OBJECTIVE: To measure the in-vitro activity of various antibiotics including tigecycline against Gram negative and positive nosocomial aerobic isolates. METHODS: A total of 430 clinical isolates of both Gram positive (143) and negative (287) aerobic bacteria were used from 3 centres during the year 2006 and 2007. Minimum inhibitory concentration (MIC) was determined using broth micro dilution panels. Antibiotic resistance was interpreted using CLSI guidelines. RESULTS: Most of the isolates were resistant to more than one drug. Resistance to tigecycline was not found. Tigecycline (1 microg/ml) had low MIC against organisms tested. CONCLUSION: This data indicates that tigecycline, a new drug in its class, has broad-spectrum in-vitro activity against both Gram negative and positive nosocomial isolates. Therefore, it may be a suitable drug to be used for the treatment of highly resistant nosocomial infections

Ahmed, Altaf

Mirza, Sajjad

Zafar, Afia

English

eCommons@AKU

eCommons@AKUDepartment of Pathology and Laboratory Medicine Medical College, PakistanJanuary 2009Antimicrobial activity of tigecycline againstnosocomial pathogens in Pakistan: a multicenterstudyAltaf AhmedLiaquat National HospitalAfia ZafarAga Khan University, afia.zafar@aku.eduSajjad MirzaArmed Forces Institute of Pathology, RawalpindiFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiolPart of the Pathology CommonsRecommended CitationAhmed, A., Zafar, A., Mirza, S. (2009). Antimicrobial activity of tigecycline against nosocomial pathogens in Pakistan: a multicenterstudy. Journal of Pakistan Medical Association, 59(4), 240-242.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiol/608Vol. 59, No. 4, April 2009 240Original ArticleAntimicrobial activity of Tigecycline against nosocomialpathogens in Pakistan: A multicenter studyAltaf Ahmed,1 Afia Zafar,2 Sajjad Mirza3Liaquat National Hospital,1 Aga Khan University Hospital,2 Karachi, Armed Forces Institute of Pathology,3 Rawalpindi.AbstractObjective: To measure the in-vitro activity of various antibiotics including tigecycline against Gram negative andpositive nosocomial aerobic isolates.Methods: A total of 430 clinical isolates of both Gram positive (143) and negative (287) aerobic bacteria wereused from 3 centres during the year 2006 and 2007. Minimum inhibitory concentration (MIC) was determinedusing broth micro dilution panels. Antibiotic resistance was interpreted using CLSI guidelines. Results: Most of the isolates were resistant to more than one drug. Resistance to tigecycline was not found.Tigecycline (1ug/ml) had low MIC against organisms tested.Conclusion: This data indicates that tigecycline, a new drug in its class, has broad-spectrum in-vitro activityagainst both Gram negative and positive nosocomial isolates. Therefore, it may be a suitable drug to be used forthe treatment of highly resistant nosocomial infections (JPMA 59:240; 2009).IntroductionIrrational use of antibiotics has resulted in theemergence of resistant bacteria globally. In Pakistan, lack ofinfection control practice and non existent formal antibioticpolicies has further augmented this problem. There have beenreports from all over the country on the rising trend ofnosocomial pathogens producing extended spectrum betalactamase (ESBL) and methicillin resistant Staphylococcusaureus.1-4 Infections due to these organisms have resulted inincreased mortality, morbidity and cost of treatment.5Tigecycline is a new injectable glycylcyclineantibacterial product. It inhibits protein translation inbacteria by binding to the 30S ribosomal subunit andblocking entry of amino-acyl tRNA molecules into the Asite of the ribosome. This prevents incorporation of aminoacid residues into elongating peptide chains resulting ininhibition of protein synthesis.This study was conducted to evaluate the in-vitroactivity of tigecycline against nosocomial pathogens(aerobic) and compare its activity with other commonly usedantibiotics in our hospitals. Materials and MethodsNosocomial isolates were tested at three differenthospital laboratories between 2006 and 2007. Thelaboratories which participated were Liaquat NationalHospital Karachi, Aga Khan University Hospital Karachi andArmed Forces Institute of Pathology, Rawalpindi. A total of430 Clinical isolates of both Aerobic Gram positive (143) andGram negative (287) aerobic bacteria were included from alltypes of specimens. Clinically significant isolates wereidentified on the basis of Gram stain, morphology andbiochemical reactions. Final confirmation of isolates was alsoperformed by Laboratories International for microbiologystudies, a division of International Health ManagementAssociates, Inc, Schaumburg, IL, USA.Minimum inhibitory concentrations (MICs) weredetermined by the broth microdilution method of theClinical and Laboratory Standards Institute (CLSI) usinggram-negative broth panels (Microscan, Dade Behring,Sacramento, CA, USA). All panels were incubated for 16-20 hours aerobically at 350C as per CLSI guidelines.6Quality control strains used were E.coli ATCC 25922,Staphylococcus aureus ATCC 29213, E.faecalis ATCC29212, S.pneumoniae ATCC 49619, and H.influenzaeATCC 49247. These were all sensitive strains. They wereused with each batch as indicated.Susceptibilities were determined according to theinterpretive criteria of CLSI.6 No interpretive criteria fordisc diffusion method have been approved fortigecycline when testing Acinetobacter spp. E.coli andK.pneumoniae were tested for ESBL production usingCLSI guidelines.MICs and susceptibilities were determined againstamoxicillin-clavulanate, piperacillin-tazobactam, levofloxacin,minocycline, ceftazidime, ceftriaxone, cefepime, imipenem,amikacin, ampicillin and tigecycline. Tigecycline, ampicillinand amoxicillin-clavulanate were not tested againstAcinetobacter spp., as no interpretive criteria were available fordisc diffusion methodology. Pseudomonas aeruginosa is notreported in this study as it is intrinsically resistant totigecycline.ResultsResults of isolates tested by both disc diffusion methodand MICs are given.Tigecycline showed no resistance by disc diffusionmethod against all 360 isolates included in the study (Table1). This included both Gram positive (Enterococcus spp.,Staphylococc aureus and Streptococcus spp.) and negativeisolates (Enterobacter spp., Klebsiella pneumoniae.,Serratia spp. and Eschericia coli). It also showed very lowMIC against all isolates including Acinetobacter spp. (Table2). Acinetobacter spp. on the other hand had higher MICsfor all antibiotics including imipenem but for tigecyclineMIC was very low (1 ug/ml) (Table 3).DiscussionWe report uniform activity of tigecyline againstnosocomial Gram negative and positive organisms isolated inthree clinical microbiology laboratories affiliated with tertiarycare hospitals. We also report low MICs (1-2 ug/ml) oftigecycline for isolates we tested. Antimicrobial resistance among Gram negative andpositive pathogens in Pakistan is on the rise. A number ofreports have been published showing presence of ESBLproducing E.coli and Klebsiella species in the community aswell as in hospitals. Recently Jabeen et al reported 40% of the2840 isolates tested as ESBL producers. Among theses ESBLpositive isolates 50% were Enterobacter species, 41% E.coliand 36% K. pneumoniae.1 In another study conducted in 1999the frequency of ESBL producing enterobacteriacae was 35%.2In a multicenter study Hafiz et al reported frequency ofisolation of MRSA as 42%.3Prevalence of multiresistant Acinetobacter spp. is alsorising in intensive care units making treatment options muchmore costly and difficult. In a recent study conducted in atertiary care hospital in Karachi, 65% isolates of Acinetobacterspecies. obtained from blood isolates of febrile neutropenicpatients were resistant to imipenem.7 The emergence ofcarbapenem resistance among Acinetobacter species isalarming. In our study imipenem resistance in Acinetobacterspp. was 63%. This study also shows high MIC 90 for severalantibiotics against Acinetobacter species. However tigecyclineshowed low MICs of <2ug/ml for majority of the isolatestested. This finding is in concordance with Diane et al.8 ForMRSA and for ESBL producing Enterobacteriaceae in-vitroresults of tigecycline are in full agreement with other studiesreported earlier.8,9 This drug was found uniformly activeagainst both groups of organisms with low MIC results. Tigecycline is the first of the glycylcyclines which has241 J Pak Med AssocTable: 1 Susceptibility pattern of tigecycline against variousisolates by disc diffusion method (n=360).Organisms Number % Susceptibility % Intermediate % ResistanceEnterobacter spp. 48 97.92 2.08 0Enterococcus spp. 44 100 0 0Eschericia coli 76 100 0 0Klebsiella pneumoniae. 71 94.29 5.71 0Staphylococcus aureus 69 100 0 0Serratia spp. 23 90.91 9.09 0Strep. pneumoniae. 30 100 0 0Table: 2 MICs of tigecycline against various pathogens (n=430).Organisms Number MICs ug/mlStaphylococcus aureus 69 0.5Acinetobacter spp. 41 1Enterobacter spp. 48 1E. coli 76 0.5K. pneumoniae 71 2Enterococcus spp. 44 0.25Haemophilus spp. 29 0.5Strept. pneumoniae 30 0.06Serratia spp. 22 2Table 3: MICs of Acinetobacter species (41) against variousantibiotics.Acinetobacter species MICs ug/mlAmikacin 128Amoxicillin/clavulanic acid 64Ampicillin 64Cefepime 64Ceftazidime 64Ceftriaxone 128Imipenem 32Levofloxacin 16Minocycline 4Piperacillin/tazobactam 256Tigecycline 1been marketed recently. It has remained unaffected by bacterialresistance due to a number of defense mechanisms such asprotein binding, beta-lactamase production (ESBL production,AmpC hyperproducers), DNA gyrase alterations, the vanresistance genes, plus other mechanisms that are used by manyof the commonly encountered isolates in community-acquiredand nosocomial infections.10-12A study published by Jabeen et al1 reported that inenterobacteriaceae resistance to non-beta lactam antibiotics(fluoroquinolones, aminoglycosides and co-trimoxazole) wasmore frequent in ESBL producing organisms (p<0.05) than innon ESBL producers. Cross resistance to amikacin,gentamicin, co-trimoxazole and ofloxacin was 14%, 51%,22%, 41% among ESBL producers than non-ESBL isolates. Inthis study none of the ESBL producing organisms were foundresistant to imipenem, similar to our study. Authors were notable to check tigecycline as it was not available in 2005. Thisstudy showed lowest MIC for imipenem and tigecyclineagainst Enterobacter species and K. pneumoniae and the sameresult was found against E.coli followed by amikacin. ESBL producing K.pneumoniae did not show higherMICs for imipenem and tigecycline. However in USA a largescale study conducted found higher MICs against imipenem.(MIC 90 16ug/ml).11Finally, it is concluded that tigecycline is not yetaffected by various resistance mechanisms affecting otherantibiotics since that requires research at a molecular level. Ithas broad spectrum activity against both Gram negative andpositive nosocomial isolates. Therefore we suggest that in thecurrent situation it can be a suitable drug for the treatment ofhighly resistant nosocomial infections and it should not be usedfor empirical treatment. For future, we recommend that to dealwith the ever-increasing antimicrobial resistance, it isnecessary to monitor resistance patterns carefully andcontinuously.AcknowledgementsThe authors acknowledge all investigators whocontributed to the study and also wish to thank HealthManagement Associates Inc, Schaumburg, IL, USA for theirconsistent support and guidance. This study was funded byWyeth Pharmaceuticals, USA.References1. Jabeen K, Zafar A, Hasan R. Frequency and sensitivity pattern of extendedspectrum beta lactamases producing isolates in a tertiary care hospital laboratoryof Pakistan. J Pak Med Assoc 2005; 55:436-9. 2. Zaman G, Karamat AK, Abbasi AS, Rafi S, Ikram A. Prevalence of extendedspectrum beta lactamases producing Enterobacteriacae in nosocomial isolates.Pak Armed Forces Med J 1999; 49: 91-6.3. Hafiz S, Hafiz AN, Ali H, Chughtai AS, Memon B, Ahmed A, et al. Methicillinresistant Staphylococcus aureus: a multicentre study. J Pak Med Assoc 2002;52:312-4.4. Mahmood A, Butt Tariq, Usman M. A study on MRSA isolates to detect reducedsusceptibility to vancomycin: A preliminary report. IDJ 2007; 16: 102-4.5. Ibrahim EH, Sherman G,Ward S, Fraser VJ, KollefMH. The influence ofinadequate antimicrobial treatment of bloodstream infections on patient outcomesin the ICU setting. Chest 2000; 118:146-55. 6. Clinical and Laboratory Standards Institute. Performance standard forantimicrobial susceptibility testing, document M100-S16. Wayne, PA:Clinical andLaboratory Standards Institute; 2006.7. Irfan S, Idrees F, Mehraj V, Habib F, Adil S, Hasan R. Emergence of Carbapenemresistant Gram negative and vancomycin resistant Gram positive organisms inbacteremic isolates of febrile neutropenic patients: a descriptive study. BMCInfect Dis 2008. Published online June 9. doi 10.1186/1471-2334-8-80.8. Diane C.Halstead, Joan Abid, Michael J. Dowzicky. Antimicrobial susceptibilityamong Acinetobacter calcoaceticus-baumannii complex and Enterobacteriaceaecollected as part of the Tigecycline evaluation and surveillance trial. J Infect.2007; 55: 49-57.9. Biedenbach DJ, Beach ML, Jones RN. In vitro antimicrobial activity of GAR-936tested against antibiotic-resistant Gram-positive blood stream infection isolatesand strains producing extended-spectrum betalactamases. Diagn Microbiol InfectDis 2001; 40:173-7. 10. Hamilton-Miller JM, Shah S. Activity of glycylcyclines CL 329998 and CL331002 against minocycline-resistant and other strains of methicillin resistantStaphylococcus aureus. J Antimicrob Chemother 1996; 37:1171-5. 11. Testa RT, Petersen PJ, Jacobus NV, Sum PE, Lee VJ, Tally FP In vitro and in vivoantibacterial activities of the glycylcyclines, a new class of semisynthetictetracyclines. Antimicrob Agents Chemother1993; 37:2270-7. 12. Weiss WJ, Jacobus NV, Petersen PJ, Testa RT. Susceptibility of enterococci,methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae to theglycylcyclines. J Antimicrob Chemother1995; 36:225-30.Vol. 59, No. 4, April 2009 242

Antimicrobial activity of tigecycline against nosocomial pathogens in Pakistan: a multicenter study

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Antimicrobial activity of tigecycline against nosocomial pathogens in Pakistan: a multicenter study

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