|Year : 2013 | Volume
| Issue : 2 | Page : 112-115
Inducible clindamycin resistance among clinical isolates of Staphylococcus aureus
Kanwal Deep Singh Lyall, Veenu Gupta, Deepinder Chhina
Department of Microbiology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
|Date of Web Publication||6-Sep-2013|
Department of Microbiology, Dayanand Medical College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
Introduction: The resistance to antimicrobial agents among staphylococci is an increasing problem. This has led to renewed interest in the usage of macrolide-lincosamide-streptogramin B (MLSB) antibiotics to treat Staphylococcus aureus infections. Clinical failure has been reported due to multiple mechanisms that confer resistance to MLSB antibiotics. The present study was aimed to detect inducible clindamycin resistance among S. aureus isolates and to study the relationship between clindamycin and methicillin resistance.
Materials and Methods: During a period of 1 year, a total of 593 S. aureus isolates from various clinical specimens were included in the study. Antimicrobial susceptibility test was done by Kirby-Bauer's disc diffusion method as per Clinical and Laboratory Standards Institute (CLSI) guidelines. For detection of inducible clindamycin resistance, D test using erythromycin and clindamycin as per CLSI guidelines was performed, and three different phenotypes were interpreted as methicillin-sensitive (MS) phenotype (D test negative), inducible MLSB (iMLSB) phenotype (D test positive), and constitutive MLSB phenotype.
Results: Of the total 593 S. aureus isolates, majority were obtained from pus (31.1%) followed by blood and body fluids (27.3%). All the isolates were sensitive to vancomycin, teicoplanin, and linezolid. Out of 306 (51.7%) erythromycin resistant isolates, 280 (91.5%) were methicillin-resistant S. aureus (MRSA) and 26 (8.5%) were methicillin-sensitive S. aureus (MSSA). iMLSB phenotype in 33.3%, MS phenotype in 44.8%, and constitutive MLSB phenotype was observed in 21.9% of isolates. Inducible clindamycin resistance was almost equal among MRSA and MSSA isolates.
Conclusion: D test should be included as a mandatory method in routine disc diffusion testing to detect inducible clindamycin resistance in staphylococci for the optimum treatment of patients.
Keywords: Clindamycin resistance, constitutive macrolide-lincosamide-streptogramin B phenotype, inducible macrolide-lincosamide-streptogramin B phenotype, methicillin-resistance S. aureus, methicillin-sensitive phenotype
|How to cite this article:|
Lyall KS, Gupta V, Chhina D. Inducible clindamycin resistance among clinical isolates of Staphylococcus aureus. J Mahatma Gandhi Inst Med Sci 2013;18:112-5
|How to cite this URL:|
Lyall KS, Gupta V, Chhina D. Inducible clindamycin resistance among clinical isolates of Staphylococcus aureus. J Mahatma Gandhi Inst Med Sci [serial online] 2013 [cited 2022 May 24];18:112-5. Available from: https://www.jmgims.co.in/text.asp?2013/18/2/112/117799
| Introduction|| |
Methicillin-resistant Staphylococcus aureus (MRSA) are increasingly being reported as multidrug resistant with high resistance to macrolides (erythromycin, clarithromycin) and lincosamides (clindamycin, lincomycin), leaving very few therapeutic options.  Newer antibiotics like vancomycin, linezolid, and quinupristin-dalfopristin have been advocated in the management of such isolates, but recent reports of resistance to these agents raise real concerns over how long these uniform susceptibilities will hold good. ,, This has led to renewed interest in the usage of macrolide-lincosamide-streptogramin B (MLS B ) antibiotics to treat S. aureus infections with, clindamycin being the preferred agent due to its excellent pharmacokinetic properties. , MLS B antibiotics are structurally unrelated; however, they are related microbiologically because of their similar mode of action. They inhibit bacterial protein synthesis by binding to 23s rRNA, which is a part of large ribosomal subunit. They have a spectrum of activity directed against gram-positive cocci, gram-negative cocci and intracellular bacteria such as chlamydiae and rickettsiae.  For years, macrolides have been used as an alternative to penicillin and cephalosporins in the treatment of infections caused by gram positive bacteria, but the worldwide development of macrolide resistance has now limited the use of these antibiotics. Macrolide resistance is by diverse mechanisms. The resistance to macrolide can be mediated by msr(A) gene coding for efflux mechanism or via erm gene encoding for enzymes that confer inducible or constitutive resistance to MLS B antibiotics. In constitutive resistance, r-RNA methylase is always produced (cMLS B ); where as in inducible, methylase is produced only in the presence of an inducing agent (iMLS B ).  Erythromycin is an effective inducer whereas clindamycin is a weak inducer. In vitro, S. aureus isolates with constitutive resistance are resistant to both erythromycin and clindamycin whereas those with inducible resistance are resistant to erythromycin and appear sensitive to clindamycin (iMLS B ).  The treatment of patients harboring iMLS B staphylococci with clindamycin leads to the development of constitutive resistance, subsequently leading to therapeutic failure.  The present study was aimed to detect inducible clindamycin resistance among S. aureus isolates and to study the relationship between clindamycin and methicillin resistance.
| Materials and Methods|| |
The present study was a prospective study conducted during a period of 1 year on the patients admitted in Dayanand Medical College and Hospital, Ludhiana. A total of 593 S. aureus isolates from various clinical specimens like pus, wound swab, aspirates, blood, body fluids, respiratory, urine, central line/neck line/umbilical catheter tips, etc. were included in the study. S. aureus isolates were identified by standard biochemical techniques.  Antimicrobial susceptibility testing was done by Kirby-Bauer's disc diffusion method using various antimicrobial agents like penicillin (5 μg), oxacillin (1 μg), gentamycin (10 μg), amikacin (30 μg), netilmicin (10 μg), erythromycin (15 μg), cotrimoxazole (1.25/23.75 μg), ciprofloxacin (5 μg)/norfloxacin (10 μg), rifampicin (5 μg), vancomycin (30 μg), teicoplanin (30 μg), linezolid (30 μg) as per CLSI guidelines.  For quality control (QC), S. aureus ATCC 25923 was used. For detection of methcillin resistance, 1 mg of oxacillin disc was placed and plates were incubated at 35°C for 24 h. Isolates with zone diameters ≤10 mm were labeled as methicillin resistant. [l1] For detection of inducible clindamycin resistance, a disk approximation test was performed by placing a 2 μg clindamycin disc from 21 mm away from the edge of a 15 μg erythromycin disc.  Following overnight incubation at 37°C, three different phenotypes were appreciated and interpreted as follows:
- Methicillin-sensitive (MS) phenotype: S. aureus isolates exhibiting resistance to erythromycin (zone size ≤13 mm), while sensitive to clindamycin (zone size ≥21 mm) and giving circular zone of inhibition around clindamycin (D test negative).
- Inducible MLS B phenotype: iMLS B S. aureus isolates which showed resistance to erythromycin (zone size ≤13 mm) while being sensitive to clindamycin (zone size ≥21 mm) and giving D shaped zone of inhibition around clindamycin with flattening towards erythromycin disc (D test positive)
- Constitutive MLS B phenotype: cMLS B S. aureus isolates which showed resistance to both erythromycin (zone size ≤13 mm) and clindamycin (zone size ≤14 mm) with circular shape zone of inhibition around clindamycin.
| Results|| |
Of the 593 S. aureus isolates, majority were obtained from pus (31.1%) followed by blood and body fluids (27.3%); central line/neck line/umbilical catheter, etc. (20.2%); urine (12.6%); and respiratory samples (8.7%). All the S. aureus isolates were sensitive to vancomycin, teicoplanin, and linezolid. Resistance to other antibiotics studied ranged from 18.8 to 80.1%, while good sensitivity was also seen towards netilmicin and amikacin. Penicillin and oxacillin showed poor response [Figure 1].
|Figure 1: Antimicrobial resistance profile of S. aureus isolates (n = 593)|
Click here to view
A total of 306 (51.7%) S. aureus isolates were resistant to erythromycin, out of which 91.5% (280) were MRSA and 8.5% (26) were MSSA [Table 1]. Among the 306 isolates resistant to erythromycin, D test was positive in 102 (33.3%) (inducible MLS B Phenotype) and negative in 137 (44.8%) isolates (MS phenotype). Constitutive MLS B phenotype was seen in 67 isolates (21.9%). Percentage of inducible, constitutive and MS phenotype resistance was almost equal among the methicillin resistant and methicillin susceptible S. aureus isolates and it was not statistically significant. D test positive isolates showed higher resistance to ciprofloxacin, cotrimoxazole, and amikacin as compared to D test negative isolates [Table 2].
|Table 1: Association of clindamycin resistance with methicillin resistance|
Click here to view
|Table 2: Percentage antimicrobial resistance in D test +ve and −ve isolates|
Click here to view
| Discussion|| |
Clindamycin is used in the treatment of skin and soft-tissue infections, caused by staphylococcal species. Good oral absorption makes this drug an important option in outpatient therapy or as a follow-up after intravenous therapy. Clindamycin is also used as an alternative for patients who are allergic to penicillin. , The strains carrying inducible erm gene are resistant to the inducer and remain susceptible to non-inducer macrolides and lincosamides.  Treatment of an infection caused by a strain carrying inducible erm gene using clindamycin or any non-inducer macrolide can lead to clinical failure. ,, Constitutive mutants can be selected in vitro in the presence of clindamycin or any other non-inducer macrolide as they are widespread among methicillin-resistant strains.  In vitro routine tests for clindamycin susceptibility may fail to detect inducible clindamycin resistance due to erm genes resulting in treatment failure, thus necessitating the need to detect such resistance by a simple D test on a routine basis.
Among the 593 S. aureus isolates studied, 51.7% isolates were erythromycin resistant, which is higher (15.7%,  28.4%,  32.4%  ) than reported in literature; inducible clindamycin resistance was observed in 33.3% isolates whereas higher rate of inducible clindamycin resistance (50.6%,  49%,  45%  ) and lower rate of inducible clindamycin resistance (10.5%,  13.1%  ) as compared to our study was reported by others. The percentage of inducible resistance was almost equal among methicillin resistant (33.2%) and methicillin susceptible (34.6%) S. aureus isolates, whereas higher inducible resistance in MRSA ,,, and MSSA , has been reported in other studies. Constitutive (21.9%) and MS phenotype (44.8%) clindamycin resistance was higher in our study as compared to reported in literature. ,
Reporting S. aureus as susceptible to clindamycin without checking for inducible resistance may result in institution of inappropriate clindamycin therapy. On the other hand, negative result for inducible clindamycin resistance confirms clindamycin susceptibility and provides a very good therapeutic option. 
Use of D test in a routine laboratory enables us in guiding the clinicians in judicious use of clindamycin, as clindamycin is not a suitable drug for D test positive isolates; while it can definitely prove to be a drug of choice in case of D test negative isolates.
| References|| |
|1.||Srinivasan A, Dick JD, Perl TM. Vancomycin resistance in staphylococci. Clin Microbiol Rev 2002;15:430-8. |
|2.||Johnson AP, Woodford N. Glycopeptide-resistant Staphylococcus aureus. J Atimicrob Chemother 2002;50:621-3. |
|3.||Eliopoulos GM. Quinupristin-dalfopristin and linezolid: Evidence and opinion. Clin Infect Dis 2003;36:473-81. |
|4.||Delialioglu N, Aslan G, Ozturk C, Baki V, Sen S, Emekdas G. Inducible clindamycin resistance in staphylococci isolated from clinical samples. Jpn J Infect Dis 2005;58:104-6. |
|5.||Deotale V, Mendiratta DK, Raut U, Narang P. Inducible clindamycin resistance in Staphylococcus aureus isolated from clinical samples. Indian J Med Microbiol 2010;28:124-6. |
|6.||Ciraj AM, Vinod P, Sreejith G, Rajani K. Inducible clindamycin resistance among clinical isolates of staphylococci. Indian J Pathol Microbiol 2009;52:49-51. |
|7.||Leclercq R. Mechanisms of resistance to macrolides and lincosamides: Nature of the resistance elements and their clinical implications. Clin Infect Dis 2002;34:482-92. |
|8.||Drinkovic D, Fuller ER, Shore KP, Holland DJ, Ellis-Pegler R. Clindamycin treatment of Staphylococcus aureus expressing inducible clindamycin resistance. J Antimicrob Chemother 2001;48:315-6. |
|9.||Siberry GK, Tekle T, Carroll K, Dick J. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis 2003;37:1257-60. |
|10.||Colle JG, Fraser AG, Marmion BP, Simmmons A, editors. Mackie and McCartney, Practical Medical Microbiology. 14 th ed. Amsterdam: Elsevier; 2006. |
|11.||Clinical and laboratory standards institute (CLSI). Performance standards for antimicrobial susceptibility testing; seventeenth informational supplement CLSI document, Wayne, PA, Jan 2007;27. |
|12.||Fiebelkorn KR, Crawford SA, McElmeel ML, Jorgensen JH. Practical disk diffusion method for detection of inducible clindamycin resistance in Staphylococcus aureus and coagulase-negative staphylococci. J Clin Microbiol 2003;41:4740-4. |
|13.||Weisblum B, Demohn V. Erythromycin inducible resistance in Staphylococcus aureus. Survey of antibiotic classes involved. J Bacteriol 1969;98:447-52. |
|14.||Watanakunakorn C. Clindamycin therapy of Staphylococcus aureus endocarditis. Clinical relapse and development of resistance to clindamycin, lincomycin and erythromycin. Am J Med 1976;60:419-25. |
|15.||Ajantha GS, Kulkarni RD, Shetty J, Shubhada C, Jain P. Phenotypic detection of inducible clindamycin resistance among Staphylococcus aureus isolates by using the lower limit of recommended inter-disk distance. Indian J Pathol Microbiol 2008;51:376-8. |
|16.||Prabhu K, Rao S, Rao V. Inducible clindamycin resistance in Staphylococcus aureus isolated from clinical samples. J Lab Physicians 2011;3:25-7. |
|17.||Goyal R, Singh NP, Manchanda V, Mathur M. Detection of clindamycin susceptibility in macrolide resistant phenotypes of Staphylococcus aureus. Indian J Med Microbiol 2004;22:251-4. |
|18.||Patel M, Waites KB, Moser SA, Cloud GA, Hoesley CJ. Prevalence of inducible clindamycin resistance among community- and hospital-associated Staphylococcus aureus isolates. J Clin Microbiol 2006;44:2481-4. |
|19.||Levin TP, Suh B, Axelrod P, Truant AL, Fekete T. Potential clindamycin resistance in clindamycin-susceptible, erythromycin-resistant Staphylococcus aureus: Report of a clinical failure. Antimicrob Agents Chemother 2005;49:1222-4. |
|20.||Perez LR, Caierao J, Antunes AL, d'Azevedo PA. Use of D test method to detect inducible clindamycin resistance in coagulase negative staphylococci (CoNS). Braz J Infect Dis 2007;11:186-8. |
[Table 1], [Table 2]
|This article has been cited by|
||Inducible Clindamycin resistance and MRSA amongst Staphylococcus aureus isolates: A phenotypic detection
| ||Purvi Gandhi,Tanvi Panwala,Dipal Jethwa |
| ||IP International Journal of Medical Microbiology and Tropical Diseases. 2021; 6(4): 222 |
|[Pubmed] | [DOI]|
||Dissemination of macrolides, fusidic acid and mupirocin resistance among Staphylococcus aureus clinical isolates
| ||Xingmei Liu,Shanshan Deng,Jinwei Huang,Yaling Huang,Yu Zhang,Qin Yan,Yanhong Wang,Yanyue Li,Chengfu Sun,Xu Jia |
| ||Oncotarget. 2017; 8(35): 58086 |
|[Pubmed] | [DOI]|
||Phenotypic and Genotypic Study of Inducible Clindamycin Resistance in Clinical Isolates of Staphylococcus aureus in Tabriz, Northwest Iran
| ||Mojtaba Nikbakht,Mohammad Ahangarzadeh Rezaee,Alka Hasani,Mohammad Reza Nahaei,Javid Sadeghi,Sirus Jedari Seifi |
| ||Jundishapur Journal of Microbiology. 2016; 10(1) |
|[Pubmed] | [DOI]|
||INDUCIBLE CLINDAMYCIN RESISTANCE IN STAPHYLOCOCCUS AUREUS ISOLATES AND ITS CORRELATION WITH MULTIDRUG RESISTANCE: A STUDY FROM NORTH INDIA
| ||Shivani Tyagi,Aroma Oberoi |
| ||Journal of Evolution of Medical and Dental Sciences. 2016; 5(16): 749 |
|[Pubmed] | [DOI]|