The Analysis of Antibiotic Consumption and Bacterial Resistance in Tertiary Healthcare Centre Niš A

The Analysis of Antibiotic Consumption and Bacterial Resistance in Tertiary Healthcare Centre Niš A Radmila M. Veličković-Radovanović1,2, Nikola Z. Stefanović2, Ivana D. Damnjanović2, Jasmina D. Petrović1, Radmila V. Mitić1, Branka D. Kocić2,3, Snežana S. Antić3, Marina M. Dinić2,3, Aleksandra K. Catić-Đorđević2 A 1 Clinical Centre of Nis, Nis, Serbia 2 Faculty of Medicine, University of Nis, Nis, Serbia 3 Public Health Institute of Nis, Nis, Serbia A SUMMARY


INTRODUCTION
Antibiotics are the most used drugs within hospitalized patients and represents 15 -30 % of all prescribed drugs at the hospitals.Providing rationale antibiotic pharmacotherapy in the tertiary health care includes antibiotic procurement, prescribing, dispensing and administration [1,2].Studies showed that in almost half of prescribed antibiotics, their usage were inadequate.Th e increasing rate of antibiotic resistance represents an increasing global public health problem in Europe and worldwide leading to less eff ective treatment of bacterial infections, growing costs and mortality [3,4].Th erefore, European countries try to implement actions to control antimicrobial resistance in the community and the hospitals as well, providing rational use of antimicrobials [5].Additionally, intra-and inter-hospital spread of resistant microorganisms, community contribution to resistance, and infection control policies and practices, may also play a role in determining the burden of resistance in a hospitals [6].Th e major pathogens in community-acquired intra-abdominal (IAI) and urinary tract infections (UTI) are coliforms, Enterobacteriaceae, especially E. coli and Klebsiella sp.[7,8].Adequate empiric therapy of these bacterial infections appears to be crucial for reducing postoperative complications and mortality rates, but carries the risk of increased bacterial resistance [9].
Th e aim of this work is the evaluation of antibiotic consumption in Clinical Centre Nis, from 2011 to 2014, with the focus on the monitoring of the ceft riaxone (CTX) and ciprofl oxacin (CIP) utilization.Secondly, we screened bacterial resistance towards monitored antibiotics used for IAI and UTI in tertiary healthcare institution.

METHODS
Antibiotics consumption and antimicrobial resistance were monitored in the Clinical Centre Nis, Serbia: a 1460-bed, tertiary care university hospital in Serbia, in the study period extended from 2011. to 2014.As this study did not have data on individual patients and surveillance was a part of quality assurance, approval by Ethical Committee was not considered necessary.Th is study has generally used the WHO classifi cation system ATC and the volume unit defi ned daily dose (DDD).Uti-lization of antibiotics in the Clinical Center Niš in the observed period was obtained from the computerized database of the Department of Clinical Pharmacology and expressed as DDD per 100 bed/days (DBD).Following implementation of a restriction policy in 2011, prescription of some antibiotics (carbapenems, piperacillin/ tazobactam, vancomycin, linezolid, tigecycline) was controlled.Th ese agents could only be prescribed aft er consultation with a clinical pharmacologist / infectious disease specialist consultation or approval by the medical director.

Microbial resistance data
Th e bacteriological laboratory of the Institute for Public Health Nis routinely screens microbial resistance/sensitivity for all cases requiring antibiotic therapy, except for prophylactic use.Bacterial strains were isolated from clinical material from hospitalized patients and susceptibility to antibiotics was assessed by the diff usion and standard microdilution methods.Th e process of testing the susceptibility of bacteria to antibacterial medicines is conducted according to the recommendations of the American National Committee for Clinical and Laboratory Standards and the European Committee for Antimicrobial Susceptibility Testing.Bacterial resistance was reported as the percentage of total isolates showing resistance.Th e burden of resistance for each antibiotic was calculated as the percentage of all 'Resistant' + 'Intermediate Resistant' results among all tested isolates from all patient samples (fluid from intra-abdominal infections, incisions, abscesses, fistulas, blood, urine, etc) [10,11].

Statistics
All calculations were performed using SPSS soft ware.

RESULTS
Trends of antibiotic consumption according to pharmacological groups from 2011. to 2014.are shown on Figure 1.
Th e most frequently used antibiotics were cephalosporins, followed by penicillins and quinolones.During the investigation period the use of cephalosporins increased by 6.39 %, from 2011. to 2013, but in 2014.there was a reduction in its consumption by 16.46 %.Penicillins consumption had a decreasing trend, whereas quinolones consumption was variable during observation period.
Figure 2 shows resistance of E. coli and Klebsiella sp. to CTX and CIP in the observed period from all patient samples.
Th ere was no signifi cant diff erence in E. coli and Klebsiella sp.resistance to CIP and CTX, during investigation period, whereas the CTX consumption (11.21-12.89DBD) was very high and CIP consumption (6.08-5 .39DBD)seemed to be moderate.
Th e distribution of pathogens in IAI and UTI (2011-2014) is shown on Figure 3.
Th e resistance of K. pneumoniae to CTX and CIP for the isolates from IAI, and resistance of E. coli to analyze antibiotics for isolates from UTI showed increasing trend within observed period of time.

DISCUSSION
Antibiotics are the background of the treatment of infectious diseases, but still one third have been prescribed inappropriately [12].Our analysis showed that cephalosporins were the most frequently prescribed antibiotics, followed by penicillins and quinolones (Figure 1).Versporten et al., report showed that Serbia took fi ft h place in antibiotic consumption among non-EU countries [13].It is assumed that demographic, cultural, and economic factors as well as supply-side factors such as the density of doctors and their prescribing policies may underlie diff erences in antibiotic use across geographical areas [14].In accordance to our results, Keuleyan et al., demonstrated an increase of third-generation cephalosporins consumption, but no change in penicillin and quinolones consumption on the territory of Bulgaria [15].Conversely, in the study conducted in Romania, the most prescribed antibiotics were penicillins plus beta-lactamase inhibitors, second-generation cephalosporins and fl uoroquinolones, but not third-generation cephalosporins [16].
An 11-year follow-up of antibiotics consumption at emergency department adults unit of an academic hospital showed increase in third-generation cephalosporins use from 9.7% of total antibiotic use to 22.6% (estimate per year, 1.2%), whereas use of fl uoroquinolones decreased from 19.5 to 12.3% (estimate per year, -0.7%) [17].Although, we noticed an decrease in third-generation cephalosporins use between 2011 and 2014, there was an increase in CTX consumption, which was the most prescribed antibiotic at our clinical centre (estimate per year, 3.7%).Conversely, we have decrease in CIP consumption within observed period (estimate per year, -2.8%).Given their ability to select bacterial resistance, especially extended-spectrum β-lactamases, particular attention should be paid to increasing use of third-generation cephalosporins in the hospital environment.Monitoring of antibiotic consumption is of crucial importance due to the increasing trend in antibiotic resistance globally.Among the rest, fl uoroquinolones and third-generation cephalosporins are particularly prone to select bacterial resistance to antibiotics [17,18,19].Our results show that high consumption of CTX from 2011 to 2014 corresponded to higher rate of E. coli and Klebsiella sp.resistance (Figure 2).Although, CIP consumption expressed in DBD, was approxi-  mately 50% less than CTX, the resistance of analyzed bacterial strains was also high to CIP.Ceft riaxone, along with other third-generation of cephalosporins, cefotaxime and ceft azidime, have been used in the treatment of IAI.Our fi ndings suggest an increase of K. pnumoniae resistance to CTX and CIP during study period for the IAI isolates (Table 1).Th is of the utmost importance due to acquired resistance to cephalosporins by the enterobacteriaceae may limit the use of those agents in high risk IAI [20].At the same observed period, E. coli resistance to CTX and CIP showed increasing trend for isolates from UTI (Table 1).Broad spectrum agents, such as fl uoroquinolones in 35%, cephalosporins in 27% and penicillins in 16% are the most commonly-used antibiotics for UTI [21].Routine antibiotic prophylaxis of all urological procedures was highest in Asia, Africa and Latin America with 86%, 85% and 84%, followed by Europe with 67%.Antibiotic prophylaxis was not always consistent with recommended guidelines [22].Tandogdu et al., showed that resistance to almost all pathogens isolated during UTI was lowest in North Europe, with no single year where an outbreak of resistance has been detected [23].Still, it was reported that resistance to CIP in E. coli from UTI in Denmark was increasing parallel to increased use of fl uoroquinolones, which also shown for another European countries [24].Resistance to CIP, which are the preferred empiric treatment for UTI, prolongs hospitalization and increases the cost of antibiotic treatment [25].

CONCLUSION
In conclusion, cephalosporins were the most frequently used antibiotics in Clinical Centre Nis, and they were followed by penicillins and quinolones.CTX was reported to have increased consumption, while CIP utilization seemed to be slightly reduced in 2011-2014 period.Th e prevalence of antibiotic resistance among E. coli and K. pneumoniae has increasing trend in recent years.Our fi ndings showed that K. pneumoniae resistance to CTX and CIP increased markedly in IAI, while E. coli resistance had increasing trend to CTX and CIP in UTI over the study period.Th is study provide additional basis for guidelines on the use of antimicrobial agents for treating Enterobacteriaceae infections, especially those caused by E. coli and K. pneumoniae.

Figure 1 .Figure 2 .
Figure 1.Trends of antibiotic consumption by pharmacological groups (in DBD) in the Clinical Center Niš from 2011 to 2014

Figure 3 .
Figure 3.The distribution of the major pathogens in IAI and UTI (2011-2014)

Table 1 .
Resistance to CTX and CIP of bacterial strains isolated from IAI and UTI