Incidence of Constitutive and Inducible Clindamycin Resistance in

Nov 24, 2003 - Conf. Antimicrob. Agents Che- mother., abstr. ... J. 21:530–534. 4. Frank, A. L., J. F. Marcinak, P. D. Managat, and P. C. Schreckenberger. 1999.
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JOURNAL OF CLINICAL MICROBIOLOGY, June 2004, p. 2777–2779 0095-1137/04/$08.00⫹0 DOI: 10.1128/JCM.42.6.2777–2779.2004 Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Vol. 42, No. 6

Incidence of Constitutive and Inducible Clindamycin Resistance in Staphylococcus aureus and Coagulase-Negative Staphylococci in a Community and a Tertiary Care Hospital Paul C. Schreckenberger,1* Elizabeth Ilendo,2 and Kathryn L. Ristow1 Microbiology Laboratory, University of Illinois Medical Center at Chicago, Chicago, Illinois 60612,1 and Microbiology Laboratory, Elmhurst Memorial Hospital, Elmhurst, Illinois 601262 Received 24 November 2003/Returned for modification 5 January 2004/Accepted 10 March 2004

The incidences of inducible clindamycin resistance at two hospitals (an inner-city hospital and a suburban community hospital) were 7 and 12% for methicillin-resistant Staphylococcus aureus, 20 and 19% for methicillin-susceptible S. aureus, and 14 and 35% for coagulase-negative staphylococci, respectively. Given the variability of inducible resistance to clindamycin found in our two hospitals, we conclude that susceptibility testing of staphylococci should include the disk diffusion induction test (D-test). use in our two laboratories. We therefore decided to test all staphylococci with the phenotype of intermediate ER resistance (ER-I) or ER resistance (ER-R) and CL susceptibility (CL-S) to determine the percentages of strains with MLSBi resistance in our two laboratories. Four hundred fifty-two MRSA, 788 methicillin-susceptible S. aureus (MSSA), and 310 coagulase-negative staphylococci (CNS) collected from consecutive clinical isolates were studied at our two hospitals. UIC is a 440-bed, inner-city, tertiary care hospital located on the near west side of Chicago and provides health care to a large, underserved population. Elmhurst Memorial Hospital (EMH) is a 450-bed suburban community hospital located 16 miles from UIC and serves a largely suburban, upper-middle-class population. Mueller-Hinton agar (MHA), CL disks (2 ␮g), and ER disks (15 ␮g) were purchase from Remel (Lenexa, Kans.). All staphylococcal isolates were tested for susceptibility to a battery of antibiotics with the Vitek 1 system (bioMe´rieux, St. Louis, Mo.). Isolates that were CL-S but ER-R or ER-I were tested for inducible resistance by the D-test. A 0.5 McFarland equivalent organism suspension was inoculated onto an MHA plate as described in the NCCLS recommendations (8). CL (2 ␮g) and ER (15 ␮g) disks were placed 15 mm apart from center to center on MHA as described by Weisblum and Demohn (10). Plates were read after 18 h of incubation at 35°C. Quality control was performed with S. aureus ATCC 25923. Interpretation of the diameters of zones of inhibition was as follows: ER-S ⫽ ⱖ23 mm, ER-I ⫽ 14 to 22 mm, ER-R ⫽ ⱕ13 mm; CL-S ⫽ ⱖ21 mm, CL-I ⫽ 15 to 20 mm, CL-R ⫽ ⱕ14 mm. If the ER zone is ⱕ13 mm and the CL zone is ⱖ21 mm and both have a circular shape, the organism is negative for inducible resistance (D-test negative). If the ER zone is ⱕ13 mm and the CL zone is ⱖ21 mm with a D-shaped zone around the CL, the organism is positive for inducible resistance (D-test positive) (10). The percentages of MLSBi resistance in MRSA in our two hospitals were similar but low (7% at UIC, 12% at EMH). The percentages of MLSBi resistance in MSSA in our two hospitals were similar and double the rate seen in MRSA (20% at UIC, 19% at EMH). The percentages of MLSBi resistance in CNS in our two hospitals differed considerably (14% at UIC, 35% at

Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by binding reversibly to the 50S ribosomal subunits of susceptible organisms. Target site modification is the most common mechanism of acquired resistance to macrolides, lincosamides, and streptogramin B (MLS) antibiotics in staphylococci and confers cross-resistance to the MLS antibiotics (the so-called MLSB phenotype) (6). MLSB resistance can be either constitutive (MLSBc) or inducible (MLSBi). When it is inducible, bacteria often test resistant to erythromycin (ER) but susceptible to clindamycin (CL). When the disk diffusion test is used to determine susceptibility, a distorted “D-shaped” zone of inhibition is observed around CL if an ER disk is placed nearby. Although isolates appear susceptible to CL in the absence of an inducing agent, there is widespread reluctance to prescribe CL for treatment of patients with infections caused by such organisms because of concerns that resistance to CL will develop during therapy. Beginning in 1990, one of our laboratories (University of Illinois Medical Center [UIC]) began to see methicillin-resistant Staphylococcus aureus (MRSA) strains that exhibited resistance only to penicillin and oxacillin with implied cross-resistance to other ␤-lactam compounds but tested susceptible to most other drug classes (4). Since most of these relatively susceptible MRSA strains originated from community-acquired infections (CAMRSA), there was interest on the part of our infectious disease clinicians in knowing the CL susceptibility of all staphylococcal isolates. The CA-MRSA isolates were found by us to be more susceptible than hospital-acquired (or nosocomial) MRSA to more antimicrobial classes, including ER and CL (4, 5). By the mid-1990s, CL-susceptible isolates accounted for most of the MRSA isolates from children at our institution (4). CL is a frequent choice for treating some staphylococcal infections because it can be given orally and is well tolerated. However, MLSBi resistance is not recognized by standard susceptibility test methods, including the Vitek system, which is the system in * Corresponding author. Mailing address: University of Illinois Medical Center at Chicago, Rm. 238 CSB, M/C 750, 840 S. Wood St., Chicago, IL 60612. Phone: (312) 996-3150. Fax: (312) 413-0156. Email: [email protected]. 2777

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TABLE 1. Incidence of MLSBi and MLSBc among MRSA, MSSA, and CNS isolates in two hospitals Phenotype

No. (%) of MRSA No. (%) of MSSA No. (%) of CNS isolates isolates isolates UIC

EMH

UIC

EMH

ER-R CL-R 170 (84) 205 (82) 10 (3) 88 (18) ER-S CL-S 16 (8) 8 (3) 227 (76) 296 (61) ER-R/I CL-S D⫹ 14 (7) 30 (12) 59 (20) 94 (19) ER-R/I CL-S D⫺ 3 (1) 6 (2) 3 (1) 11 (2) Total

203

249

299

489

UIC

EMH

58 (37) 47 (30) 21 (14) 29 (19)

40 (26) 14 (9) 55 (35) 46 (30)

155

155

EMH) (Table 1). Overall, 17% of MRSA, 8% of MSSA, and 50% of CNS isolates that exhibited the ER-R CL-S phenotype did not demonstrate MLSBi resistance and therefore can be reported as susceptible to CL. Overall CL susceptibility was highest for MSSA and lowest for MRSA (Table 2). In our study, we performed the disk approximation test as described by Weisblum and Demohn (10). Fiebelkorn et al. (2) have recently shown that the D-test can be performed by a routine disk diffusion procedure by placing the CL and ER disks at adjacent positions in the disk dispenser. These same authors have also shown that the D-test can be performed by placing ER and CL disks 15 mm from edge to edge in the heavy-inoculum area of standard blood agar plates used for purity checks with automated susceptibility test systems (J. H. Jorgensen, S. A. Crawford, L. M. McElmeel, and K. R. Fiebelkorn, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. D-241, 2003). Accurate susceptibility data are important for appropriate therapy decisions; however, little is known about the prevalence of inducible CL resistance in CA-MRSA isolates. In one study conducted in Minnesota, 58 (84%) of 69 isolates that tested ER-R CL-S were found to be inducibly resistant by the D-test (K. Como-Sabetti, A. Glennen, J. Bartkus, S. Vetter, K. LeDell, D. Boxrud, R. Danila, and R. Lynfield, Abstr. 40th Annu. Meet. Infect. Dis. Soc. Am., abstr. 92, 2002). In contrast, a study conducted at the University of Iowa demonstrated that 65 (62%) of 105 Staphylococcus sp. isolates with the ER-R CL-S phenotype showed the MLSBi resistance phenotype (9). In a study conducted at the University of Sa˜o Paulo, Sa˜o Paulo, Brazil, 11.3% of S. aureus and 13.7% of CNS isolates were found to have the MLSBi resistance phenotype (I. M. Van der Heijden, S. Sinto, C. Oplustil, and C. Mendes, Abstr. 101st Gen. Meet. Am. Soc. Microbiol., abstr. A-86, 2001). Van Horn reported that 80% of S. aureus and 63% of CNS isolates with

TABLE 2. Susceptibility to CL among all staphylococci Organism-hospital (no. of isolates)

No (%) with inducible resistance

No. (%) with constitutive resistance

No. (%) susceptible

MRSA-UIC (203) MRSA-EMH (249) MSSA-UIC (299) MSSA-EMH (489) CNS-UIC (155) CNS-EMH (155)

14 (7) 30 (12) 59 (20) 94 (19) 21 (14) 55 (35)

170 (84) 205 (83) 10 (3) 88 (18) 58 (37) 40 (26)

19 (9) 14 (6) 230 (77) 307 (63) 76 (49) 60 (39)

the ER-R CL-S phenotype demonstrated inducible resistance in a New York City medical center (K. G. Van Horn and C. Toth, Abstr. 103rd Gen. Meet. Am. Soc. Microbiol., abstr. C-074, 2003). In a study conducted at the University of Texas Health Science Center, 34% of 114 ER-R S. aureus isolates demonstrated constitutive resistance to CL and 29% showed inducible resistance, while 70% of CNS isolates demonstrated constitutive CL resistance and 30% demonstrated inducible resistance (2). These data suggest that the occurrence of the MLSBi resistance phenotype varies widely by hospital and geographic region. Failure to identify inducible CL resistance when the ER-R CL-S phenotype is detected may lead to clinical failure of CL therapy (1). Conversely, labeling all ER-R staphylococci as CL-R or not reporting CL resistance when ER resistance is present will likely prevent the use of CL in treating infections that would likely respond to CL therapy (3, 7). Our data show that the MLSBi resistance phenotype is prevalent in clinical laboratories in the Chicago metropolitan area; however, the incidence differs from that reported in other U.S. cities and internationally. Furthermore, the incidence of inducible resistance to CL varied between the MRSA and CNS isolates tested in our two hospitals. The cost benefit of routinely performing the D-test must be evaluated in each laboratory setting after first determining the incidence of the MLSBi and MLSBc resistance phenotypes. For example, in both of our hospitals, the incidence of the ER-R/I CL-S phenotype in MRSA was low, 8% at UIC and 14% at EMH, and of these isolates, approximately 83% were D-test positive. On the other hand, a large percentage of CNS isolates exhibited the ER-R/I CL-S phenotype and only 42% (UIC) and 54% (EMH) were D-test positive. Given these data, one might consider a policy of performing the D-test only on CNS isolates and considering all MRSA isolates with the ER-R/I CL-S phenotype to be D-test positive because the number of MRSA isolates with the MLSBc phenotype in our two hospitals was very small. Decisions about routine testing of staphylococci with the ER-R/I CL-S phenotype should be made on an institution-by-institution basis after obtaining local prevalence data. REFERENCES 1. Drinkovic, D., E. R. Fuller, K. P. Shore, D. J. Holland, and R. Ellis-Pegler. 2001. Clindamycin treatment of Staphylococcus aureus expressing inducible clindamycin resistance. J. Antimicrob. Chemother. 48:315–329. 2. Fiebelkorn, K. R., S. A. Crawford, M. L. McElmeel, and J. H. Jorgensen. 2003. Practical disk diffusion method for detection of inducible clindamycin resistance in Staphylococcus aureus and coagulase-negative staphylococci. J. Clin. Microbiol. 41:4740–4744. 3. Frank, A. L., J. F. Marcinak, P. D. Managat, J. T. Tjhio, S. Kelkar, P. C. Schreckenberger, and J. P. Quinn. 2002. Clindamycin treatment of methicillin-resistant Staphylococcus aureus infections in children. Pediatr. Infect. Dis. J. 21:530–534. 4. Frank, A. L., J. F. Marcinak, P. D. Managat, and P. C. Schreckenberger. 1999. Increase in community-acquired methicillin-resistant Staphylococcus aureus in children. Clin. Infect. Dis. 29:935–936. 5. Frank, A. L., J. F. Marcinak, P. D. Managat, and P. C. Schreckenberger. 1999. Community-acquired and clindamycin-susceptible methicillin-resistant Staphylococcus aureus in children. Pediatr. Infect. Dis. J. 18:993–1000. 6. Leclercq, R., and P. Courvalin. 1991. Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification. Antimicrob. Agents Chemother. 35:1267–1272. 7. Martinez-Aguilar, G., W. A. Hammerman, E. O. Mason, Jr., and S. L. Kaplan. 2003. Clindamycin treatment of invasive infections caused by community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus in children. Pediatr. Infect. Dis. J. 22:593–598.

VOL. 42, 2004 8. National Committee for Clinical Laboratory Standards. 2000. Performance standards for antimicrobial disk susceptibility tests; approved standard— seventh edition. NCCLS document M2-A7. National Committee for Clinical Laboratory Standards, Wayne, Pa. 9. Sanchez, M. L., K. K. Flint, and R. N. Jones. 1993. Occurrence of macrolidelincosamide-streptogramin resistances among staphylococcal clinical isolates

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at a university medical center. Is false susceptibility to new macrolides and clindamycin a contemporary clinical and in vitro testing problem? Diagn. Microbiol. Infect. Dis. 16:205–213. 10. Weisblum, B., and V. Demohn. 1969. Erythromycin-inducible resistance in Staphylococcus aureus: survey of antibiotic classes involved. J. Bacteriol. 98:447–452.