- Email: [email protected]
The influence of protein binding on in vivo effectiveness of antimicrobial agents
IIDNI Volume 9, Number 4, April 1990
Editor
Associate Editors
Charles W. Stratton, MD
Roger G. Finch, FRCP, MRC Path
Ruth M. Lawrence,
Department of Pathology Vanderbilt University Medical Center
Nottingham City Hospital Nottingham, United Kingdom
Veterans Administration Outpatient Clinic Sacramento, California
H. Bradford Hawley, MD
John T. Sinnott IV, MD
Wright State School of Medicine Dayton, Ohio
University of South Florida Tampa, Florida
Nashville, Tennessee
Richard F. Jacobs,
MD
MD
Arkansas Children's Hospital Little Rock, Arkansas
The Influence of Protein Binding on In Vivo Effectiveness of Antimicrobial Agents
~ontent~
Charles W. Stratton, M D
The Influence of Protein Binding on In Vivo Effectiveness of Antimicrobial Agents Charles W. Stratton
Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN
25
Cryptosporidium-induced Diarrhea: From the Exotic to the
Commonplace? Deborah J. Zygmunt CASE R E P O R T Grace M. Wesolow
28 29
Ofelia Calubiran Burke A. Cunha COMMENTS ON CURRENT PUBLICATIONS
Elsevier 0278-2316/90/$0.00 + 2.20
30
One of the factors often considered in the therapeutic selection of an antibiotic is the degree of protein binding, Unfortunately, the diverse effects of protein binding on the in vivo effectiveness of an antimicrobial agent are often not well appreciated. Protein binding has marked effects on both the pharmacokinetic disposition and the activity of antibiotics. The purpose of this article, then, is to review these diverse influences of protein binding on antimicrobial effectiveness.
Effect of Protein Binding on Serum Concentrations In the absence of significant renal tubular secretions, agents with the highest degree of protein binding (eg, ~>90%) possess higher serum concentrations over time and exhibit slower elimination (ie, have longer elimination half-lives). Higher serum concentrations may, in part, be due to the fact that most highly protein-bound
agents have smaller volumes of distribution due to less effective penetration of tissues. As relatively few infections are intravascular, these higher serum concentrations, per se, offer no therapeutic advantage.
Effect of Protein Binding on Tissue Concentrations Protein binding is a major factor that determines the penetration of antibiotics into tissue or tissue fluids where passive diffusion governs the influx of these agents. These tissues and tissue fluids include bone, muscle, skin, ascites, pleural effusion, and peritoneal fluid. Tissue sites with active transport mechanisms such as renal tubules, those with barriers such as CSF, those that are walled off to diffusion such as abscesses, and those that are excretory tissues such as the liver are governed by other factors besides protein binding in terms of antibiotic penetration. Penetration of antimicrobial agents
0278-2316 IDINDN 9(4) 25°32, 1990
26 Infectious Diseases NewsLetter 9(4) April 1990 must be preceded by dissociation of free molecules of antibiotic from their carrier macromolecules before diffusion through the vascular lining pores can occur. Bergan et al have noted a linear relationship between serum protein binding and the penetration ratio (defined as the area-under-thecurve values for peripheral lymph vs. serum) in humans. They also note that high serum protein binding i>90%) limits extravascular levels to approximately 20% of serum concentrations. Relative antimicrobial agent concentrations in lymph and serum (ie, the ratio between the area under the curve of these concentrations) can be predicted from serum protein binding. It appears, moreover, that the serum half-life is a major factor determining the passage of drug into lymph. Clearly, diffusion of free antibiotic takes time and thus the halflife becomes important. In sum, the penetration of antibiotics into tissue is more related to the total areas under the curve in serum than a concentration at a single point in time such as peak serum concentrations, Once free drug has entered extracellular fluids and tissues, protein binding then occurs in these fluids/ tissues because there is protein present in them. The antibiotic binding that occurs in these extravascular spaces can produce a reservoir effect with the bound antibiotic exhibiting a slower clearance from these extracellular fluids/tissues,
Effect of Protein Binding on Antimicrobial Activity A number of studies have suggested that the unbound fraction of an antibiotic is the pharmacologically active form. Merrikin and colleagues examined the in vivo effect of protein binding in an intraperitoneal infection
mouse model with Staphylococcus aureus by determining the in vitro and in vivo activity against S. aureus for a group of penicillins all belonging to the same class. An excellent relationship was determined to exist between the percentage of free antibiotic in mouse serum and the ultimate protective activity of these penicillins for 50% of the animals studied (LDs0). Similarly, Peterson et al have used an experimental rabbit model that simulates a closed-space infection in a neutropenic host in order to evaluate the influence of protein binding on the therapeutic efficacy of cefoperazone. Cefoperazone, as a member of the 13lactam class of antimicrobial agents, exhibits time-dependent killing of microorganisms suggesting that optimal killing will be achieved by maintaining the drug above the minimum inhibitory concentration (MIC). In this study done by Peterson's group, when the MIC for the infection bacteria was exceeded by the free cefoperazone concentration at the site of infection, the reduction of bacteria was enhanced significantly over that when the free drug level was below the MIC (p ~< 0.0005). This same group has studied synergy with an aminoglycoside and a 13-1actam and has found that in vitro synergy was predictive of in vivo success if the free antibiotic concentrations at the site of infection in the same infected chamber model in neutropenic rabbits exceeded the minimum bactericidal concentration (MBC) of the aminoglycoside when tested alone and the MBC of the 13-1actam agent when tested in combination with the aminoglycoside. Lam et al have evaluated in healthy volunteers the effect of protein binding for ceftazidime and cefoperazone by assessing the serum bactericidal activities and have clearly
shown in humans the potential for overestimating the activity of a highly protein-bound agent. Finally, Dudley and colleagues have expressed the relationship between the in vitro activity and in vivo pharmacokinetics of cefonicid as the area under the serum concentration time curve exceeding the MIC9o (AUC/MIC9o) of isolates of S. aureus in a given medium. Cefonicid provided an AUC/MIC90 of S. aureus in Mueller-Hinton broth (MHB) that was larger than that for cefazolin (643 vs. 224, respectively). Antibiotics tested in a 1:1 mixture of MHB and human serum resulted in a significant reduction in area for cefonicid, but not cefazolin (153 vs. 198, respectively).
Correlation of Free Drug Activity and Clinical Outcome Although the in vitro effects of protein binding on antimicrobial activity are well known, there continues to be debate as to the clinical relevance of this phenomenon. Chambers et al studied cefonicid for the therapy of staphylococcal endocarditis and found that this highly protein-bound agent failed to clear the blood of S. aureus or to produce a resolution of clinical findings by day 5 of therapy in three of four patients. This was despite measured peak serum concentrations in two patients that were 20 to 40 times the MIC for the infecting isolate. However, when human serum was added to the medium for susceptibility testing, MICs for the infecting isolates rose four- to eightfold and serum bactericidal titers were ~<1:8 at peak for all three patients who failed. Gelfand et al evaluated cefamandole or cefonicid for prophylactic efficacy in a prospective, randomized doubleblind study of 400 patients who received median sternotomies for
NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, producus, instructions or ideas contained in the material herein. No suggested test or procedure should he carried out unless, in the reader's judgment, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verfication of diagnoses and drug dosages should be made. Discussions, views and recommendations as to medical procedures, choice of drugs and drag dosages ate the responsibility of the authors. Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York I0010. Printed in USA at Hanover. PA 17331. Subscription price per year: institutions, $148.00; individuals, $86.00. For postage outside the U.S., add $37.00 (Canada and Mexico require no additional postage). Second-class postage paid at New York, NY, and at additional mailing offices Postmaster: Send address changes to Infectious Diseases Newsletter, Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York. New York 10010. © 1 9 9 0 E l s e v i e r S c i e n c e P u b l i s h i n g C o . , Inc. 0278-2316/90/$0.00 + 2.20
27 Infectious Diseases Newsletter 9(4) April 1990 elective cardiovascular surgery. They found that chest wound and donor site infections and early prosthetic valve
patients in order to predict what a 12 g/d dose of cefoperazone would produce in terms of extravascular levels
endocarditis occurred more frequently with cefonicid (11 patients) than with cefamandole (4 patients) (p = 0.05). They postulate that free cefonicid serum and tissue levels may have been too low. In yet another study evaluating teicoplanin for the therapy
of cefoperazone. Total mean levels in serum were predicted to range from 75 to 250 I~g/mL, whereas extravascular levels of free cefoperazone were predicted to range from 15 to 25 I~g/mL. This correlates nicely with the clinical observations of Bolivar.
of severe staphylococcal infections, Calain et al described 6 clinical failures of teicoplanin despite measured trough concentrations of total teicoplanin that exceeded the MIC for the infecting isolate of S. aureus by 50 to 35 times in four of these pa-
Summary Clearly, there is ample evidence for the importance of protein binding on the in vivo effectiveness of antimicrobial agents. Although protein binding may have a minimal influence
tients. Teicoplanin is a glycopeptide similar to vancomycin except that it is highly protein bound (1>90% vs. 50% for vancomycin) and has a longer half-life (32 hours vs. 6 hours for vancomycin); free drug in these four patients was noted to be less than the
on activity for bacteria that are exquisitely sensitive, it can become a limiting factor when dealing with moderate or marginally sensitive organisms. Protein binding also can limit the rate of penetration of antibiotics into extracellular fluids and
MIC even at peak concentrations, Warren and colleagues evaluated cefoperazone versus cefamandole-tobramycin for the empiric therapy for suspected gram-negative bacillary bacteremia in which patients in the cefoperazone group received 1.5 g of cefoperazone every 6 hours. The
tissues. Future studies should be focusing on the correlation of efficacy with area under the curve of free antibiotic as suggested by Barriere et al. This could be facilitated by the recent work by Leggett et al on the use of serum ultrafiltrates. It is in this manner that the pharmacokinetics and
outcome of patients with documented gram-negative bacillary bacteremia receiving this dosing schedule were predicted in a blinded manner based
pharmacodynamics of antimicrobial agents can best be correlated with clinical outcome.
on the predicted trough concentration of free drug being higher (success) or
Bibliography
human serum. J Infect Dis 148:178, 1983. Gelfand MS, Simmons, BP, Schoettle OB, et al: Cefamandole versus cefonicid prophylaxis in cardiovascular surgery: A prospective study. Ann Thorac Surg, in press. George RH: Influence of protein binding on antistaphylococcal activity of drugs. J Antimicrob Chemother 17:539-540, 1986. Kunin CM: Protein binding of antibiotics does affect their antistaphylococcal activity. J Antimicrob Chemother 17:263, 1986. Lam YWF, Duroux MH, Gambertoglio JG, et al: Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers. Antimicrob Agents Chemother 32:298-302, 1988. Leggett JE, Wolz SA, Craig WA: Use of serum ultrafiltrate in the serum dilution test. J Infect Dis 160:616-623, 1989.
Bamberger DM, Peterson LR, Gerding DN, et al: Ciprofloxacin, azlocillin, ceftizoxime and amikacin alone and in combination against gram-negative bacillin in an infected chamber model. J Antimicrob Chemother 18:51-63, 1986. Barriere SL, Ely E, Kapusnik JE: Analysis of a new method for assessing activity of combinations of antimicrobials: Area under the bactericidal curve. J Antimicrob Chemother 16:49-59, 1985. Bergan T, Engeset A, Olszewski W: Does serum protein binding inhibit tissue penetration of antibiotics? Rev Infect Dis 9:713-718, 1987. Bolivar R, Fainstein D, Elting K, et al: Cefoperazone for treatment of infections in patients with cancer. Rev Infect Dis 5(suppl 1):181-187, 1983.
Merrikin DJ, Briant J, Rolinson GN: Effect of protein binding on antibiotic activity in vivo. J Antimicrob Chemother 11:233-238,1983. Peterson LR, Moody JA, Fasching CE, et al: Influence of protein binding on therapeutic efficacy of cefoperazone. Antimicrob Agents Chemother 33:566-568, 1989. Warren JW, Miller EH, Fitzpatrick B, et al: A randomized, controlled trial of cefoperazone vs. cefamandole-tobramycin in the treatment of putative, severe infections with gram-negative bacilli. Rev Infect Dis 5:173, 1983. Wise R: The relevance of pharmacokinetics to in vitro models: Protein binding--Does it matter? J Antimicrob Chemother 15(suppl A):77-83, 1985.
lower (failure) than the MIC of the infecting isolate. Of ten patients, nine were correctly predicted. The single misprediction was a patient who died less than 24 hours after admission. Bolivar et al also evaluated cefoperazone (12 g/d) as single-agent therapy in cancer patients. These investigators were able to achieve success in 80% (44 of 55) of cases in which the infecting organism had an MIC for cefoperazone ~<25 I~g/mL. Therapeutic efficacy fell to 27% when the infecting organism had an MIC >125 wg/mL. Peterson used pharmacokinetic concepts on this group of
© 1990 Elsevier Science Publishing Co., Inc.
0278-2316/90/$0.00 + 2.20
Calain P, Krause KH, Vandaux P, et al: Early termination of a prospective, randomized trial comparing teicoplanin and flucloxacillin for tresting severe staphylococcal infections. J Infect Dis 155:187-191,1987. Chambers HF, Mills J, Drake TA, et al: Failure of a once-daily regimen of ce° fonicid for treatment of endocarditis due to Staphylococcus aureus. Rev Infect Dis 6(suppl 4):$870-$874, 1984. Drusano GL: Role of pharmacokinetics in the outcome of infections. Antimicrob Agents Chemother 32:289-297, 1988. Dudley MN, Nightingale CH, Quintiliani R, et al: In vitro activity of cefonicid, ceforanide, and cefazolin against Staphylococcus aureus and Staphylococcus epidermidis and the effect of
Editor
Associate Editors
Charles W. Stratton, MD
Roger G. Finch, FRCP, MRC Path
Ruth M. Lawrence,
Department of Pathology Vanderbilt University Medical Center
Nottingham City Hospital Nottingham, United Kingdom
Veterans Administration Outpatient Clinic Sacramento, California
H. Bradford Hawley, MD
John T. Sinnott IV, MD
Wright State School of Medicine Dayton, Ohio
University of South Florida Tampa, Florida
Nashville, Tennessee
Richard F. Jacobs,
MD
MD
Arkansas Children's Hospital Little Rock, Arkansas
The Influence of Protein Binding on In Vivo Effectiveness of Antimicrobial Agents
~ontent~
Charles W. Stratton, M D
The Influence of Protein Binding on In Vivo Effectiveness of Antimicrobial Agents Charles W. Stratton
Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN
25
Cryptosporidium-induced Diarrhea: From the Exotic to the
Commonplace? Deborah J. Zygmunt CASE R E P O R T Grace M. Wesolow
28 29
Ofelia Calubiran Burke A. Cunha COMMENTS ON CURRENT PUBLICATIONS
Elsevier 0278-2316/90/$0.00 + 2.20
30
One of the factors often considered in the therapeutic selection of an antibiotic is the degree of protein binding, Unfortunately, the diverse effects of protein binding on the in vivo effectiveness of an antimicrobial agent are often not well appreciated. Protein binding has marked effects on both the pharmacokinetic disposition and the activity of antibiotics. The purpose of this article, then, is to review these diverse influences of protein binding on antimicrobial effectiveness.
Effect of Protein Binding on Serum Concentrations In the absence of significant renal tubular secretions, agents with the highest degree of protein binding (eg, ~>90%) possess higher serum concentrations over time and exhibit slower elimination (ie, have longer elimination half-lives). Higher serum concentrations may, in part, be due to the fact that most highly protein-bound
agents have smaller volumes of distribution due to less effective penetration of tissues. As relatively few infections are intravascular, these higher serum concentrations, per se, offer no therapeutic advantage.
Effect of Protein Binding on Tissue Concentrations Protein binding is a major factor that determines the penetration of antibiotics into tissue or tissue fluids where passive diffusion governs the influx of these agents. These tissues and tissue fluids include bone, muscle, skin, ascites, pleural effusion, and peritoneal fluid. Tissue sites with active transport mechanisms such as renal tubules, those with barriers such as CSF, those that are walled off to diffusion such as abscesses, and those that are excretory tissues such as the liver are governed by other factors besides protein binding in terms of antibiotic penetration. Penetration of antimicrobial agents
0278-2316 IDINDN 9(4) 25°32, 1990
26 Infectious Diseases NewsLetter 9(4) April 1990 must be preceded by dissociation of free molecules of antibiotic from their carrier macromolecules before diffusion through the vascular lining pores can occur. Bergan et al have noted a linear relationship between serum protein binding and the penetration ratio (defined as the area-under-thecurve values for peripheral lymph vs. serum) in humans. They also note that high serum protein binding i>90%) limits extravascular levels to approximately 20% of serum concentrations. Relative antimicrobial agent concentrations in lymph and serum (ie, the ratio between the area under the curve of these concentrations) can be predicted from serum protein binding. It appears, moreover, that the serum half-life is a major factor determining the passage of drug into lymph. Clearly, diffusion of free antibiotic takes time and thus the halflife becomes important. In sum, the penetration of antibiotics into tissue is more related to the total areas under the curve in serum than a concentration at a single point in time such as peak serum concentrations, Once free drug has entered extracellular fluids and tissues, protein binding then occurs in these fluids/ tissues because there is protein present in them. The antibiotic binding that occurs in these extravascular spaces can produce a reservoir effect with the bound antibiotic exhibiting a slower clearance from these extracellular fluids/tissues,
Effect of Protein Binding on Antimicrobial Activity A number of studies have suggested that the unbound fraction of an antibiotic is the pharmacologically active form. Merrikin and colleagues examined the in vivo effect of protein binding in an intraperitoneal infection
mouse model with Staphylococcus aureus by determining the in vitro and in vivo activity against S. aureus for a group of penicillins all belonging to the same class. An excellent relationship was determined to exist between the percentage of free antibiotic in mouse serum and the ultimate protective activity of these penicillins for 50% of the animals studied (LDs0). Similarly, Peterson et al have used an experimental rabbit model that simulates a closed-space infection in a neutropenic host in order to evaluate the influence of protein binding on the therapeutic efficacy of cefoperazone. Cefoperazone, as a member of the 13lactam class of antimicrobial agents, exhibits time-dependent killing of microorganisms suggesting that optimal killing will be achieved by maintaining the drug above the minimum inhibitory concentration (MIC). In this study done by Peterson's group, when the MIC for the infection bacteria was exceeded by the free cefoperazone concentration at the site of infection, the reduction of bacteria was enhanced significantly over that when the free drug level was below the MIC (p ~< 0.0005). This same group has studied synergy with an aminoglycoside and a 13-1actam and has found that in vitro synergy was predictive of in vivo success if the free antibiotic concentrations at the site of infection in the same infected chamber model in neutropenic rabbits exceeded the minimum bactericidal concentration (MBC) of the aminoglycoside when tested alone and the MBC of the 13-1actam agent when tested in combination with the aminoglycoside. Lam et al have evaluated in healthy volunteers the effect of protein binding for ceftazidime and cefoperazone by assessing the serum bactericidal activities and have clearly
shown in humans the potential for overestimating the activity of a highly protein-bound agent. Finally, Dudley and colleagues have expressed the relationship between the in vitro activity and in vivo pharmacokinetics of cefonicid as the area under the serum concentration time curve exceeding the MIC9o (AUC/MIC9o) of isolates of S. aureus in a given medium. Cefonicid provided an AUC/MIC90 of S. aureus in Mueller-Hinton broth (MHB) that was larger than that for cefazolin (643 vs. 224, respectively). Antibiotics tested in a 1:1 mixture of MHB and human serum resulted in a significant reduction in area for cefonicid, but not cefazolin (153 vs. 198, respectively).
Correlation of Free Drug Activity and Clinical Outcome Although the in vitro effects of protein binding on antimicrobial activity are well known, there continues to be debate as to the clinical relevance of this phenomenon. Chambers et al studied cefonicid for the therapy of staphylococcal endocarditis and found that this highly protein-bound agent failed to clear the blood of S. aureus or to produce a resolution of clinical findings by day 5 of therapy in three of four patients. This was despite measured peak serum concentrations in two patients that were 20 to 40 times the MIC for the infecting isolate. However, when human serum was added to the medium for susceptibility testing, MICs for the infecting isolates rose four- to eightfold and serum bactericidal titers were ~<1:8 at peak for all three patients who failed. Gelfand et al evaluated cefamandole or cefonicid for prophylactic efficacy in a prospective, randomized doubleblind study of 400 patients who received median sternotomies for
NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, producus, instructions or ideas contained in the material herein. No suggested test or procedure should he carried out unless, in the reader's judgment, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verfication of diagnoses and drug dosages should be made. Discussions, views and recommendations as to medical procedures, choice of drugs and drag dosages ate the responsibility of the authors. Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York I0010. Printed in USA at Hanover. PA 17331. Subscription price per year: institutions, $148.00; individuals, $86.00. For postage outside the U.S., add $37.00 (Canada and Mexico require no additional postage). Second-class postage paid at New York, NY, and at additional mailing offices Postmaster: Send address changes to Infectious Diseases Newsletter, Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York. New York 10010. © 1 9 9 0 E l s e v i e r S c i e n c e P u b l i s h i n g C o . , Inc. 0278-2316/90/$0.00 + 2.20
27 Infectious Diseases Newsletter 9(4) April 1990 elective cardiovascular surgery. They found that chest wound and donor site infections and early prosthetic valve
patients in order to predict what a 12 g/d dose of cefoperazone would produce in terms of extravascular levels
endocarditis occurred more frequently with cefonicid (11 patients) than with cefamandole (4 patients) (p = 0.05). They postulate that free cefonicid serum and tissue levels may have been too low. In yet another study evaluating teicoplanin for the therapy
of cefoperazone. Total mean levels in serum were predicted to range from 75 to 250 I~g/mL, whereas extravascular levels of free cefoperazone were predicted to range from 15 to 25 I~g/mL. This correlates nicely with the clinical observations of Bolivar.
of severe staphylococcal infections, Calain et al described 6 clinical failures of teicoplanin despite measured trough concentrations of total teicoplanin that exceeded the MIC for the infecting isolate of S. aureus by 50 to 35 times in four of these pa-
Summary Clearly, there is ample evidence for the importance of protein binding on the in vivo effectiveness of antimicrobial agents. Although protein binding may have a minimal influence
tients. Teicoplanin is a glycopeptide similar to vancomycin except that it is highly protein bound (1>90% vs. 50% for vancomycin) and has a longer half-life (32 hours vs. 6 hours for vancomycin); free drug in these four patients was noted to be less than the
on activity for bacteria that are exquisitely sensitive, it can become a limiting factor when dealing with moderate or marginally sensitive organisms. Protein binding also can limit the rate of penetration of antibiotics into extracellular fluids and
MIC even at peak concentrations, Warren and colleagues evaluated cefoperazone versus cefamandole-tobramycin for the empiric therapy for suspected gram-negative bacillary bacteremia in which patients in the cefoperazone group received 1.5 g of cefoperazone every 6 hours. The
tissues. Future studies should be focusing on the correlation of efficacy with area under the curve of free antibiotic as suggested by Barriere et al. This could be facilitated by the recent work by Leggett et al on the use of serum ultrafiltrates. It is in this manner that the pharmacokinetics and
outcome of patients with documented gram-negative bacillary bacteremia receiving this dosing schedule were predicted in a blinded manner based
pharmacodynamics of antimicrobial agents can best be correlated with clinical outcome.
on the predicted trough concentration of free drug being higher (success) or
Bibliography
human serum. J Infect Dis 148:178, 1983. Gelfand MS, Simmons, BP, Schoettle OB, et al: Cefamandole versus cefonicid prophylaxis in cardiovascular surgery: A prospective study. Ann Thorac Surg, in press. George RH: Influence of protein binding on antistaphylococcal activity of drugs. J Antimicrob Chemother 17:539-540, 1986. Kunin CM: Protein binding of antibiotics does affect their antistaphylococcal activity. J Antimicrob Chemother 17:263, 1986. Lam YWF, Duroux MH, Gambertoglio JG, et al: Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers. Antimicrob Agents Chemother 32:298-302, 1988. Leggett JE, Wolz SA, Craig WA: Use of serum ultrafiltrate in the serum dilution test. J Infect Dis 160:616-623, 1989.
Bamberger DM, Peterson LR, Gerding DN, et al: Ciprofloxacin, azlocillin, ceftizoxime and amikacin alone and in combination against gram-negative bacillin in an infected chamber model. J Antimicrob Chemother 18:51-63, 1986. Barriere SL, Ely E, Kapusnik JE: Analysis of a new method for assessing activity of combinations of antimicrobials: Area under the bactericidal curve. J Antimicrob Chemother 16:49-59, 1985. Bergan T, Engeset A, Olszewski W: Does serum protein binding inhibit tissue penetration of antibiotics? Rev Infect Dis 9:713-718, 1987. Bolivar R, Fainstein D, Elting K, et al: Cefoperazone for treatment of infections in patients with cancer. Rev Infect Dis 5(suppl 1):181-187, 1983.
Merrikin DJ, Briant J, Rolinson GN: Effect of protein binding on antibiotic activity in vivo. J Antimicrob Chemother 11:233-238,1983. Peterson LR, Moody JA, Fasching CE, et al: Influence of protein binding on therapeutic efficacy of cefoperazone. Antimicrob Agents Chemother 33:566-568, 1989. Warren JW, Miller EH, Fitzpatrick B, et al: A randomized, controlled trial of cefoperazone vs. cefamandole-tobramycin in the treatment of putative, severe infections with gram-negative bacilli. Rev Infect Dis 5:173, 1983. Wise R: The relevance of pharmacokinetics to in vitro models: Protein binding--Does it matter? J Antimicrob Chemother 15(suppl A):77-83, 1985.
lower (failure) than the MIC of the infecting isolate. Of ten patients, nine were correctly predicted. The single misprediction was a patient who died less than 24 hours after admission. Bolivar et al also evaluated cefoperazone (12 g/d) as single-agent therapy in cancer patients. These investigators were able to achieve success in 80% (44 of 55) of cases in which the infecting organism had an MIC for cefoperazone ~<25 I~g/mL. Therapeutic efficacy fell to 27% when the infecting organism had an MIC >125 wg/mL. Peterson used pharmacokinetic concepts on this group of
© 1990 Elsevier Science Publishing Co., Inc.
0278-2316/90/$0.00 + 2.20
Calain P, Krause KH, Vandaux P, et al: Early termination of a prospective, randomized trial comparing teicoplanin and flucloxacillin for tresting severe staphylococcal infections. J Infect Dis 155:187-191,1987. Chambers HF, Mills J, Drake TA, et al: Failure of a once-daily regimen of ce° fonicid for treatment of endocarditis due to Staphylococcus aureus. Rev Infect Dis 6(suppl 4):$870-$874, 1984. Drusano GL: Role of pharmacokinetics in the outcome of infections. Antimicrob Agents Chemother 32:289-297, 1988. Dudley MN, Nightingale CH, Quintiliani R, et al: In vitro activity of cefonicid, ceforanide, and cefazolin against Staphylococcus aureus and Staphylococcus epidermidis and the effect of