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.

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.

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.

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.

Achieving an optimal outcome in the treatment of infections. The role of clinical pharmacokinetics and pharmacodynamics of antimicrobials.

Over the past few decades, the importance of applying pharmacokinetic principles to the design of drug regimens has been increasingly recognised by clinicians. From the perspective of antimicrobial chemotherapy, an improvement in clinical outcome and/or a reduction in toxicity are of primary interest. Before application of these pharmacokinetic theories can be effective, the interrelationships between antimicrobial, pathogen and host factors must be clearly defined. Information regarding the pharmacokinetics of the antimicrobial and the quantification of pathogen susceptibility is required. Even though susceptibility end-points such as minimum inhibitory concentration (MIC) and minimum bactericidal concentration are widely employed, they do not provide any information on dynamic changes of bacterial densities. In this regard, time-kill studies can provide more basic knowledge of the complex bacterial responses to the antimicrobial. Better prediction of these responses can be afforded by the use of mathematical models. More recently, various surrogate end-points employing a combination of suitable pharmacokinetic parameters and susceptibility data, for example the ratio of peak concentration to MIC, the area under the concentration-time curve above the MIC (AUC > MIC), the time above the MIC, or the area under the inhibitory curve (AUIC), have been suggested for better prediction of the activity of different classes of antimicrobials. To allow more extensive investigations of the contribution of pharmacokinetics to the pharmacodynamics of antimicrobials, various in vitro kinetic models have been developed. However, certain limitations exist, and it is necessary to avoid over-interpretation of the data generated by these models. Two important microbial dynamic responses, postantibiotic effect and resistance selection, must be further explored before the full impact of pharmacokinetics on antimicrobial chemotherapy can be depicted. The present paper aims at discussing all the relevant factors and provides some pertinent information on the use of pharmacokinetic-pharmacodynamic principles in antimicrobial therapy.

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.

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.

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.

Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group.

Intravenously administered ciprofloxacin was compared with imipenem for the treatment of severe pneumonia. In this prospective, randomized, double-blind, multicenter trial, which included an intent-to-treat analysis, a total of 405 patients with severe pneumonia were enrolled. The mean APACHE II score was 17.6, 79% of the patients required mechanical ventilation, and 78% had nosocomial pneumonia. A subgroup of 205 patients (98 ciprofloxacin-treated patients and 107 imipenem-treated patients) were evaluable for the major efficacy endpoints. Patients were randomized to receive intravenous treatment with either ciprofloxacin (400 mg every 8 h) or imipenem (1,000 mg every 8 h), and doses were adjusted for renal function. The primary and secondary efficacy endpoints were bacteriological and clinical responses at 3 to 7 days after completion of therapy. Ciprofloxacin-treated patients had a higher bacteriological eradication rate than did imipenem-treated patients (69 versus 59%; 95% confidence interval of -0.6%, 26.2%; P = 0.069) and also a significantly higher clinical response rate (69 versus 56%; 95% confidence interval of 3.5%, 28.5%; P = 0.021). The greatest difference between ciprofloxacin and imipenem was in eradication of members of the family Enterobacteriaceae (93 versus 65%; P = 0.009). Stepwise logistic regression analysis demonstrated the following factors to be associated with bacteriological eradication: absence of Pseudomonas aeruginosa (P < 0.01), higher weight (P < 0.01), a low APACHE II score (P = 0.03), and treatment with ciprofloxacin (P = 0.04). When P. aeruginosa was recovered from initial respiratory tract cultures, failure to achieve bacteriological eradication and development of resistance during therapy were common in both treatment groups (67 and 33% for ciprofloxacin and 59 and 53% for imipenem, respectively). Seizures were observed more frequently with imipenem than with ciprofloxacin (6 versus 1%; P = 0.028). These results demonstrate that in patients with severe pneumonia, monotherapy with ciprofloxacin is at least equivalent to monotherapy with imipenem in terms of bacteriological eradication and clinical response. For both treatment groups, the presence of P. aeruginosa had a negative impact on treatment success. Seizures were more common with imipenem than with ciprofloxacin. Monotherapy for severe pneumonia is a safe and effective initial strategy but may need to be modified if P. aeruginosa is suspected or recovered from patients.

Clinical and economic evaluation of oral ciprofloxacin after an abbreviated course of intravenous antibiotics.

PURPOSE: Oral ciprofloxacin has the requisite pharmacokinetic and antibacterial properties to rival the potency of intravenous antibiotics. This study was designed to determine whether oral ciprofloxacin could abbreviate the course of intravenous antibiotics in the treatment of serious infections. PATIENTS AND METHODS: Hospitalized adult patients were eligible for enrollment if they had a serious infection that was expected to require 8 or more days of intravenous antibiotic treatment. After conventional intravenous antibiotics were administered for 3 days, informed consent was obtained and patients were randomly assigned to either continue parenteral antibiotics (n = 53) or switch to oral ciprofloxacin 750 mg taken twice daily (n = 52). Ninety-nine of the 105 patients were evaluable for the assessment of efficacy. Clinical and bacteriologic efficacy, adverse events, and costs of the two treatments were compared. RESULTS: The two treatment groups were comparable for demographic characteristics, types of infections, bacteria isolated, initial intravenous antibiotic regimens, and duration of antibiotic treatment. The most common infections were of the skin and skin structure; bacteremia and infections of the lower respiratory tract, urinary tract, and bone and joint were also represented. The most commonly isolated pathogens were Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The most frequently prescribed intravenous antibiotics before randomization included aminoglycosides, cephalosporins, vancomycin, and nafcillin; 52 evaluable patients were treated with combination therapy while 47 received monotherapy. The clinical and bacteriologic outcomes and adverse reaction frequency with oral ciprofloxacin were comparable to those of the continued intravenous antibiotic regimens. Ciprofloxacin was associated with an average cost savings of $293 per patient. CONCLUSION: When used after 3 days of intravenous antibiotics, oral ciprofloxacin was as safe and effective as full courses of intravenous antibiotics and provided substantial cost savings.

Clinical and economic impact of oral ciprofloxacin as follow-up to parenteral antibiotics.

This study assessed the effects of switching to ciprofloxacin hydrochloride in patients initially treated with parenteral antibiotics for respiratory tract (RTI), skin or skin structure (SSS), bone or joint (BJI), or urinary tract infection (UTI). A total of 766 patients from 54 institutions were concurrently monitored and the projected effect of ciprofloxacin on duration of hospitalization and parenteral therapy was assessed based on previous experiences with each type of patient. The median duration of parenteral antibiotic therapy prior to oral ciprofloxacin was 4, 6, 6, and 7.5 days; the median duration of oral ciprofloxacin prior to discharge was 2, 2, 2, and 4 days for UTI, RTI, SSS, and BJI, respectively. It was estimated that more than 70 percent of patients would have continued parenteral antibiotics on an inpatient basis and only 10 percent would have received an alternative oral agent if ciprofloxacin were not available. Use of oral ciprofloxacin significantly affected both duration of parenteral therapy and duration of hospitalization. It was estimated that 16,732 doses of parenteral antibiotics were avoided and, after subtracting the cost of oral ciprofloxacin, resulted in a likely net savings of $187 146.50. An estimated total of 2266 hospital days were saved in 418 patients, resulting in estimated savings of $739 100. Total drug plus hospitalization cost savings were projected to be $980 246.50. Further research is required to determine if, and where, more aggressive intervention will achieve additional cost savings.

Kinetics and dynamics of tobramycin action in patients with bacteriuria given single doses.

We studied the effect of a single intravenous dose of tobramycin on the rate of bacterial eradication from urine in 10 patients with bladder catheters. The catheter was replaced 4 to 6 h after the tobramycin dose. Pseudomonas aeruginosa was found in 7 of the 10 patients, while members of the family Enterobacteriaceae accounted for the remaining pathogens. The MIC for each bacterium was determined in both broth and urine. Tobramycin eradicated the bacteria from eight patients. Bacteriuria resolved in 21.8 +/- 18.0 h, and urine bactericidal activity persisted for 43.4 +/- 20.3 h after the dose of tobramycin. Most patients were recolonized by another bacterial species if use of Foley catheters was resumed on a continuous basis. Two patients required additional doses of tobramycin to eradicate the original pathogen. There were significant temporal relationships between the pharmacokinetics of tobramycin and the change in colony count of bacteria in urine.

P&T Committee review of fluconazole: an effective alternative to antifungal therapy.

Fluconazole is a new antifungal agent available in both oral and parenteral formulations. According to the experts in this roundtable discussion, fluconazole represents a major clinical advance in the treatment of candidiasis and cryptococcosis in cancer patients, patients with AIDS, organ transplant recipients, and other patients at risk for opportunistic mycoses. The pharmacokinetic profile for fluconazole permits infrequent dosing and also makes it ideal for tissue site infections. Fluconazole's low toxicity gives it an advantage over currently available antifungal therapy and will permit prompt presumptive treatment of selected infections.

Evaluation of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections. Impact of plasma concentrations, organism, minimum inhibitory concentration, and clinical condition on bacterial eradication.

Fifty patients with gram-negative lower respiratory tract infections were treated with intravenous ciprofloxacin to evaluate efficacy and safety. Relationships between individual pharmacokinetics and clinical and bacteriologic outcome were studied. Ciprofloxacin concentrations in plasma were determined by high-performance liquid chromatography. Respiratory secretion cultures were obtained daily to determine the eradication day of the infecting organism. Susceptibility (minimum inhibitory concentration) to ciprofloxacin and other antimicrobials was determined using standard microdilution techniques. The mean age of the patients was 70 years. They had multiple underlying diseases, and two thirds of them were ventilator dependent at entry. Approximately 50% of the patients had failed previous treatment for the same infections. Patients infected with Enterobacteriaceae or Haemophilus influenzae with minimum inhibitory concentrations of less than 0.25 mg/L responded well to intravenous ciprofloxacin therapy (200 mg every 12 hours). The organisms were eradicated from sputum cultures usually within 1 day after ciprofloxacin therapy was started. Most clinical failures occurred in patients who were infected with Pseudomonas aeruginosa and had multiple underlying diseases. Pseudomonas aeruginosa was isolated from 10 patients with pneumonia, 2 patients with lung abscess, and 1 patient with bronchiectasis. The Pseudomonas isolate acquired resistance during ciprofloxacin treatment in 7 patients with pneumonia and in all of the remaining 3 patients. We conclude that ciprofloxacin is safe and effective at a dosage of 200 mg administered intravenously every 12 hours for nosocomial lower respiratory tract infections caused by Enterobacteriaceae or Haemophilus species. Many patients who had failed previous antibiotic treatment for Enterobacteriaceae infections had good clinical response to ciprofloxacin therapy. Studies using either higher dosages of ciprofloxacin or combination therapy should be conducted to determine if acquired resistance can be avoided in Pseudomonas infections.

Oral ciprofloxacin in the treatment of serious soft tissue and bone infections. Efficacy, safety, and pharmacokinetics.

Forty-eight patients were enrolled in a clinical study of oral ciprofloxacin for the treatment of soft tissue or bone infections. Patients received 500 to 750 mg of ciprofloxacin every 12 hours. In the predominantly older population studied, there were 13 patients with osteomyelitis, 24 diabetic patients with soft tissue infection and probable osteomyelitis, and 11 patients with other soft tissue infections. Infecting pathogens included Pseudomonas aeruginosa in 25 patients, Serratia species in nine patients, Staphylococcus aureus in 13 patients, and other aerobic gram-negative rods in 21 patients. Clinical response (defined as resolution or improvement) was noted in 84 percent of patients with non-diabetic osteomyelitis, in 79 percent of patients with diabetic infections, and in 91 percent of patients with soft tissue infections. Microbiologic outcome was very favorable in 75 percent of cases, and Pseudomonas responded as well as any other pathogen. Pharmacokinetic properties of ciprofloxacin were evaluated in 12 patients, and the data were analyzed using both compartmental and non-compartmental analyses. Mean values for compartmental rate constants (hours-1) were as follows: absorption rate constant = 1.15; intercompartmental rate constants, k12 = 0.48, and k21 = 0.58; elimination rate constant = 0.46; distribution rate constant = 1.31; and terminal elimination rate constant = 0.19. The apparent volume of distribution at steady state/bioavailability was 196 liters and total body clearance/bioavailability was 45.9 liters/hour. The mean time to peak concentration was 1.3 hours. The mean peak concentration as determined by compartmental fitting (2.4 micrograms/ml) underestimated the observed peak (3.2 micrograms/ml) by 24.8 percent. Clearance of ciprofloxacin was similar regardless of the method used to fit the data, whereas the volume of distribution was significantly different when the two analysis techniques were compared. Ciprofloxacin was well tolerated, with the most frequent adverse reactions being rash, gastrointestinal intolerance, and increased levels of liver enzymes, each of which occurred in five patients.

Treatment with aztreonam or tobramycin in critical care patients with nosocomial gram-negative pneumonia.

During the course of one year, 47 critical care patients with gram-negative bacillary pneumonia at Millard Fillmore Hospital were randomly assigned to aztreonam or tobramycin therapy (two to one). Of these, 40 were fully evaluable for microbiologic and clinical response. All evaluable patients had gram-negative organisms in tracheal aspirate culture specimens and confirmed susceptibility of the organism to both study drugs. There was no difference between the two groups with respect to the percentage of patients who received concurrent antibiotics for gram-positive organisms. More than 60 percent of the patients received mechanical ventilation. Essentially, all had new lung infiltrates as shown by chest radiography, leukocytosis, recent onset of fever, and increased volume of purulent secretions. Half had multilobar pulmonary infiltrates. Their mean age was 73 years, with none under age 50. Most had chronic obstructive pulmonary disease, congestive heart failure, or both. By the prognostic nutritional index criteria, over 70 percent were nutritionally deficient at entry. The majority of infections were caused by Pseudomonas, Enterobacter, Klebsiella, and Escherichia coli. Aztreonam eradicated 92 percent of the causative gram-negative organisms, compared with 57 percent for tobramycin (p less than 0.05). Aztreonam produced a favorable clinical response (cure or improvement) in 93 percent of patients, compared with 50 percent for tobramycin (p less than 0.05). There were no differences in the minor adverse effects observed in the two treatment groups. Overall, aztreonam was superior to tobramycin for treatment of pneumonia due to susceptible gram-negative bacteria in these critical care patients.

Clinical risk factors for prolonged PT/PTT in abdominal sepsis patients treated with moxalactam or tobramycin plus clindamycin.

Factors associated with prolongation of the prothrombin time were analyzed in 94 patients with intra-abdominal sepsis. Patients were randomized prospectively to receive either the combination of tobramycin and clindamycin (TM/C) or moxalactam (MOX). This paper presents a retrospective review designed to compare the frequency of prolonged clotting times and to analyze predisposing factors. Prothrombin time (PT) prolongation occurred more frequently in patients given moxalactam (19 of 47 patients) than in patients given the combination of tobramycin and clindamycin (9 of 47 patients) (p less than 0.05). Prolongation of the partial thromboplastin time (PTT) occurred in all patients with a prolonged PT. Liver disease, upper gastrointestinal surgery, and use of cimetidine were more frequent in those patients with abnormal PT/PTT values (p less than 0.05). Two moxalactam-treated patients with subsequent PT/PTT prolongation had individual clotting factors assayed before moxalactam treatment and at the time of detection of the abnormal PT. The activity of clotting factors II, VII, VIII, IX, X, and XII was reduced during MOX therapy. Treatment with vitamin K reversed the abnormality. In view of underlying abnormalities and rapid response to parenteral vitamin K, the mechanism is probably an acute vitamin K deficiency superimposed upon chronic vitamin K deficiency. In patients with intra-abdominal infection, those treated with MOX are more likely to develop abnormal PT than those treated with TM/C. Since abnormal PT/PTT was common even in TM/C patients, supplemental vitamin K should be considered for all seriously ill, older patients with abdominal infections.

Integration of pharmacokinetics and pharmacodynamics of methicillin in curative treatment of experimental endocarditis.

The rabbit model for Staphylococcus aureus endocarditis was used to compare cure rate and pharmacokinetic profile of four dosing regimens of methicillin. Equal daily doses (120 mg/kg) in five day treatment periods were given to 40 rabbits. Doses were given by bolus 20 mg/kg every 4 h (q 4 h), 40 mg/kg every 8 h (q 8 h), 60 mg/kg every 12 h (q 12 h) or by continuous infusion. The methicillin pharmacokinetics resulting from each regimen were monitored along with the course of the infection in each rabbit. For each regimen, time above MBC, peak height, area under the curve (AUC) above MIC and MBC were measured. Post antibiotic effect (PAE) duration and log growth time (LGT) values were obtained from the literature. Significantly more rabbits treated by q 4 h and q 8 h (P less than 0.05) survived 14 days after cessation of methicillin treatment than did rabbits treated q 12 h or continuous infusion. The four regimens differed in peak concentration and time above MBC. Despite producing the highest peak concentrations, the q 12 h regimen was the least effective. The duration above MBC was 2.0, 1.5, and 0.6 hours for q 12 h, q 8 h and q 4 h regimens, respectively. Continuous infusion produced methicillin concentration just above MBC over the entire five day treatment period, but was not as effective as q 4 h or q 8 h regimens. The most successful intermittent bolus regimens were those in which the sum of time above MBC, the duration of PAE, and one LGT were approximately equal to the actual dosage interval.