Lawrence V. Friedrich

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

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

Comparison of methods of interpretation of checkerboard synergy testing

Four different methods for interpreting the results of checkerboard synergy testing were compared by applying each to a set of synergy study data. Statistically significant differences in synergy were detected among methods (% synergy ranged from 10 to 83%). As interpretations were found to vary widely based upon method, one should be aware of this in interpreting the relevant literature.

Assessment of the Relationship between Antimicrobial Usage and Susceptibility: Differences between the Hospital and Specific Patient-Care Areas

Current evidence suggests that controlling antibiotic resistance requires the monitoring of both susceptibility trends and antimicrobial usage within specific patient-care areas of the hospital. To assess the differences between antimicrobial usage-versus-susceptibility relationships found in the hospital and those relationships found in specific patient-care areas, susceptibility and antimicrobial usage data collected over a 5-year period (1992-1996) at the Medical University of South Carolina were analyzed. For each area, the relationship between drug use and susceptibility was analyzed for 8 gram-negative organisms with respect to 19 different agents and for 3 staphylococci with respect to 10 agents with use of simple linear regression. The relationships found in the hospital had a poorer overall agreement with the relationships found in the intensive care units (ICUs; <20%) than they did with the relationships found in the non-ICUs ( approximately 65%). Surveillance should include both susceptibility and drug usage patterns in individual areas within an institution.

Fatal hypoglycemia associated with levofloxacin

Fluoroquinolones are generally regarded as safe antimicrobial agents with relatively few adverse effects or drug interactions. Thus, they enjoy widespread use for treatment of community‐ and hospital‐acquired infections. Although uncommon, hypoglycemia has been reported with all the fluoroquinolones and appears to occur most frequently in elderly patients with type 2 diabetes mellitus who are receiving therapy with oral hypoglycemics. The exact mechanism of this effect is unknown but is postulated to be a result of blockage of adenosine 5′‐triphosphate–sensitive potassium channels in pancreatic β‐cell membranes. We report a case of fatal hypoglycemia related to levofloxacin administration in an elderly patient with diabetes. As with other fluoroquinolones, levofloxacin can cause profound and prolonged hypoglycemia. Clinicians should be cognizant of this potential adverse effect in patients with diabetes who are receiving levofloxacin therapy.

Impact of Use of Multiple Antimicrobials on Changes in Susceptibility of Gram-Negative Aerobes

Evaluation of antimicrobial usage vs. susceptibility relationships typically involves single agents. However, susceptibility profiles may be affected by multiple drugs. From 1992 through 1996, we studied relationships between drug usage and the susceptibility (only susceptibility rates of > or = 70%) of Acinetobacter anitratus (baumannii), Enterobacter aerogenes, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Serratia marcescens to 22 agents. Linear regression was used to assess usage of each agent vs. susceptibility to it and to all agents. Only relationships with a coefficient of determination of > or = 0.5 and a negative slope were evaluated and classified as increasing drug use and decreasing susceptibility (increasing D, decreasing %S) or decreasing drug use and increasing susceptibility (decreasing D, increasing %S). The mean numbers (range) of drugs associated with a change in susceptibility were 1.7 (0-14) and 0.6 (0-7), respectively, for increasing D, decreasing %S and decreasing D, increasing %S relationships. Multiple antimicrobials are associated with susceptibility to other drugs; thus, surveillance of these relationships should not be limited to single drugs.

Aztreonam pharmacokinetics in burn patients.

The pharmacokinetics of aztreonam in eight adult patients with severe burn injuries (total body surface area burn, 49% +/- 21% [mean +/- standard deviation]) were studied. The time of initiation of study following burn injury was 7.0 +/- 1.4 days. Four patients at first dose and at steady state were studied. Aztreonam concentrations were measured by high-performance liquid chromatography, and a two-compartment model was used to fit the data. No significant differences in any pharmacokinetic parameters between first dose and steady state were observed. Volume of distribution of the central compartment after first dose (0.14 liters/kg) and volume of distribution at steady state (0.31 liters/kg) were approximately 30% higher than those reported for other patient populations. Total drug clearance and renal drug clearance when normalized to creatinine clearance (CLCR) were similar to those previously reported for other critically ill patients. CLCR was strongly correlated with renal drug clearance (r = 0.94) and total drug clearance (r = 0.95). The extent and degree of burn (percent second or third degree burn) were poorly correlated with all pharmacokinetic parameters with the exception of the volume of distribution at steady state, which was correlated with both total body surface area burn (r = 0.95) and percent second degree burn (r = 0.83). Aztreonam pharmacokinetics are altered as a result of thermal injury; however, CLCR can be used to assess the clearance of aztreonam in burn patients.

Effect of removal of duplicate isolates on cumulative susceptibility reports

The objective of our study is to assess the impact of different methods of duplicate isolate removal on cumulative susceptibility reports. Over a 1-year period, we studied the effect of 3 methods of duplicate isolate removal on the cumulative percentage susceptibility of 9 Gram-negative bacilli to 15 antimicrobials. Raw data from which no duplicate isolates were removed (NR) were generated by the Sensititre breakpoint susceptibility testing system. D3 and D7 were methods of duplicate isolate removal defined as follows: same patient, bacterial species, irrespective of susceptibility within either three (D3) or seven (D7) calendar days of the date of the previous culture. The third method evaluated was an algorithm utilized by Cerner, a laboratory management program that defines duplicate isolates as follows: same patient, bacterial species, and NCCLS susceptibility category to an individual antimicrobial. Differences in percentage susceptibility between the three methods of duplicate isolate removal and NR were assessed. The number of isolates studied ranged from 80 (E. aerogenes) to 681 (P. aeruginosa). Of the methods of duplicate isolate removal, the highest percentage susceptibility occurred most frequently with Cerner followed by D7 and D3. Differences in percentage susceptibility between methods of removal and NR ranged from -11 to 25%, -5 to 8%, and -3 to 10%, with Cerner, D3, and D7, respectively. The percentage susceptibility was at least 5% higher than NR with a method of removal for 15 individual organism/antimicrobial combinations in which susceptibility was > or = 70% by at least one of the methods. These occurred most frequently with Enterobacter species and Cerner. Although there is no consensus on the ideal method of duplicate isolate removal, one should be cognizant that these manipulations may produce different cumulative susceptibility reports.

The Effect of Tourniquet Inflation on Cefazolin Tissue Penetration During Total Knee Arthroplasty

Patients undergoing total knee arthroplasty were randomized to tourniquet inflation 1, 2, or 5 minutes after a 1‐g dose of cefazolin. Serum, soft tissue, and bone samples were obtained at 10, 30, and 60 minutes after inflation, immediately prior to tourniquet release (PTR), and 5 minutes after release. Areas under the concentration‐time curve (AUC10‐PTR) were calculated using the linear trapezoidal method and normalized to actual body weight, creatinine clearance, and length of tourniquet inflation. The percentage of penetration was calculated using the normalized values for the respective AUCs. Differences among the groups were analyzed using analysis of variance or the Kruskal‐Wallis test where appropriate. Groups were similar for age, actual body weight, duration of tourniquet inflation, and creatinine clearance (p > 0.05). The median percentages of penetration for soft tissue and bone at 5, 2, and 1 minute were 14.5% and 4.6%, 6.7% and 3.0%, and 5.9% and 4.6%, respectively. Only the percentage of soft tissue penetration between 5 and 1 minute was significantly different (p = 0.015). Gender and type of anesthesia (general, epidural) had no effect on cefazolin penetration into soft tissue or bone. Although increasing the time interval between cefazolin administration and tourniquet inflation resulted in higher soft tissue drug concentrations, a 1 ‐ minute interval resulted in soft tissue and bone cefazolin concentrations at or above the minimum inhibitory concentration for microorganisms likely to be encountered in this surgical procedure.

Pharmacodynamics of trimethoprim-sulfamethoxazole in Listeria meningitis: a case report.

Infections in the cerebrospinal fluid (CSF) occur in an area of impaired host defenses; therefore, bactericidal antibiotics that reach adequate concentrations in the CSF are necessary for treatment. Measurements of antibiotic penetration into the CSF include CSF inhibitory and bactericidal titers, the absolute antibiotic concentration in the CSF, and the CSF: serum concentration ratio. We present the case of a patient with Listeria monocytogenes meningitis who failed to respond clinically to standard therapy, and whose organism demonstrated tolerance to Ampicillin (MBC: MIC = 258: 1) that successfully responded to trimethoprim‐sulfamethoxazole (TMP‐SMX). The CSF peak bactericidal titer to TMP‐SMX was 1:8, corresponding to that reported as necessary for successful outcome in patients with meningitis. The CSF peak: MBC ratios for TMP and SMX were less than 3:1 and equal to 3:1, respectively. These individual ratios are lower than those suggested for successful treatment of meningitis; however, the recommended ratios were established using single agents and did not account for synergistic activity with a drug combination such as TMP‐SMX. The failure of standard therapy in this patient underscores the importance of MIC/MBC testing when tolerance is suspected or when CSF penetration of antibiotics is relatively poor. In addition, measurements of CSF inhibitory and bactericidal titers, which incorporate the antibiotic concentration in the CSF, susceptibility of the infecting microorganism, and host defense factors, may be useful in monitoring patients with meningitis.

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

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