Streptococcus pneumoniae in the USA: in vitro susceptibility and pharmacodynamic analysis

Edward O. Mason, Jra,b,c,*, Linda B. Lamberthc, Nerisa L. Kershawa,b,c, Barbara La T. Prosserd, Annette Zoed and Paul G. Ambrosed

a Departments of Pediatrics, b Microbiology and Immunology, Baylor College of Medicine, c Infectious Disease Laboratory, Texas Children's Hospital, Houston, TX 77030; d Bristol–Myers Squibb, Plainsboro, NJ 08536, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ninety-two laboratories in the USA submitted isolates of Streptococcus pneumoniae to a single laboratory for susceptibility testing. Overall, 64% of 4489 isolates were susceptible to penicillin, 24% were intermediate and 13% were resistant to penicillin, although susceptibilities varied depending on geographical region. Macrolide/azalide resistance varied from 4 to 30%, with some regions having macrolide/azalide resistance higher than penicillin resistance. Children 12 years of age were significantly more likely to be infected with a penicillin-resistant pneumococcus than were adolescents or adults. Isolates from the respiratory tract were more likely to be penicillin resistant and >50% of pneumococci from the ear were resistant to penicillin. Almost 25% of penicillin-susceptible isolates had cefaclor MICs 2.0 mg/L and 15% of penicillin-susceptible isolates had loracarbef MICs 2.0 mg/L. These isolates would be erroneously reported as susceptible using NCCLS guidelines, and this finding may explain the lack of clinical response in patients treated with these antibiotics. 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; 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. None of the cephalosporins evaluated achieved a substantial time above the geometric mean MIC during its dosing interval for fully penicillin-resistant S. pneumoniae.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Increasing resistance to antibiotics commonly used to treat infections caused by Streptococcus pneumoniae is of continuing world-wide concern. The concentration of penicillin needed to inhibit and kill pneumococci continues to rise and is associated with decreased susceptibility to other antibiotics.13 However, susceptibility varies in different regions of the world and even within the USA.4 Whereas ß-lactam therapy of non-CNS infections caused by S. pneumoniae with intermediate susceptibility to penicillin may be possible, the treatment of meningitis and perhaps other deep-seated infections requires modification of existing empirical choices.5 As initial therapy is largely empirical, local or regional susceptibility patterns may be useful in selecting initial antibiotic therapy.

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
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In vitro susceptibility studies

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 Mueller–Hinton 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 (3–6) x 104 cfu per replicator spot, as determined by quantitative culture. Plates were incubated at 35°C for 20–22 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 (Bristol–Myers 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 concentration–time curves, for each of the antimicrobials were collected. Pharmacokinetic concentration–time 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 concentration–time 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
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The prevalence of penicillin non-susceptible (MIC >= 0.125 mg/L) isolates varied from 27 to 54% in sections of the USA (Table IGo). Although the determination of states within the regions was arbitrary, there were, overall, more penicillin-resistant isolates in the southern USA (Florida 45%, the Gulf Coast 54% and South East 47%). Overall, 2849/4489 (63.5%) isolates were susceptible to penicillin, 1059/4489 (23.6%) showed intermediate susceptibility and 581/4489 (12.9%) were resistant to penicillin. Macrolide/ azalide resistance also varied from 4–8 to 25–30% regionally although with a somewhat different pattern than for penicillin resistance (Table IIGo).


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Table I. Susceptibility to penicillin by geographical region (values in parentheses are percentages)
 

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Table II. Susceptibility to macrolide/azalide by geographical region (values in parentheses are percentages)a,b
 
There was a significant difference ({chi}2 = 42.04, P < 0.000001, Table IIIGo) in penicillin susceptibility based on patient age. Forty-three per cent of children of 12 years or less had a non-susceptible isolate compared with 33% of adolescents or adults. There was no difference in susceptibility of isolates to penicillin between males and females. The distribution of penicillin susceptibility was no different in patients seen as in-patients or as out-patients (34% versus 39% non-susceptible). There was no way of separating acute from long-term in-patient facilities, nor were day care and recent hospitalizations determined for those seen in the out-patient setting. Table IVGo shows penicillin susceptibility by anatomical site of the isolate. The highest percentage of non-susceptible isolates (intermediate and resistant) came from the respiratory tract, notably from the ear (>50%).


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Table III. Distribution of S. pneumoniae susceptible, intermediate and resistant to penicillin by age of patient (values in parentheses are percentages)
 

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Table IV. S. pneumoniae susceptibility to penicillin listed by anatomical source (values in parentheses are percentages)
 
The in vitro activity (MIC50, MIC90, MIC range and geometric mean MIC) of the antibiotics tested grouped by isolate susceptibility to penicillin is presented in Table VGo. At least 90% of the penicillin-susceptible isolates were inhibited at <=0.25 mg/L by all other antibiotics except cefaclor, loracarbef and cefixime. Amoxycillin and amoxycillin/clavulanic acid showed greater inhibition against penicillin-intermediate isolates than the other antimicrobials tested, with cefaclor and loracarbef having the highest MIC90 at >=64 mg/L and cefixime with an MIC90 of 16 mg/L. Penicillin-resistant isolates were least inhibited by any of the antibiotics tested, with the macrolides and azalides being the most active with the lowest geometric mean. However, the MIC90s of the macrolides and azalides were >=64 mg/L for the penicillin-resistant isolates, indicating a bimodal distribution. Susceptibility to amoxycillin and amoxycillin/clavulanic acid was identical and predicted by penicillin susceptibility. Overall, resistance to the three macrolides/azalides was similar: azithromycin >=2.0 mg/L, 12.7%; clarithromycin >=1.0 mg/L, 12.6%; erythromycin >=1.0 mg/L, 16%. In general, in vitro ß-lactam activity was in the following order: amoxycillin/amoxycillin plus clavulanic acid > cefpodoxime >cefuroxime > cefprozil > cefixime > loracarbef > cefaclor.


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Table V. In vitro activity (MIC in mg/L) of selected antibiotics for S. pneumoniae based on susceptibility to penicillin
 
Penicillin susceptibility was not found to be a consistent predictor of susceptibility to all the oral ß-lactams (Table VIGo). There were 2849 isolates that were susceptible to penicillin, which, by NCCLS guidelines, would be considered susceptible to all the oral cephalosporins. However, for 2373 of the 2849 penicillin-susceptible isolates (83.3%), cefaclor MICs were >=1.0 mg/L. Similarly, for 2180/2849 (76.5%) penicillin-susceptible isolates, loracarbef MICs were >=1.0 mg/L and for 307/2849 (10.8%) penicillin-susceptible isolates, cefixime MICs were >=1.0 mg/L. In contrast, for 50/2849 (1.8%) penicillin-susceptible isolates, cefprozil MICs were >=1.0 mg/L, for 31/2849 (1.1%) penicillinsusceptible isolates, cefuroxime MICs were >=1.0 mg/L and for 21/2849 (0.7%) penicillin-susceptible isolates, cefpodoxime MICs were >=1.0 mg/L.


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Table VI. MICs (mg/L) for isolates designated as susceptible by NCCLS guidelines to ß-lactam antibiotics on the basis of penicillin susceptibility
 
Pharmacodynamic analysis

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 (FigureGo). 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.



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Figure. Per cent time of dosing interval in which the serum concentration is above the MIC (clinically relevant time above the MIC of 40% is reflected by the dashed horizontal line) for selected antibacterials. {diamondsuit}, cefprozil 15 mg/kg; +, cefaclor 15 mg/kg; {diamond}, cefuroxime 15 mg/kg; {circ}, cefpodoxime 5 mg/kg; {triangleup}, cefixime 400 mg tablet; {blacksquare}, loracarbef 15 mg/kg; {square}, amoxycillin 250 mg; x, azithromycin 500 mg suspension.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Results of pneumococcal antibiotic resistance surveillance studies vary with the geographical location, anatomical source of the isolates and the age of the population studied, but the trend shows increasing numbers of non-penicillin-susceptible isolates and increasing proportions of penicillin- resistant isolates (Table VIIGo). In a similar study performed in 1993–1994 involving 33 sites from 19 states in the USA, we found that 10.4% of isolates were intermediate and 5.7% of isolates were resistant to penicillin.12 The present study involving a similar population, a larger geographical area and 4489 isolates shows that the intermediate and true penicillin resistance has approximately doubled to 23.6 and 12.9%, respectively. This study included mostly community hospitals and six children's hospitals, which should be representative of the general population. Both of these surveys included isolates from children and adults, all anatomical sites and in geographical locations throughout the USA. Results of a study of respiratory pneumococcal isolates by Doern et al., performed in the same period, showed very similar proportions of penicillin resistance (27.8% intermediate and 16% resistant).13 Risk factors for infection with a penicillin-resistant isolate include younger age, day-care attendance and prior antibiotic therapy. Kaplan et al. reported that 52% of episodes of infection by S. pneumoniae non-susceptible to penicillin were in children who had received an antibiotic within 30 days in comparison with 28% of non-susceptible infections in children who had not received prior antibiotics.14 In that same report, day-care attendance was also linked to infection by a non-susceptible isolate, but day-care attendance without prior antibiotic therapy did not influence penicillin susceptibility. We were able to document the same association of younger age with isolation of non-susceptible isolates but this study was not designed to collect information regarding day-care attendance or prior antibiotic therapy.


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Table VII. Summary of penicillin resistance in recent reports
 
With the advent of penicillin resistance in S. pneumoniae, empirical therapy for non-meningeal infections has shifted from penicillin to amoxycillin, amoxycillin plus clavulanic acid, the second- and third-generation cephalosporins and the macrolides or azalides.15 Increasing resistance to the third-generation cephalosporins has been slower than the development of resistance to penicillin, but solid information on susceptibility to many of the oral cephalosporins is not available because of a lack of published breakpoints by the NCCLS. Guidelines by this agency base susceptibility of pneumococci to cefpodoxime, cefaclor, cefixime, loracarbef and cefprozil on susceptibility to penicillin. In an effort to report data on susceptibility to these compounds, investigators have adopted the breakpoint for cefuroxime (R >= 2 mg/L) or simply reported the MIC90 for each compound. Thornsberry in 1993 and Doern in 1998 reported that penicillin susceptibility is not a consistent predictor of cephalosporin susceptibility.16,17 One of the most striking results of the present study is the higher MICs of cefaclor, loracarbef and cefixime found in penicillin-susceptible isolates. The lack of an official breakpoint precludes the ability to quantify the magnitude of this error but it remains a provocative explanation of reported clinical failures in the treatment of otitis media with these agents.18

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 85–100% 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
 
This study was funded in part from a grant by Bristol– Myers Squibb, Princeton, NJ 08536, USA. We sincerely thank the individual laboratory personnel at the following institutions participating in this study: Lowell General Hospital, Lowell, MA 01854; South Shore Hospital, South Weymouth, MA 02190; Norwalk Hospital, Norwalk, CT 06856; Rhode Island Hospital, Providence, RI 02903; Memorial Hospital of RI, Pawtucket, RI 02860; Landmark Medical Center, Woonsocket, RI 02895; Dartmouth– Hitchcock Medical Center, Lebanon, NH 03756; White Plains Hospital Center, White Plains, NY 10601; St Vincent's Hospital, New York, NY 10011; St Peter's Hospital, Albany, NY 12208; The Genesee Hospital, Rochester, NY 14607; Fairfax Hospital, Falls Church, VA 22042; Mercy Hospital, Buffalo, NY 14220; Children's Hospital of Buffalo, Buffalo, NY 14222; Winchester Medical Center, Winchester, VA 22601; United Health Services, Johnson City, NY 13790; Lynchburg General Hospital, Lynchburg, VA 24501; Chippenham Hospital, South Richmond, VA 23225; Williamsburg Community Hospital, Williamsburg, VA 23187; Maryview Hospital, Portsmouth, VA 23708; Medical Center of Delaware, Newark, DL; Akron Children's Hospital, Akron, OH 44308; Reading Hospital and Medical Center, West Reading, PA 19603; Toledo Hospital, Toledo, OH 43606; Akron City Hospital, Akron, OH 44304; Delaware County Memorial Hospital, Drexel Hill, PA 19026; Bryn Mawr Hospital, Bryn Mawr, PA 19010; Saint Mary's Hospital, Huntington, WV 25702; ACL, Erie, PA 16501; Medical College of Georgia, Augusta, GA 30901; Medical Center of Central Georgia, Macon, GA 31201; New Hanover Regional Medical Center, Wilmington, NC 28401; Baptist Hospital East, Louisville, KY 40207; LeBonheur Children's Medical Center, Memphis, TN 38103; Forsyth Memorial Hospital, Winston–Salem, NC 27103; Northside Hospital, Atlanta, GA 30342; North Carolina Baptist Hospital, Winston–Salem, NC 27157; Grady Memorial Hospital, Atlanta, GA 30335; Memorial Hospital of Chattanooga, Chattanooga, TN 37404; University of North Carolina Hospital, Chapel Hill, NC 27514; Wake County Medical Center, Raleigh, NC 27610; University of Mississippi Medical Center, Jackson, MS 39216; Bay Medical Center, Panama City, FL 32401; St Dominic Jackson Memorial, Jackson, MS 39216; Children's Hospital of Alabama, Birmingham, AL 35233; University Medical Center, Jacksonville, FL 32209; Holy Cross Hospital, Fort Lauderdale, FL 33308; Baptist Medical Center, Jacksonville, FL 32207; Carle Clinic Association, Urbana, IL 61801; Methodist Hospital, Indianapolis, IN 46206; Illinois Masonic Medical Center, Chicago, IL 60657; Christ Hospital, Oak Lawn, IL 60453; Munson Medical Center, Traverse City, MI 49684; Evanston Hospital, Evanston, IL 60201; Park View Hospital, Ft Wayne, IN 46805; St John's Hospital, Springfield, IL 62769; Children's Memorial Medical Center, Chicago, IL 60614; Decatur Memorial Hospital, Decatur, IL 62526; St Joseph Medical Center, Joliet, IL 60435; University of Michigan, Ann Arbor, MI 48109; University of Illinois Hospital, Chicago, IL 60612; St John's Medical Center, Tulsa, OK 74104; St Luke's Methodist Hospital, Cedar Rapids, IA 52402; Shawnee Mission Medical Center, Shawnee Mission, KS 66204; Arkansas Children's Hospital, Little Rock, AR 72202; Med Labs, Cedar Rapids, IA 52402; Medical Art Laboratory, Oklahoma City, OK 73103-2620; Barnes/Jewish Hospital, St Louis, MO 63110; St Alexius Medical Center, Bismarck, ND 58506; Mayo Clinic Rochester, Rochester, MN 55905; St Luke's Medical Center, Milwaukee, WI 53201; GML, Madison, WI 73706; Scott & White Memorial Hospital, Temple, TX 76508; Brackenridge, Austin, TX 78701; University of Texas Southwestern Medical School, Dallas, TX 75235-9072; Tulane University Hospital, New Orleans, LA 70112; Methodist Hospital, Lubbock, TX 79430; UC Davis Medical Center, Sacramento, CA 95817; San Francisco General Hospital, San Francisco, CA 94110; Good Samaritan Regional Medical Center, Phoenix, AZ 85006; Pathology Medical Labs, San Diego, CA 92121; Kaiser Regional Laboratory, Berkeley, CA 94710; UC San Francisco, San Francisco, CA 94143; White Memorial Medical Center, Los Angeles, CA 90033; Kaiser Permanente, North Hollywood, CA 91605; Scottsdale Memorial Hospital North, Scottsdale, AZ 85258; Mount Zion Hospital, San Francisco, CA 94115; Lovelace Medical Center, Albuquerque, NM 87108; UCLA Medical Center, Los Angeles, CA 90024; Santa Barbara Hospital, Santa Barbara, CA 93105; Rogue Valley Medical Center, Medford, OR 97504; McKay–Dee Hospital Center, Ogden, UT 84403.


    Notes
 
* Correspondence address. Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Tel: +1-713-770-4330; Fax: +1-713-770-4347; E-mail: emason{at}bcm.tmc.edu Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 27 May 1999; returned 12 October 1999; revised 29 October 1999; accepted 20 December 1999