Vol. 29, No. 2

JOURNAL OF CLINICAL MICROBIOLOGY, Feb. 1991, p. 363-366

0095-1137/91/020363-04$02.00/0

Copyright © 1991, American Society for Microbiology

Interpretive Criteria and Quality Control Guidelines for Neisseria gonorrhoeae Susceptibility Test Standardization for Cefotetan R. N. JONES,1 2* E. H. GERLACH,3 F. P. KOONTZ,' P. R. MURRAY,4 M. A. PFALLER,"12 J. A. WASHINGTON,5 M. E. ERWIN,' AND C. C. KNAPP5 University of Iowa College of Medicine' and Department of Veterans Affairs Medical Center,2 Iowa City, Iowa 52242; St. Francis Regional Medical Center, Wichita, Kansas 672143; Barnes Hospital, St. Louis, Missouri 631104; and The Cleveland Clinic Foundation, Cleveland, Ohio 441065 Received 10 September 1990/Accepted 13 November 1990

Cefotetan was tested in a multilaboratory study to standardize susceptibility testing criteria and quality control guidelines for Neisseria gonorrhoeae. Cefotetan was most active against penicillinase-producing and penicillin-susceptible strains (MIC for 50% of strains tested, 0.5 ,ug/ml) and was least active against the chromosomally resistant isolates (MIC for 50% of strains tested, 2 ,ug/ml). The recommended 30-,ug disk cefotetan interpretive criteria were as follows: susceptible at .26 mm (c2 rig/ml), intermediate at 20 to 25 mm (4 ,ug/ml), and resistant at l19 mm (.8 ,Lg/ml). Quality control guidelines for agar dilution and disk diffusion tests were established by using numerous GC agar lots, three cefotetan 30-,ug disk lots, two quality control organisms, and a volume of tests consistent with National Committee for Clinical Laboratory Standards M23-T guidelines.

replicate testing. The organisms included N. gonorrhoeae ATCC 49226 and Staphylococcus aureus ATCC 25923 or ATCC 29213. The 102 gonococcal strains used to determine susceptibility test breakpoints were selected to possess various drug resistances as follows: penicillinase-producing N. gonorrhoeae isolates (31 strains); penicillin-resistant, f-lactamase-negative N. gonorrhoeae isolates (42 strains); and penicillin-susceptible, recent clinical isolates (29 strains). In addition, several of these strains were resistant to tetracycline and spectinomycin. All isolates were confirmed to be gonococci by rapid conventional testing procedures. The susceptibility tests were performed by the GC agar dilution and disk diffusion methods recently recommended by NCCLS (14, 15). All tests were made on agar by using a defined XV growth supplement devoid of cysteine (3, 14, 15). Incubation was carried out at 35°C in 5 to 7% CO2, and endpoints (MIC or zone size) were read at 20 to 24 h. All strains used for regression-interpretive criteria studies (102 isolates) were tested in triplicate by each susceptibility testing method. The mean zone size rounded to the nearest whole millimeter and the modal log2 dilution MIC result were used to calculate the regression statistics. QC trials generated 300 zones and 120 MICs per drug-organism pair at the participating facilities, each of which used a unique GC agar lot (13). The participants also used a common lot of agar, thus producing 90 zone diameters and 30 MICs (13). Details concerning the study design have been described in previous reports (9, 10). Cefotetan MICs were compared with their zone diameters around commercially prepared 30-jig disks by using regression analysis adapted to computers. When possible, suggested susceptible breakpoints conformed to those of similar agents (cephamycins and broadspectrum cephems) with published NCCLS criteria (9, 1315).

Cefotetan is a cephamycin antimicrobial agent with a wide spectrum of antimicrobial activity, especially against gramnegative microorganisms (8). Neisseria gonorrhoeae strains are generally susceptible to cefotetan, and the Centers for Disease Control (CDC) has recommended its use for pelvic inflammatory disease (2). Susceptibility tests for cefoxitin, another cephamycin, against gonococci have recently been standardized by using GC agar base medium (9). These more simplified procedures should predict the favorable clinicalbacteriologic response to single-dose gonorrhea therapy, e.g., 2 g of cefoxitin plus a predose of 1 g of probenicid (9, 12, 17, 21). Since cefotetan has superior pharmacokinetics compared with those of cefoxitin, probenicid is not required (16). Clinical success with single 500-mg or 1-g cefotetan regimens have been reported (7, 11, 20). In this report we summarize the development of cefotetan gonococcal susceptibility test interpretive criteria by using methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS) and CDC (3, 10, 14, 15). Quality control (QC) guidelines were also determined by a multilaboratory trial conforming to the NCCLS M23-T study guidelines (13). MATERIALS AND METHODS

Cefotetan was obtained from Stuart Pharmaceuticals Inc., Wilmington, Del. Cefotetan was also tested with 30-jig disks manufactured by Becton Dickinson Microbiology Systems (Cockeysville, Md.). Diffusion test disk lots for QC studies were obtained from Becton Dickinson Microbiology Systems and Difco Laboratories (Detroit, Mich.). Three lots wiere used, one Becton Dickinson Microbiology Systems lot and two Difco lots. Two groups of organisms were tested, one for the QC trials and one for the determinations of cefotetan interpretive criteria. The three QC organisms currently recommended by NCCLS (14, 15) were provided to the participants for

RESULTS AND DISCUSSION

The cefotetan MIC and zone diameter scattergram and

*

proposed interpretive criteria are found in Fig. 1 and Table 1,

Corresponding author. 363

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J. CLIN. MICROBIOL.

JONES ET AL.

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Cefotetan Zone Diameter (mm) FIG. 1. Cefotetan scattergram correlating 30-p.g disk interpretive criteria.

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diameters with MICs for 102 strains. Vertical lines

respectively. This 1-lactamase-stable, broad-spectrum cephamycin generally had less antigonococcal activity (MIC for 50% of strains tested, 1 jg/ml; range, 0.06 to 16 p,g/ml) than cefoxitin (9). All 30-jig cefotetan disk zones were .15 mm. Clinical failures with the clinical trial-recommended cefotetan doses (0.5 to 1 g) have been rare (7, 11, 20). Two reported clinical series (7, 20) rarely contained N. gonorrhoeae strains for which the cefotetan MICs were >4 p,g/ml. Therapeutic failures were observed to occur among some P-lactamase-negative gonococci which were possibly strains with chromosomally mediated penicillin resistance (MIC of cefotetan for 50% of strains tested, 2 ,ug/ml). For the organism from one patient with a reported treatment failure, the cefotetan MIC was 8 ,ug/ml (20). Furthermore, therapy against some gonococci for which the cefotetan MICs were >2 ,ug/ml failed in another clinical trial (11). Until greater experience with N. gonorrhoeae strains for which cefotetan MICs are >2 p,g/ml have been accumulated (MIC of ce-

are

proposed

zone

fotetan for 90% of strains tested, 8 jig/ml), we propose a tentative susceptible breakpoint of .2 jig/ml (zone diameter, .26 mm) and a resistant breakpoint at .8 jig/ml (zone diameter, s19 mm). Similarly, until consistent clinical responses are characterized among the infrequent strains with cefotetan MICs of 4 ,ug/ml, this MIC and corresponding zone diameter range (20 to 25 mm) will be designated as intermediate. These breakpoints conform closely to the regression equation-calculated zones and were similar to those previously reported for cefoxitin and cefuroxime (Table 1). No very major or major interpretive errors and only eight minor errors (7.8%) were observed in this isolate series by using the recommended interpretive criteria (Fig. 1). The MIC/zone diameter correlation (r = 0.85) was acceptable. Cross-resistance analyses comparing the cefotetan MICs with the penicillin MICs demonstrated linearity. For strains for which the cefotetan MICs were high, penicillin MICs were usually in the elevated, resistant range (.2 jig/ml). This

TABLE 1. Regression statistics and proposed susceptibility criteria for cefotetan and two other broad-spectrum cephalosporins calculated from studies of 100 to 102 N. gonorrhoeae strains Antimicrobial agent (disk content [Rg])

Regression formula (r)

Cefotetan (30) Cefoxitin (30)c Cefuroxime (30)C

y = 15.4 - 0.22x (0.85) y = 16.4 - 0.22x (0.93) y = 16.2 - 0.23x (0.95)

Proposed zone criteria (mm) for: Iermediate or

ItSusceptible Susceptible ~moderately susceptible'

Resistant

.26 (-

Interpretive criteria and quality control guidelines for Neisseria gonorrhoeae susceptibility test standardization for cefotetan.

Cefotetan was tested in a multilaboratory study to standardize susceptibility testing criteria and quality control guidelines for Neisseria gonorrhoea...
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