: the volume of distribution of the central compartment was equal to 0.249 liter/kg, the volume of distribution of the peripheral compartment was equal to 0.173 liter/kg, the distributional clearance between the central and peripheral compartments was equal to 0.2251 liter/h/kg, the slope of the total clearance (CL) versus the creatinine clearance (CLCR) was equal to 0.000736 liter/h/kg of CL/1 ml/min/1.73 m2 of CLCR, and nonrenal clearance was equal to + 0.00527 liter/h/kg. Optimal sampling times were dependent on CLCR; for CLCR of > or = 30 ml/min/1.73 m2, the optimal sampling times were 0.583, 3.0, 7.0, and 16.0 h and, for CLCR of < 30 ml/min/1.73 m2, optimal sampling times were 0.583, 4.15, 11.5, and 24.0 h. The study demonstrates that because pharmacokinetic information from volunteers may often not be reflective of specialty populations such as critically ill elderly individuals, iterative two-stage population pharmacokinetic analysis, MAP-Bayesian parameter estimation, and optimal, sparse sampling strategy can be important tools in characterizing their pharmacokinetics.

Legionella urinary antigen testing: potential impact on diagnosis and antibiotic therapy.

Although Legionella is an important cause of severe pneumonia, difficulty still exists in its diagnosis. Because at least 80% of patients with legionellosis excrete the Legionella antigen in their urine, various methods have been investigated for urinary antigen detection. Specificity for these methods has been reported to be 100%, and sensitivity has been shown to vary between 70 and 100%. The advantages of these methods include ease of specimen collection, the ability to obtain large quantities of specimen for concentration, the ability to detect antigen after initiation of antibiotic therapy, and the ability to obtain results quickly. Disadvantages include the ability to only reliably detect urinary L. penumophila serogroup 1 antigen and the inability to diagnose relapse or reinfection due to persistence of antigen excretion. Of the commercially-available detection methods, the polyclonal enzyme-linked immunosorbent assay (ELISA) appears to be most efficient. Its use with routine Legionella screening procedures should be considered in target populations, with the intent of early diagnosis and antibiotic therapy streamlining.

Cost considerations in oral antibiotic therapy.

The total cost of antibiotic treatment may be computed from basic treatment and indirect costs. Basic treatment costs represent the product of the per-dose acquisition cost and the number of doses. Agents with a high per-dose acquisition cost and an infrequent (eg, once daily), short duration of therapy may have lower total costs than agents with a low per-dose acquisition cost and a high-frequency (eg, four times daily), long-duration regimen. Indirect cost reflects expenditures associated with noncompliance, treatment failure, adverse events, and drug interactions. These costs result, in turn, from additional office visits, treatment with alternative or additional medications, hospitalization, and lost productivity. Older agents, though likely to have lower acquisition costs, may have reduced efficacy against clinically important pathogens, side effects, drug interactions, and the requirement for multiple daily doses and long dosage regimens--factors that may increase the probability of poor outcome and the overall treatment cost. Newer broad-spectrum agents are effective and generally well tolerated and may have fewer drug interactions; however, most require long and relatively complex dosage regimens. These limitations increase the basic treatment cost and influence indirect costs through negative effects on patient compliance. Broad-spectrum antibiotics with low acquisition costs, simple dosing regimens, and relatively favorable safety and tolerability profiles may provide benefits in the treatment of common infections.