a Departments of Pediatrics, b Microbiology and Immunology, Baylor College of Medicine, c Infectious Disease Laboratory, Texas Children's Hospital, Houston, TX 77030; d BristolMyers Squibb, Plainsboro, NJ 08536, USA
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The NCCLS publishes guidelines for the interpretation of susceptibility results of S. pneumoniae using defined methods and conditions. S. pneumoniae breakpoints for the interpretation of results on susceptibility to the oral cephalosporins other than cefuroxime are not yet defined. Instead, the guidelines state that susceptibility to commonly used ß-lactams can be inferred by susceptibility to penicillin.6 A recent study raises concerns about using a single breakpoint for all oral cephalosporins because of previous studies showing therapeutic failures in the treatment with cephalosporin antibiotics of otitis media caused by pneumococci that were considered susceptible in vitro.7
We report results of surveillance of a large number of S. pneumoniae isolates from a variety of infections and clinical settings in the USA to demonstrate regional trends in susceptibility patterns and to test the correlation between penicillin susceptibility and oral cephalosporin susceptibility.
In vitro susceptibility does not always correlate with clinical success, which is also dependent upon drug-specific pharmacokinetics. Pharmacodynamics is a science that integrates microbiological and pharmacokinetic data. Therefore, on the basis of the susceptibility data we collected in this study and published pharmacokinetic data, we performed a pharmacodynamic analysis. This type of analysis may help estimate the clinical relevance of in vitro activity.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A total of 5344 organisms identified by 92 laboratories in the continental USA as S. pneumoniae were submitted to the Infectious Disease Laboratory at Texas Children's Hospital, Houston, between June 1996 and April 1997. This study included mostly community hospitals and six children's hospitals, and the laboratories sent sequential isolates during the study period. Duplicate isolates from the same patient were excluded from analysis. Antibiotic susceptibility by agar dilution was attempted on all isolates. Contaminated cultures (840) and fastidiously growing isolates (15) were excluded for expediency from further study. A total of 4489 isolates was found suitable for evaluation. Patient information collected included anatomical site of isolation, age, gender and whether collected from in-patients or out-patients.
MICs were determined by the agar dilution method of the NCCLS.8 Dilutions of antibiotics were incorporated into plates containing MuellerHinton agar (BBL Microbiology Systems, Cockeysville, MD, USA) supplemented with 3% lysed horse blood (final concentration). The inoculum was prepared from overnight growth on sheep blood agar and adjusted to a turbidity equal to a 0.5 McFarland standard. A 1:10 dilution of this preparation with Mueller Hinton broth reliably resulted in an inoculum of (36) x 104 cfu per replicator spot, as determined by quantitative culture. Plates were incubated at 35°C for 2022 h without CO2. S. pneumoniae ATCC isolate 49619, with a penicillin MIC of 0.25 mg/L, was used as a control.
All isolates were tested for susceptibility to penicillin and cefprozil (BristolMyers Squibb, Princeton, NJ, USA), amoxycillin and amoxycillin/clavulanic acid (SmithKline Beecham, Philadelphia, PA, USA), azithromycin (Pfizer Pharmaceuticals, Groton, CT, USA), clarithromycin (Abbott Laboratories, Chicago, IL, USA), cefaclor, erythromycin and loracarbef (Eli Lilly, Indianapolis, IN, USA), cefixime (Lederle Laboratories, Pearl River, NY, USA), cefpodoxime (Pharmacia & Upjohn, Kalamazoo, MI, USA) and cefuroxime (Glaxo Wellcome, Uxbridge, UK). Penicillin susceptibility was determined between 0.03 and 16 mg/L. Susceptibility to the other 11 antibiotics was determined between 0.125 and 64 mg/L. NCCLS guidelines for penicillin are: susceptibility (S) defined as an MIC < 0.1 mg/L, intermediate (I) as an MIC between 0.1 and 1.0 mg/L, and resistant (R) as an MIC > 1.0 mg/L.8 Breakpoints for azithromycin are: susceptible 0.5 mg/L, intermediate 1 mg/L and resistant
2.0 mg/L; for clarithromycin and erythromycin: susceptible
0.25 mg/L, intermediate 0.5 mg/L and resistant
1.0 mg/L.
Pharmacodynamic analysis
Pharmacokinetic data from published sources, including concentrationtime curves, for each of the antimicrobials were collected. Pharmacokinetic concentrationtime curves for the suspension formulations were used whenever possible. If complete time points for a drug's dosing interval were not available, then the data were extrapolated based on the drug's half-life. The drugs, dosage and dosing interval (dosing interval based on the package insert) used to calculate the pharmacokinetics/pharmacodynamics were as follows: cefprozil 15 mg/kg q12h,9 cefaclor 13.3 mg/ kg q8h,10 cefuroxime 15 mg/kg q12h, cefpodoxime 5 mg/kg q12h, cefixime 200 mg q24h, loracarbef 15 mg/kg q12h, amoxycillin 250 mg q8h and azithromycin 500 mg suspension q24h.11
The percentage of the dosing interval that the drug plasma concentration was above the geometric mean MIC was obtained from the plasma concentrationtime curves for the oral cephalosporins cited in the literature or package insert. Geometric mean, which measures the central tendency of a population by stabilizing the value of the outliers, was calculated for the MIC of each antibiotic from the anti-log of the mean of the natural logarithms.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
The predicted plasma concentrations of all cephalosporins tested exceeded the geometric mean MIC for at least 40% of the dosing interval for penicillin-susceptible S. pneumoniae (cefprozil 100%, cefuroxime 100%, cepodoxime 94%, cefixime 69%, loracabef 43% and cefaclor 40%). For penicillin-intermediate S. pneumoniae, only cefprozil (56%), cefuroxime (64%) and cefpodoxime (63%) reached >40% of time above the geometric mean MIC in the dosing interval, whereas loracarbef (17%), cefixime (0%) and cefaclor (0%) failed to reach 40% of the above the geometric mean during the dosing interval. None of the cephalosporins evaluated achieved a significant time above the geometric mean MIC during its dosing interval for fully penicillin-resistant S. pneumoniae.
The percentage of the dosing interval in which the drug plasma concentration is above the MIC was plotted against the MIC for selected antibacterials tested in this in vitro study (Figure). Cefprozil (15 mg/kg), which is dosed q12h, exceeded 40% time above the MIC at an MIC of 2 mg/L. Two mg/L was the maximum MIC for which any drug exceeded 40% time above the MIC. However, amoxycillin (250 mg q8h), cefaclor (13.3 mg/kg q8h), cefpodoxime (5 mg/kg q12h), cefuroxime (15 mg/kg q12h) and loracarbef (15 mg/kg q12h) achieved approximately 40% time above the MIC at 1 mg/L. Cefixime (200 mg q24h) achieved 35% time above the MIC at an MIC of 1 mg/L and achieved over 40% at 0.5 mg/L.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Whereas pharmacokinetics is the science of the absorption, distribution, metabolism and elimination of a drug, pharmacodynamics correlates the plasma concentration of the drug with its pharmacological effect. For antibiotics, pharmacodynamics describes the relationship between drug concentration and its ability to kill or inhibit the growth of microorganisms. For decades, many clinicians have applied pharmacodynamic principles to explain clinical efficacy.1921 The results from these previous studies have led to changes in dosing regimens for various antimicrobials.22,23
Classifying antibiotics based on their bactericidal activity profile has been done previously. The efficacy of concentration-dependent antibiotics such as aminoglycosides and fluoroquinolones depends largely on the drug's peak serum concentration,24 whereas the efficacy of time-dependent antimicrobials such as ß-lactams and macrolides depends on its time of exposure.21,25,26 As this in vitro study evaluates only time-dependent antibiotics, we applied the latter pharmacodynamic principles.
Animal models of infection and human clinical outcome data have demonstrated that antibiotic concentrations do not have to exceed the MIC for the entire dosing interval to maximize antibacterial effect. In animals infected with S. pneumoniae and treated with cephalosporins, survival approached 100% when the duration of time that serum concentrations exceeded the MIC was 40% of the dosing interval.26 Data from trials in children with acute otitis media that have included tympanocentesis of middle ear fluid to determine S. pneumoniae eradication have indicated that the time above the MIC of >40% correlates with an 85100% bacteriological cure rate when treated with cephalosporins.27 These data are further supported by the observation that there was no difference in clinical outcome when hospitalized patients were treated with either intermittent or continuous infusion cefuroxime in the therapy of community-acquired pneumonia.28
In the current analysis, penicillin susceptibilities had a significant impact on the time above the MIC. Plasma concentrations for all of the oral cephalosporins achieved this clinically relevant 40% time above the geometric mean MIC for penicillin-susceptible S. pneumoniae. However, in penicillin-intermediate S. pneumoniae, only cefprozil, cefuroxime and cefpodoxime achieved clinically substantial time above the geometric mean MIC. Finally, of the cephalosporins evaluated, each provided essentially zero time above the MIC for fully penicillin-resistant isolates.
The differences in the pharmacodynamic profiles of antibiotics have implications for the optimal antibiotic selection. For most community-acquired respiratory tract infections, S. pneumoniae continues to be the most important and commonly isolated pathogen. As most treatment is empirical, it seems reasonable to select agents with the best pharmacodynamic profile against the suspected pathogens. These data suggest that cephalosporins such as cefprozil, cefuroxime and cefpodoxime as well as penicillins such as amoxycillin and amoxycillin plus clavulanic acid provide the most reliable pharmacodynamic profiles against both penicillin-susceptible and penicillin-intermediate pneumococci. Other factors determining the choice of therapy are local susceptibility patterns, safety, tolerability, dosing interval, palatability and compliance.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . Chesney, P. J. (1992). The escalating problem of antimicrobial resistance in Streptococcus pneumoniae. American Journal of Diseases of Children 146, 9126.
3 . Doern, G. V., Brueggemann, A., Holley, H. P., Jr & Rauch, A. M. (1996). Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study. Antimicrobial Agents and Chemotherapy 40, 120813.[Abstract]
4 . Mason, E. O., Jr & Kaplan, S. L. (1995). Penicillin-resistant pneumococci in the United States. Pediatric Infectious Disease Journal 14, 10178.[ISI][Medline]
5
.
American Academy of Pediatrics Committee on Infectious Diseases. (1997). Therapy for children with invasive pneumococcal infections. Pediatrics 99, 28999.
6 . National Committee for Clinical Laboratory Standards. (1998). Performance Standards for Antimicrobial Susceptibility TestingEighth Informational Supplement: M100-S8. NCCLS, Wayne, PA.
7 . Dagan, R., Abramson, O., Leibovitz, E., Lang, R., Goshen, S., Greenberg, D. et al. (1996). Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pediatric Infectious Disease Journal 15, 9805.[ISI][Medline]
8 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFourth Edition: Approved Standard M7-A4. NCCLS, Wayne, PA.
9 . Saez-Llorens, X., Shyu, W. C., Shelton, S., Kumiesz, H. & Nelson, J. (1990). Pharmacokinetics of cefprozil in infants and children. Antimicrobial Agents and Chemotherapy 34, 21525.[ISI][Medline]
10 . Kafetzis, D. A., Carabinos, C., Bairamis, T. & Apostolopoulos, N. (1993). Diffusion of four oral cephalosporins into the middle ear exudate (MEE) of children suffering from acute otitis media (AOM). In Program and Abstracts of the Thirty-Third Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, LA, 1993. Abstract 941, p. 291. American Society for Microbiology, Washington, DC.
11 . Foulds, G., Luke, D. R., Teng, R., Willavize, S. A., Friedman, H. & Curatolo, W. J. (1996). The absence of an effect of food on the bioavailabilty of azithromycin administered as tablets, sachet or suspension. Journal of Antimicrobial Chemotherapy 37, Suppl. C, 3744.[ISI][Medline]
12 . Mason, E. O., Jr, Lamberth, L., Lichenstein, R. & Kaplan, S. L. (1995). Distribution of Streptococcus pneumoniae resistant to penicillin in the USA and in-vitro susceptibility to selected oral antibiotics. Journal of Antimicrobial Chemotherapy 36, 10438.[Abstract]
13 . Doern, G. V. (1996). Antimicrobial resistance among lower respiratory tract isolates of Haemophilus influenzae: results of a 199293 western Europe and USA collaborative surveillance study. The Alexander Project Collaborative Group. Journal of Antimicrobial Chemotherapy 38, Suppl. A, 5969.[Abstract]
14
.
Kaplan, S. L., Mason, E. O., Jr, Barson, W. J., Wald, E. R., Arditi, M., Tan, T. Q. et al. (1998). Three-year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics 102, 53845.
15
.
Kaplan, S. L. & Mason, E. O., Jr (1998). Management of infections due to antibiotic-resistant Streptococcus pneumoniae. Clinical Microbiology Reviews 11, 62844.
16 . Thornsberry, C., Brown, S. D., Yee, Y. C., Bouchillon, S. K., Marler, J. K. & Rich, T. (1993). Increasing penicillin resistance in Streptococcus pneumoniae in the U.S.: effect on susceptibility to oral cephalosporins. Infections in Medicine 10, Suppl. D, 1524.
17 . Doern, G. V., Pfaller, M. A., Kugler, K., Freeman, J. & Jones, R. N. (1998). Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program. Clinical Infectious Diseases 27, 76470.[ISI][Medline]
18 . Dagan, R., Abramson, O., Leibovitz, E., Greenberg, D., Lang, R., Goshen, S. et al. (1997). Bacteriologic response to oral cephalosporins: are established susceptibility breakpoints appropriate in the case of acute otitis media? Journal of Infectious Diseases 176, 12539.[ISI][Medline]
19 . Craig, W. A. (1995). Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagnostic Microbiology and Infectious Disease 22, 8996.[ISI][Medline]
20 . Drusano, G. L. (1988). Role of pharmacokinetics in the outcome of infections. Antimicrobial Agents and Chemotherapy 32, 28997.[ISI][Medline]
21 . Eagle, H., Fleischman, R. & Levy, M. (1953). Continuous' vs. Discontinuous' therapy with penicillin. The effect of the interval between injections on therapeutic efficacy. New England Journal of Medicine 248, 4818.[ISI]
22 . Craig, W. (1993). Pharmacodynamics of antimicrobial agents as a basis for determining dosage regimens. European Journal of Clinical Microbiology and Infectious Diseases 12, Suppl. 1, S68.[Medline]
23 . Nicolau, D. P., Freeman, C. D., Belliveau, P. P., Nightingale, C. H., Ross, J. W. & Quintiliani, R. (1995). Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrobial Agents and Chemotherapy 39, 6505.[Abstract]
24
.
Preston, S. L., Drusano, G. L., Berman, A. L., Fowler, C. L., Chow, A. T., Dornseif, B. et al. (1998). Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. Journal of the American Medical Association 279, 1259.
25 . Lacy, M. K., Owens, R. C., Xu, X., Nicolau, D. P., Quintiliani, R. & Nightingale, C. H. (1997). Comparison of bactericidal activity after multidose administration of clarithromycin, azithromycin and cefuroxime axetil against Streptococcus pneumoniae. International Journal of Antimicrobial Agents 10, 27983.
26 . Craig, W. A. (1998). Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing in mice and men. Clinical Infectious Diseases 26, 112.[ISI][Medline]
27 . Craig, W. A. & Andes, D. (1996). Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatric Infectious Disease Journal 15, 2559.[ISI][Medline]
28 . Ambrose, P. G., Quintiliani, R., Nightingale, C. H. & Nicolau, D. P. (1998). Continuous vs. intermittent infusion of cefuroxime for the treatment of community-acquired pneumonia. Infectious Diseases in Clinical Practice 7, 46370.[ISI]
29
.
Barry, A. L., Fuchs, P. C. & Brown, S. D. (1997). Macrolide resistance among Streptococcus pneumoniae and Streptococcus pyogenes isolates from out-patients in the USA. Journal of Antimicrobial Chemotherapy 40, 13940.
30 . Barry, A. L., Pfaller, M. A., Fuchs, P. C. & Packer, R. R. (1994). In vitro activities of 12 orally administered antimicrobial agents against four species of bacterial respiratory pathogens from U.S. Medical Centers in 1992 and 1993. Antimicrobial Agents and Chemotherapy 38, 241925.[Abstract]
Received 27 May 1999; returned 12 October 1999; revised 29 October 1999; accepted 20 December 1999