Contrary to the literature about drug removal during hemodialysis, data regarding drug removal during plasmapheresis are sparse. Over the last 40 years, approximately 70 publications-mostly case reports of overdoses-have described the effects of plasmapheresis on pharmaceutical agents. Important issues are drug extraction during plasma exchange with chemotherapy, as well as drug classes such as antiinfectives, anticoagulants, antiepileptics, cardiovascular agents, and immunosuppressants. Other considerations are the merits and pitfalls of the different methods used in published reports and recommendations for future pharmacokinetic studies in this field.

An in vitro model was used to compare the effects of linezolid, clindamycin, and penicillin, alone and in combination, on streptococcal pyrogenic exotoxin A (SPE A) release against virulent group A streptococci (GAS). All regimens exhibited lower (P < 0.05) SPE A release at 1 h than those with penicillin alone. Linezolid and clindamycin, alone or in combination with penicillin, may optimize the treatment of GAS infections by reducing bacterial burden and exotoxin release.Management of severe infections due to Streptococcus pyogenes requires aggressive antibiotic treatment and supportive measures. S. pyogenes continues to be susceptible to penicillin and other ␤-lactam antibiotics. Although penicillin remains the drug of choice for uncomplicated S. pyogenes infections, the overall response to treatment with penicillin has decreased and can be associated with high morbidity and mortality (4,5,17,18). Clindamycin, whether used in monotherapy or in combination with antimicrobial agents, has been shown to be beneficial in in vitro evaluations and in the clinical treatment of invasive S. pyogenes infections (5,11,18). Linezolid is active against S. pyogenes and is similar to clindamycin in that it inhibits protein synthesis by binding to the 50S ribosomal subunit and exhibits a relatively long postantibiotic effect (3,22,23). In an effort to characterize the effects of antimicrobial agents on bacterial killing and the exotoxin release of S. pyogenes, we simulated regimens of linezolid, penicillin, and clindamycin, alone and in combination, by using an in vitro model. A known streptococcal pyrogenic exotoxin A (SPE A)-producing S. pyogenes isolate (MGAS166; hereafter referred to as 166) and its hypervirulent mutant (MGAS2616; hereafter referred to as 2616) were acquired from Cary Engleberg at the University of Michigan (Ann Arbor, Mich.) (8, 13). Susceptibility testing was determined by broth microdilution according to NCCLS guidelines (14).Todd-Hewitt broth supplemented with 0.5% yeast extract (Difco Laboratories, Detroit, Mich.) was utilized for implementation of the previously described in vitro pharmacodynamic models (2). Simulated regimens included linezolid (Pharmacia, Kalamazoo, Mich.) at 600 mg every 12 h, clindamycin (Sigma Chemical Co., St. Louis, Mo.) at 900 mg every 8 h, and penicillin G (Sigma Chemical Co.) at 4,000,000 U every 4 h. In addition, combinations of penicillin and clindamycin, penicillin and linezolid, and clindamycin and linezolid were evaluated. A peristaltic pump (Masterflex; Cole-Parmer Instrument Company, Chicago, Ill.) was used to simulate the half-lives of linezolid (6 h), clindamycin (3 h), and penicillin G (1 h). For the combination regimens, an additional supplemental compartment was used to compensate for different halflives (1). Growth control simulations were performed at the shortest half-life of the tested antimicrobial agents (1 h). Each model was placed in a water bath and maintained at 37°C for the entire 24-h study period. Model experiments were performed in duplicate to ensu...

Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log 10 CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED 50 ) and 80% (ED 80 ) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 g/ml. Model fitting resulted in an r 2 of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log 10 CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED 50 and ED 80 values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED 50 and ED 80 values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED 80 values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED 80 ) against these multidrug-resistant S. aureus and E. faecium isolates.

Use of combinations of antimicrobials that together achieve synergistic activities against targeted microorganisms is one potential strategy for overcoming bacterial resistance. As the incidence of infections caused by multidrug-resistant staphylococci and enterococci increases, the importance of devising additional synergistic drug combinations for these bacteria is magnified. We evaluated a number of antimicrobial combinations, with a focus on quinupristin-dalfopristin (Q-D), cefepime, and linezolid, using a previously described in vitro pharmacodynamic model.