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 ~  Abstract
 ~  Materials and Me...
 ~  Results
 ~  Discussion
 ~  Acknowledgements
 ~  References

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BRIEF COMMUNICATION
Year : 2004  |  Volume : 22  |  Issue : 2  |  Page : 107-111
 

Sensitivity index of antimicrobial agents: A new treatment criteria proposed for rational use of antimicrobials


National Institute of Biologicals, Min. Health and Family Welfare, A-32, Sector-62, Institutional Area, Noida - 201307, Uttar Pradesh, India

Correspondence Address:
National Institute of Biologicals, Min. Health and Family Welfare, A-32, Sector-62, Institutional Area, Noida - 201307, Uttar Pradesh, India

 ~ Abstract 

The treatment guidelines are generally decided on the basis of either percent resistant (%R) or percent sensitive (%S) bacterial population tested with a given antimicrobial that vary geographically and represent only a part of total bacterial population existing in response to the antimicrobial used. The isolates with intermediate sensitivity (%I) are either not reported or clubbed with resistant isolates though the two may differ in clinical response. Sensitivity Index (SI) of an antimicrobial is sensitive to change in any of the three co-existing bacterial population and may be a better criterion for rational use of antimicrobial.

How to cite this article:
Achla P, Sudha V, Soni G R, Khare S, Bhatia R. Sensitivity index of antimicrobial agents: A new treatment criteria proposed for rational use of antimicrobials. Indian J Med Microbiol 2004;22:107-11


How to cite this URL:
Achla P, Sudha V, Soni G R, Khare S, Bhatia R. Sensitivity index of antimicrobial agents: A new treatment criteria proposed for rational use of antimicrobials. Indian J Med Microbiol [serial online] 2004 [cited 2019 Sep 22];22:107-11. Available from: http://www.ijmm.org/text.asp?2004/22/2/107/8082


The treatment with an antimicrobial is decided either on the basis of antibiogram of the individual isolate or, if sensitivity testing data is available, on the basis of % Resistant (%R) and / or %Sensitive (%S) bacterial population. In doing so either single isolate or, in latter case, only one of the three variables (co-existing sensitive, resistant and intermediate bacterial populations in relation to a drug) is considered. The response of intermediate isolates (with low level resistance) is unpredictable and may result in treatment failure especially under selection pressure of the drug. Sensitivity Index of antimicrobial, (SI) calculated from percent Resistant Intermediate Sensitive (%RIS) results generated using standard NCCLS testing method and uniform analysis by WHONET5 might be a uniform and better criterion for rational use of antimicrobials.

 ~ Materials and Methods Top

A total of 326 isolates of  E.coli   were collected during June 2000- Mar, 2002 from a net work of four institutes- Lady Hardinge Medical College (LHMC- 1), Ram Manohar Lohia Hospital (RML- 41), Majeedia Hospital (MH-165) and Lal's Pathology Lab (LAL-119) on nutrient agar slopes provided by National Institute of Biologicals (NIB). These isolates were from various sample types; urine-232, stool-46, pus-28 and others-20 (blood-9, pleural fluid-1, semen-2, throat-1, and vaginal swab-6, aspirate-1). All E.coli isolates along with standard ATCC 25922 were tested with 19 drugs and the data was analysed by WHONET5 software.[1],[2] Control strains showed normal results during study period.

 ~ Results Top

WHONET5 %RIS analysis of data is given in [table]. It was observed that %S was > 50 for amikacin, gentamicin, netilimicin, imipenem and nitrofurantoin and that %R was < 20 for imipenem and amikacin, which are similar to other reports.[3],[4],[5],[6] Percent I population for drugs with %S>50 range between 1.4 - 26.1 with %R varying between 5.8 - 43.3. For drugs with %R< 20 the %I and %S are 1.4, 26.1 and 92.8, 54.9 respectively.
Till the 20th of total 69 E.coli isolates tested with imipenem the %S was 100 and %R and I remained as 0 % and in accordance to the report that IPM and meropenem are the most effective drugs against E.coli [Figure - 1]. The 20th isolate was resistant changing %S to 95 and %R to 5 with %I still at 0. As more R strains appeared (1- 64th isolate) %S changed marginally from 95-92.5%, %R varied from 5- 6.2 through a maximum of 8.8 % with %I still remaining at 0 %. The first Intermediate isolate was 65th isolate when %S became 92.3, %R-6.2% and %I-1.5%. In contrast to small changes in % populations, with each R or I strain, there is a clear decrease in corresponding SI value. Considering only %S (92.5), at 67th isolate, small and negligible proportions of I and R isolates present among a total of 69 isolates are likely to be ignored. SI values on the other hand, decrease from 100 to 15.4 with appearance of just few R and I strain. This shows that SI, as a single value, is more sensitive to change in any of the three co-existing population of bacteria for a given drug than individual %S or %R at a given point of time.

 ~ Discussion Top

In spite of uniform and standard testing as well as analysis method, in present work, variation of %S, R and I populations are seen for E.coli isolates for all drugs (5-15% for individual drug at six month duration). Such variation of % populations was observed, at a given time, for isolates from different samples and institutes also. Considering only one of three co-existing populations (%R / %S), as done usually, not only gives variation of interpretation (hence drug policy) but also ignores %I. Intermediate population, a category implying clinical efficacy in body sites where the drugs are physiologically concentrated or when a higher than the normal dosage of a drug can be used, is either not reported or reported as R and their response rates may be lower than for susceptible isolates.[1],[7] The response of isolates with low level resistance (co-existing with S and R strains) is unpredictable and this not only complicates but also makes it difficult at times to manage treatment leading to irrational use of antimicrobials.[3],[4],[5],[6],[7],[8],[9],[10],[11] Owing to the lack of resistance trends to antibiotics and a clear guideline; treatment is given on the basis of individual report, by hit and trial, using combination therapy with newer broad-spectrum antibiotics for speedy recovery. When decided on the basis of only one of the three bacterial populations co-existing under selection pressure of the drug, that too varying geographically, may result in inappropriate treatment and / or its failure.[6],[7],[8],[9],[10]
While analysing %RIS data of E.coli a curious correlation between %S / %R ratio for different drugs (coined the term Sensitivity Index -SI of the antimicrobial) was seen that changed as soon as a resistant or intermediate isolate emerged in data. To interpret SI - greater the numerator (%S in case of SI); greater is SI value, and as denominator (%R in SI) becomes close/ equal to numerator (%S) SI value becomes £1. In present work SI of many drugs for E.coli was £1 indicating overall balance of the two populations in favour of resistance [Table]. This is in spite of %R or %S being in acceptable range when considered individually (not including %I) explaining non-satisfactory treatment outcome.[3],[4],[5],[6],[7],[8],[9],[10] For cefotaxime %I was the highest (35.9%) amongst 19 drugs with SI also <1. There are reports about use as well as resistance and / or delayed response to cefotaxime (due to increased I population?) implying need to regulate its use.[6],[8],[9],[10],[11],[12]
A drug is usually used till its %S is 60-70 and by that time %R and %I emerge in small proportions that are likely to be ignored.[5],[7],[10] Infectious Disease Society of America (IDSA), recommends using alternative of trimethoprim (SXT) for treating E.coli urinary tract infection (UTI) in a population with resistance to it ranging between 10-20% and more.[5] By considering only %R as 20, the actual scenario is missed and treatment failure with sulphamethazole-trimethoprim might be encountered even at resistance prevalence of <20%.[3],[4],[5],[6],[10] Presuming that in a population with 10-20% resistance rate, 80-90% population is sensitive to trimethoprim, the corresponding SI values for sulphamethazole-trimethoprim would range between 4 -9 implying the judicious use of sulphamethoxazole-trimethoprim when its SI approaches 10 (or on safer side somewhere 10-15). In present study, SI of 17 of 19 tested is either less than or close to 1 indicating either resistance or shift towards it. Present state not only indicates lack of monitoring and data analysis in past but also continued use/misuse of antimicrobials that could have been checked earlier by the cautious use of these drugs when their SI was about 10. SI of an antimicrobial, therefore, may warn much earlier than the drug actually becomes ineffective for treatment. Resistance in UTI due to E.coli, as told by a practicing gynecologist, microbiologists of network institutes, clinicians at RML Hospital and also reported may be due to this reason.[3],[4],[5],[6],[10] To prescribe such a cut off SI value, a clinical correlation is needed and clinicians have expressed and felt the need of such criterion.
Percent I population being at the interface of the S and R, is crucial and acts like a 'wedge' on which the balance of the S and R populations rests. With SI remaining about 1.5 from 254th - 326th isolates, an interesting dynamics of three populations was in fact observed on analysis of E.coli %RIS data for ceftazidime in present study [Figure:2].
As per value of SI, the net population equilibrium for ceftazidime is in favour of resistance, which is not evident from only %S that varies from 50-60% or %R that remains stable at 30%. There is ballooning of %I (254th through 282nd isolate) population with simultaneous and inverse changes of %S without much change in %R. This reflects a crucial phase - the lag phase or the phase of slow emergence and spread of resistance under continued drug use as SI decrease to 1-2 thereby, probably, undergoing population dynamics as presently seen for ceftazidime.
Similar findings, that %R remained low despite continued use of ciprofloxacin, have been reported for E.coli and  S.typhi  .[5],[10] During present study in the year 2001 there was an outbreak of typhoid at Delhi showing resistance to the empiric therapy with ciprofloxacin though outbreak isolates were sensitive to ciprofloxacin (%RIS as 2.9, 26.3 and 70.9 and SI=24.4 at that time) as earlier reported.[8],[9],[11],[12],[13] This can be explained by the highest % I and the lowest SI value, as per our criteria for ciprofloxacin, with %S or %R showing undetectable individual change. At present for S typhi (details not given) %S for ciprofloxacin, cefotaxime, ceftriaxone and ofloxacin are in good figures (69.5, 90.2, 91.5 and 95.7 % respectively) with very small / similar %R (3,S.typhi  class="ref" name="ft3" href="#ref3">3,3,0.6 respectively) and % I being (27.4, 6.7, 5.5, 3.7 respectively) still there are reports of treatment failure/ delayed response/sensitivity to only high dose and / or increase in MIC to one or the other drug.[8],[9],[11],[12],[13] SI analysis of same data gives a clearer interpretation; with SI~100; ofloxacin is expected to be most effective followed by ceftriaxone (SI-30.5), cefotaxime (SI-30.06) and ciprofloxacin likely to be effective with an existing SI-23.1 and this correlates with the reported clinical experiences.[8],[9],[11],[12],[13] Gradual re-emergence of % sensitivity of S.typhi with possible reconsideration to use chloramphenicol for treatment of typhoid, after almost 10 years of its discontinued use, has been reported.[13]. Present SI value of chloramphenicol is 1.205 (i.e., favouring resistance) and its re-introduction for typhoid treatment may not be wise at present (data not shown). SI of an antimicrobial can, thus, indicate timely implementation of introduction / re- introduction, elimination, restriction and / or rotation of drugs to minimise their selection pressure.
By SI analysis irrespective of variation in % population the choice in decreasing order is imipenem, amikacin, nitrofurantoin, netilimicin and ceftazidime for E.coli infections at all the four institutions (average SI 16, 2.75, 2.5, 1.93 and 1.57 respectively) [Table]. Isolates from private / commercial institutes that do not analyse data showed higher resistance. SI analyses of data for different sample isolates indicates that imipenem (SI-4) and amikacin (2.14) are the two drugs of choice for pus isolates and only amikacin (4.14) is expected to work on stool isolates. For urine isolates nitrofurantoin and amikacin should be used first before treating with imipenem (SI-3.3, 2.6 and 18.6 respectively). Such distinction could not be made on the basis of %R or %S data.
To summarise, SI of an antimicrobial, as a single figure, may be a more rational, precise, geographically uniform and sensitive indicator for formulating /modifying guidelines for empiric treatment, based on actual shift amongst co-existing population categories of bacteria in response to drug use. SI criteria, if suitably validated by clinical correlation, would also fulfill first three of the four strategies of Joint Committee on the Prevention of Antimicrobial Resistance (JCPAR).[12] SI is simple to calculate from the routine data, generated in any microbiology laboratory using Kirby Bauer disk diffusion (NCCLS) method for antibiotic susceptibility testing, and its uniform analysis by WHONET5.[1],[2] Local networking of institutes, as in present work, can generate reliable and uniform national data on Antimicrobial Resistance Monitoring (ARM) that can be shared among network laboratories.[2],[12],[14]

 ~ Acknowledgements Top

We are thankful to Prof. PK Pillai, (MH) New Delhi; Dr. Geeta Mehta, LHMC, New Delhi; Dr. Charu Hans, RMLH, New Delhi; Dr. A Lal, New Delhi, for providing the samples for this study. We are also thankful to the staff of network institutes for their co-operation in collection of clinical isolates for this study. 

 ~ References Top

1.National Committee for Clinical Laboratory Standards. Performance standards for Antimicrobial Disk Susceptibility Tests; Approved Standards, 7th ed. 2000,20:1.  Back to cited text no. 1    
2.WHONET5, Microbiology Laboratory Database Software. WHO. Department of Communicable Diseases Surveillance and Response. World Health Organization, CSR/DRS, 1211 Geneva, 27, Switzerland.  Back to cited text no. 2    
3.Gupta V, Yadav A, Joshi RM. Antibiotic resistance pattern in uropathogens. Indian J Med Microbiol 2002;20:96-98.  Back to cited text no. 3    
4.Kumar CSV, Jairam A, Chetan S, Sudesh P, Kapur I, Srikaramallya. Asymptomatic bacteriuria in school going children. Indian J Med Microbiol 2002;20:29-32.  Back to cited text no. 4    
5.Sahm DF, Thornsberry C, Mayfield DC, Jones ME, Karlowsky JA. Multidrug - Resistant Urinary Tract Isolates of Escherichia coli: Prevalence and Patient Demographics in United States in 2000. Antimicrob Agents Chemother 2000;45:1402-1406.  Back to cited text no. 5    
6.European Antimicrobial Resistance Surveillance System. EARSS Newsletter, No.4: 2002.Ed.EARSS Management Team, National Institute of Public Health and the Environment(RIVM, the Netherlands)  Back to cited text no. 6    
7.Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, Dean N, File T, Fine MJ, Gross PA, Martinez F, Marrie TJ, Plouffe JF, Ramirez J, Sarosi GA, Torres A, Wilson R, Yu LL, American Thoracic Society. Guidelines for the Management of Adults with Community Acquired Pneumonia. Executive Summary. Am J Respir Crit Care Med 2001;163(7):1730-1754.  Back to cited text no. 7    
8.Adhikari KM, Prabha MR, Baliga S. Ciprofloxacin resistant typhoid with incomplete response to Cefotaxime. JAPI 2002;50:428-29  Back to cited text no. 8    
9.Chogle A R. Multidrug resistant salmonellosis: an escalating problem. JAPI 2002; 50:375-377.  Back to cited text no. 9    
10.Kücükates E, Kocazybeck B. High resistance rate against 15 different antibiotics in aerobic gram-negative bacteria isolates of cardiology intensive care unit patients. Indian J Med Microbiol 2002;20:208-210.  Back to cited text no. 10    
11.Gopal N, Rajeev K. Pattern of multi-drug resistance and phage types in Salmonella enterica subspecies enterica serotype Typhi in Varanasi during 1979-1997.Indian J Med Microbiol 1999;17:97-98.  Back to cited text no. 11    
12.Chaudhary A. In vitro activity of Cefpirome: A new fourth generation Cephalosporin. Indian J Med Microbiol.2003;21:52-53.   Back to cited text no. 12    
13.Sood S, Arti K, Das BK, Seth P. Typhoid Fever Treatment: A Continuing Challenge. Indian J Med Microbiol 1999;17(3):153.  Back to cited text no. 13    
14.Shales DM, Gerding DN, John JF, Craig WA, Bornstein DL, Duncan RA, Eckman MR, Farrer WE, Greene WH, Lorian V, Levy S, McGowan JE, Paul SM, Ruskin J, Tenover FC, Watanakunakorn C. Guidelines for the Prevention of Antimicrobial Resistance in hospitals by Society for Health Care Epidemiology of America and Infectious Disease Society of America Joint Committee on the Prevention of Antimicrobial Resistance (JCPAR). Clin.Infect.Dis.1997;25:584-599.  Back to cited text no. 14    
15.O'Brien TF, Stelling JM. WHONET: Removing obstacles to the full use of information about antimicrobial resistance. Diag Microbiol Infect Dis 1996;25:162-168.  Back to cited text no. 15    
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