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

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.

Pharmacokinetics and metabolism of moxifloxacin.

Moxifloxacin is a recently developed fluoroquinolone antibiotic. It is rapidly absorbed following oral administration, reaching a mean peak drug plasma concentration (C(max)) of approximately 3.56 mg/l within 2 h after a 400 mg dose. The rate and extent of absorption are not significantly affected by food or elevated gastric pH. Moxifloxacin binds weakly to plasma proteins and penetrates well into most tissue and fluid compartments, with generally higher drug concentrations in tissue and fluid compartments than those observed in plasma. Moxifloxacin is metabolized to an N-sulfate conjugate and an acyl glucuronide in humans. The N-sulfate and the unchanged moxifloxacin are detected in plasma, urine and feces. The acyl-glucuronide is detected in plasma and urine, but not in feces. The plasma elimination half-life ranges from 8.2-15.1 h in healthy individuals. The urinary excretion of the unchanged drug accounts for 19-22% of the given dose. Neither renal nor hepatic impairment significantly affect the pharmacokinetics of moxifloxacin.

E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators.

CONTEXT: Knowledge and understanding of gram-negative sepsis have grown over the past 20 years, but the ability to treat severe sepsis successfully has not. OBJECTIVE: To assess the efficacy and safety of E5 in the treatment of patients with severe gram-negative sepsis. DESIGN: A multicenter, double-blind, randomized, placebo-controlled trial conducted at 136 US medical centers from April 1993 to April 1997, designed with 90% power to detect a 25% relative risk reduction, incorporating 2 planned interim analyses. SETTING: Intensive care units at university medical centers, Veterans Affairs medical centers, and community hospitals. PATIENTS: Adults aged 18 years or older, with signs and symptoms consistent with severe sepsis and documented or probable gram-negative infection. INTERVENTION: Patients were assigned to receive 2 doses of either E5, a murine monoclonal antibody directed against endotoxin (n = 550; 2 mg/kg per day by intravenous infusion 24 hours apart) or placebo (n = 552). MAIN OUTCOME MEASURES: The primary end point was mortality at day 14; secondary end points were mortality at day 28, adverse event rates, and 14-day and 28-day mortality in the subgroup without shock at presentation. RESULTS: The trial was stopped after the second interim analysis. A total of 1090 patients received study medication and 915 had gram-negative infection confirmed by culture. There were no statistically significant differences in mortality between the E5 and placebo groups at either day 14 (29.7% vs 31.1%; P = .67) or day 28 (38.5% vs 40.3%; P = .56). Patients presenting without shock had a slightly lower mortality when treated with E5 but the difference was not significant (28.9% vs 33.0% for the E5 and placebo groups, respectively, at day 28; P = .32). There was a similar profile of adverse event rates between E5 and placebo. CONCLUSIONS: Despite adequate sample size and high enrollment of patients with confirmed gram-negative sepsis, E5 did not improve short-term survival. Current study rationale and designs should be carefully reviewed before further large-scale studies of patients with sepsis are conducted.

Ciprofloxacin concentrations in lung tissue following a single 400 mg intravenous dose.

Intravenous ciprofloxacin is frequently prescribed for the treatment of infections due to nosocomially acquired gram-negative organisms, including those originating in the respiratory tract. In this study, the concentrations of ciprofloxacin in serum and lung tissue were determined by HPLC in patients undergoing lung surgery. A total of 22 patients scheduled for lung surgery received a single 400 mg i.v. dose of ciprofloxacin administered as a 1 h infusion. A specimen of healthy lung tissue was obtained from resected lung from 18 of the patients for analysis of ciprofloxacin concentration during the following time intervals after infusion (one sample/patient): 0-2, 2-4, 4-8 and 8-12 h. Corresponding mean serum and tissue concentrations were 2.37 mg/L and 3.84 mg/kg (0-2 h), 1.18 mg/L and 1.92 mg/kg (2-4 h), 0.69 mg/L and 1.77 mg/kg (4-8 h), and 0.13 mg/L and 0.67 mg/kg (8-12 h). Ciprofloxacin distributed rapidly to lung tissue, as seen by the high concentrations in the lung tissue as early as 2 h after infusion. Concentrations in lung tissue were generally higher than those in serum (tissue:serum ratios ranged from 1.7 to 7.1). The mean tissue concentrations found in this study remained above the MIC for most susceptible organisms.

Genesis of methicillin-resistant Staphylococcus aureus (MRSA), how treatment of MRSA infections has selected for vancomycin-resistant Enterococcus faecium, and the importance of antibiotic management and infection control.

We extensively studied the epidemiology and time course of endemic methicillin-resistant Staphylococcus aureus (MRSA) in the Millard Fillmore Hospital, a 600-bed teaching hospital in Buffalo. The changeover from methicillin-susceptible S. aureus to MRSA begins on the first hospital day, when patients are given cefazolin as presurgical prophylaxis. Under selective antibiotic pressure, colonizing flora change within 24 to 48 hours. For patients remaining hospitalized, subsequent courses of third-generation cephalosporins further select and amplify the colonizing MRSA population. Therefore, managing antibiotic selective pressure might be essential. Other strategies include attention to dosing, so that serum concentrations of drug exceed the minimum inhibitory concentration, and antibiotic cycling. Although there are some promising new antibiotics on the horizon, it is necessary to deal with many resistance patterns by using the combined strategies of infection control and antibiotic management.

Assessing antibacterial pharmacoeconomics in the intensive care unit.

Intensive care units (ICUs) represent areas of high use of antibacterials and other pharmacy goods and services. Many institutions view their ICUs as a target for drug-use surveillance and cost-containment programmes. Economic assessment of antibacterial interventions in the ICU should include all direct costs and patient outcomes. Nonetheless, many of these institutions focus their efforts at reducing antibacterial costs without considering the consequences of these actions. It is possible that devoting more resources to antibacterials can have an overall positive economic impact if more appropriate antibacterial use reduces length of stay, decreases bacterial resistance or lowers frequency of adverse complications. Two consequences of antibacterial use which can result in substantial economic burdens to institutions are drug-induced complications (toxicities and adverse events) and the development of antibacterial-resistant organisms. These events are logical targets for performing pharmacoeconomic studies to evaluate appropriate and inappropriate antibacterial use. Either of these problems can increase length of stay, which is the single most important variable influencing the overall cost of patient care. The primary goal of patient care is to hasten patients' clinical improvement. This will result in decreased antibacterial acquisition costs, decreased lengths of ICU and hospital stays, and ultimately decreased consumption of hospital resources. These can be accomplished by using strategies to guide antibacterial use in order to reduce failures, adverse events, toxicity and antimicrobial resistance.

Changing the infection control paradigm from off-line to real time: the experience at Millard Fillmore Health System.

In 1993, several departments at Millard Fillmore Health System joined efforts to initiate a new approach to infection control. The main emphasis of this program is to move infection control to a real-time mode to manage patient outcomes daily. The principal objective was to decrease the number of nosocomial infections by 10%, with a particular emphasis on surgical-site infections. Besides real-time surveillance, we are critically evaluating several aspects of the management of nosocomial infections. High-level computer support has been the frame-work upon which this program was built. We have microcomputers that are linked directly to microbiology, pharmacy, billing, and admissions, downloading data several times daily. An expert software system merges all of the data, and from this we can target patients for real-time interventions. The computer system allows all inpatients to be screened for either infection control or antibiotic management interventions on a daily basis, with minimal time being spent on data collection and maximal efforts devoted to interventions at the bedside. Additionally, the infection management program will assist in maintaining the extraordinarily low expenditures on antimicrobial agents. During 1993, the Millard Fillmore Health System spent $924,884 on antibiotics, an amount approximately 50% that of comparably sized hospitals.

In nosocomial pneumonia, optimizing antibiotics other than aminoglycosides is a more important determinant of successful clinical outcome, and a better means of avoiding resistance.

In in vitro and animal models, antibiotics show good relationships between concentration and response, when response is quantified as the rate of bacterial eradication. The strength of these in vitro relationships promises their utility for dosage regimen design and predictable cure of infections such as nosocomial pneumonia. In spite of their intuitive logic, close relationships between dosage and bacterial eradication have not been easy to show in clinical studies of nosocomial pneumonia. Presumably, a variety of patient, disease, bacterial, and pharmacokinetic variables cloud these relationships in patients, and delay their elucidation in patient trials. Patients with serious infections like nosocomial pneumonia require bactericidal antimicrobial activity. Studies in our laboratory show that the minimum effective antimicrobial action is an area under the inhibitory titer (AUIC) of 125, in which AUIC is calculated as the 24 hour serum area under the curve (AUC) divided by the minimum inhibitory concentration (MIC) of the pathogen. This target AUIC may be achieved with either a single antibiotic or it can be the sum of AUIC values of two or more antibiotics. There is considerable variability in the actual AUIC value for patients when antibiotics are administered in their usual recommended dosages. Examples of this variance will be provided using aminoglycosides, fluoroquinolones, and beta-lactams. The achievement of minimally effective antibiotic action, consisting of an AUIC of at least 125, is associated with bacterial eradication in about 7 days for beta-lactams and quinolones. Adding an aminoglycoside to beta-lactams may produce a slight increase in their rate of bacterial killing in vivo, but because of their narrow therapeutic window, and the associated low doses in relation to MIC, there are situations in which the aminoglycosides may be unable to add sufficient additional AUIC. Antibiotic activity indices allow clinicians to evaluate individualized patient regimens. Furthermore, antibiotic activity is a predictable clinical endpoint with predictable clinical outcome. This value also is highly predictive of the development of bacterial resistance. Antimicrobial regimens that do not achieve an AUIC of at least 125 cannot prevent the selective pressure that leads to overgrowth of resistant bacterial subpopulations. The methods based on the determination of AUIC have clinical applicability in routine practice, through software developed for this purpose. These indices can assist with patient management strategies in a prospective manner because they can identify patients at high risk of therapeutic failure or acquired resistance early in therapy before therapy fails. Our studies show that calculations of AUIC can be used to prospectively target regimens to improve the chances of cure with nosocomial pneumonia and other serious infections. A clinical intervention team has been organized to optimize antimicrobial regimens as early in therapy as possible, to lower the high cost events such as failure and acquired bacterial resistance.

Use of benchmarking techniques to justify the evolution of antibiotic management programs in healthcare systems.

OBJECTIVE: To apply basic benchmarking techniques to hospital antibiotic expenditures and clinical pharmacy personnel and their duties, to identify cost savings strategies for clinical pharmacy services. DESIGN: Prospective survey of 18 hospitals ranging in size from 201 to 942 beds. Each was asked to provide antibiotic expenditures, an overview of their clinical pharmacy services, and to describe the duties of clinical pharmacists involved in antibiotic management activities. Specific information was sought on the use of pharmacokinetic dosing services, antibiotic streamlining, and oral switch in each of the hospitals. RESULTS: Most smaller hospitals (< 300 beds) did not employ clinical pharmacists with the specific duties of antibiotic management or streamlining. At these institutions, antibiotic management services consisted of formulary enforcement and aminoglycoside and/or vancomycin dosing services. The larger hospitals we surveyed employed clinical pharmacists designated as antibiotic management specialists, but their usual activities were aminoglycoside and/or vancomycin dosing services and formulary enforcement. In virtually all hospitals, the yearly expenses for antibiotics exceeded those of Millard Fillmore Hospitals by $2,000-3,000 per occupied bed. In a 500-bed hospital, this difference in expenditures would exceed $1.5 million yearly. Millard Fillmore Health System has similar types of patients, but employs clinical pharmacists to perform streamlining and/or switch functions at days 2-4, when cultures come back from the laboratory. CONCLUSIONS: The antibiotic streamlining and oral switch duties of clinical pharmacy specialists are associated with the majority of cost savings in hospital antibiotic management programs. The savings are considerable to the extent that most hospitals with 200-300 beds could readily cost-justify a full-time clinical pharmacist to perform these activities on a daily basis. Expenses of the program would be offset entirely by the reduction in the actual pharmacy expenditures on antibiotics.

Mathematical examination of dual individualization principles (II): The rate of bacterial eradication at the same area under the inhibitory curve is more rapid for ciprofloxacin than for cefmenoxime.

OBJECTIVE: To compare two antibiotics at equal ranges of area under the inhibitory curve (AUIC) exposure to determine if the rate of bacterial eradication differed between these antibiotics. DESIGN: Retrospective comparison of two previously collected studies of similar patients with nosocomial pneumonia. SETTING: Hospitalized patients, most intubated in critical care units with nosocomial pneumonia. PARTICIPANTS: Patients treated with either i.v. ciprofloxacin (n = 74) or the i.v. third-generation cephalosporin cefmenoxime (n = 43) were compared for their length of treatment required to eradicate bacterial pathogens from their respective infection sites, using serial cultures from the site of infection. All patients were also assessed for clinical outcomes. Serum samples were obtained to evaluate individual patient antibiotic pharmacokinetics, which were used to model pharmacodynamics of response. The HPLC assay used for each antibiotic had interday coefficients of variation < 10 percent. Serum concentration versus time profiles were fit using the computer program ADAPT II to determine pharmacokinetic parameters for each patient. The primary drug exposure measure that related to response was the AUIC, calculated as steady-state AUC0-24/minimum inhibitory concentration. RESULTS: AUIC values in the patients ranged from 6.0 to more than 7000, yet the AUIC value was highly predictive of time to bacterial eradication (p < 0.001). Although more than 75 percent of patients eventually achieved eradication of pathogens from tracheal aspirate cultures, ciprofloxacin and cefmenoxime differed significantly in the time required to sterilize these cultures. At appropriate AUIC values (> 250) for ciprofloxacin, the median time to eradication was two days, while cefmenoxime (also at AUIC values > 250) required six days to achieve the same result. CONCLUSIONS: We conclude that the more rapid in vitro bacterial killing, which is characteristic of ciprofloxacin at optimal AUIC values, can manifest in vivo as more rapid clearance of bacteria from the respiratory tract of patients, even when both agents are controlled for initial antibacterial exposure (i.e., same AUIC).

The development of a bedside algorithm capable of targeting anti-endotoxins to the responder subpopulations.

The published selection criteria for use of anti-endotoxin antibodies are modeled on the criteria used in protocol enrollment of patients. These criteria are not suitable for therapeutic decision-making, because the trials themselves prove that the enrollment criteria have both low sensitivity and low specificity. In order to develop a selection method with greater sensitivity and specificity, we examined the charts and records of 23 patients that we enrolled in the multicenter trials of E5 and HA-1A. We retrospectively determined that seven of our 23 enrolled patients were optimal candidates, based on a pattern of rapid clinical deterioration followed by improvement in 24-96 h. We then explored a variety of different modes of bedside patient selection, in search of a method to select as many of the seven optimal candidates as possible while at the same time rejecting the greatest number of the 16 who showed no benefit when treated. None of the resulting selection methods has perfect performance, but nearly all were better than the original protocol enrollment criteria. In our patients, bacteremia had 57% sensitivity and 56% specificity, which was quite similar to the findings in the HA-1A multicenter trial. Shock had 100% sensitivity and 44% specificity, while a baseline organ dysfunction score of > or = 5 had 100% sensitivity and 69% specificity. A new algorithm that we developed based on a patient's need for vasopressors and baseline organ dysfunction had 100% sensitivity and 81% specificity. This algorithm could identify all seven of the optimal candidates, plus three more.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin.

Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean +/- standard deviation = 7 +/- 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CLT in liters per hour) was related to body size and renal function (creatinine clearance [CLCR] in milliliters per minute per 1.73 m2) by the equation CLT = (0.00145.CLCR + 0.167).weight. However, only 30% of the variance in CLT was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CLT (by 44%; P < 0.001) than weight- and CLCR- matched stable volunteers. OSSs provided parameter estimates that showed good to excellent estimates of CLT (or area under the concentrations-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was > 0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.

Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients.

Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two-compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-1.h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent probabilities of clinical and microbiologic cures were 42 and 26%, respectively. At an AUIC above 125 (45 patients), the probabilities were 80% (P < 0.005) and 82% (P < 0.001), respectively. There were two significant breakpoints in the time-to-bacterial-eradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication was 6.6 days: and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.