Phuture 15 2008

I P S F

E D U C A T I O N A L

S U P P L E M E N T

ISSUE NO. 15 JULY 2008

Message From IPSF

Table of Contents

Dear Readers,

Antibiotic Use and Emerging Bacterial Resistance 3

It is the pleasure of International Pharmaceutical Students' Federation (IPSF) to present you this issue of Phuture under the theme “Antibiotic resistance”. Through this issue, IPSF wants to spread some information of antibiotic resistance and discuss the ways to prevent and alleviate this problem.

Dr. Robert E. Siegel

Over the past decade, the dramatic upsurge in the spread of drug-resistant microbes throughout the globe has occurred. Many infectious diseases are becoming complex and difficult to treat and the treatment is becoming expensive.

Emergence and spread of antibiotic resistance in bacterial pathogens with special emphasis on

Antibiotic resistance is a major problem of present therapy. Antibiotic resistance is a major global problem worldwide especially in the developing countries. Increasing use of antimicrobials in humans, animals, and agriculture has resulted in many microbes developing resistance to these drugs. Many infectious diseases are increasingly difficult to treat because of antimicrobial-resistant organisms. The irrational prescribing, polypharmacy, self medication and lack of legislative framework for antibiotic prescription are the key factors for the development of antibiotic resistance. It is time that we take action. Many things can be done from the position where you are: whether you are a policy-maker, health care professional, health advocate or member of the public, can do to help tackle the problem. In this context, IPSF has published this scientific supplement on the theme antibiotic resistance.

ESBL producing bacteria: Growing problem for antibiotic resistance

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Dr. Malay Ranjan Sen and Amitabha Bhattacharjee

nosocomial infections 7 Prof. Dr. Wolfgang Witte

National Antibiotic Policy in the context of India Arati Sharma

Preventing

Antimicrobial

Resistance:

pharmacy students 10 Atmika Paudel and Binaya Sapkota

This issue contains articles by expertise in the field of microbiology, antibiotics research and students.

We are very grateful to all the authors for their kind contributions. Though antibiotic resistance is a broad term to embrace in this supplement, we have tried to show a glance on this growing global problem. We expect that the information and thoughts presented here will be useful and be able to stimulate and encourage readers to contribute in prevention and control for this growing problem to some extent.

Enjoy reading!

Suresh Panthee IPSF Chairperson of Education 2007-08

2 International Pharmaceutical Students’ Federation

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Cover design by Tendy Rusdiana

Role

of

Antibiotic Use and Emerging Bacterial Resistance Dr. Robert E. Siegel, Director, Pulmonary and Critical Care Medicine, James J. Peters Veterans Affairs Medical Center, 130 W. Kingsbridge Road, Bronx NY, 10468, Associate Professor of Medicine, Mount Sinai School of Medicine, New York, NY E-mail: robert.siegel@va.gov, Telephone: 917-842-6975, Fax: 718-741-4623

Doctors frequently prescribe antibiotics for upper respiratory tract infections (URI) even though most of are viral in origin.

Patient expectations to assure they can return to work or school places caregivers in an uncomfortable position, in which they cannot withhold antibiotics. A study of primary care practice shows that there are approximately 25 million visits to physicians for URI symptoms, and that although less than 1% are estimated to be due to bacteria, approximately one third of 4 patients are prescribed an antibiotic. Acute bronchitis, in otherwise healthy nonsmokers, is usually a viral illness and a meta-analysis of 8 placebo controlled trials showed that antibiotic reduced the duration of patient symptoms by less than a day.5 The presence of purulent sputum does not indicate a bacterial etiology and symptoms of cough and sputum production commonly last 1-2 weeks. Many patients complain that without antibiotics infection spreads into their chest, but they may actually be suffering virally induced bronchospasm, which may respond to inhaled bronchodilators.

The recommended approach for acute bronchitis, consists of medications to treat symptoms, including cough suppression, and reassurance that antibiotic will be prescribed if the condition deteriorates. When antibiotics are necessary, a macrolide or doxycycline to cover atypical pathogens and Streptococcus pneumoniae is usually adequate.

Prolonged, more traditional courses of antibiotics are now discouraged. The CDC recommends implementing policies to limit antibiotic overuse, and the World Health Organization suggests the use of the most potent antibiotic for the shortest duration. In a study of children ages 6 mos-5 years with URI symptoms, conducted in the Dominican Republic, patients were randomized to amoxicillin with standard dosing of 40 mg/kg/day for 10 days or high-dose, short course (HDSC) therapy of 90 mg/kg/day for 5 days. At the end of a month, the pharynx was swabbed to detect penicillin-resistant S. pneumoniae (PRSP).

Resistance rates were 24% for HDSC, 32% for standard dose p=.03, and there was less TMP/SMZ resistance in the HDSC group as well.6 The 2005 ATS/IDSA Guidelines for the treatment of HAP, VAP and Healthcare-acquired pneumonia (HCAP) recommends that VAP be treated for 7-8 days of antimicrobial therapy if the patient is started on the appropriate antibiotic from the beginning and responds to therapy.6 Longer treatment duration simply lead to colonization with resistant bacteria, since sensitive bacteria are killed, and resistant mutants survive to become the dominant pathogen.

Resistance:

Target alteration, as seen with altered penicillin binding proteins (PBP) 2.

Chemical warfare, as seen with beta-lactamase production and 3. Decreased antibiotic concentration in bacteria, either by porin protein changes reducing antibiotic entry or up regulation of efflux pump activity, extruding more antibiotic from the bacteria.

Higher resistance rates are being reported in community organisms, such as MDR Streptococcus pneumoniae and MRSA, as well as Gram negative pathogens such as E. coli and Enterobacter cloacae. In the critical care setting, rising rates of Pseudomonas aeruginosa and Acinetobacter baumannii are additional problems, with highly resistant pathogens leaving clinicians few treatment alternatives. The rigid division between community-acquired organisms and hospital-acquired organisms has been blurred since so many patients visit the hospital for therapy or reside in nursing homes.

Community Organisms: Rising rates of PRSP and multi-drug resistance S. pneumonia (MDRSP) are changing the way pulmonary infections are treated.

Resistance to β-lactam antibiotics is due to expression of a low affinity PBPs. Macrolide resistance is due to one of two mechanisms: up regulation of the efflux pump Mef(A), leading to low-level resistance which may be overcome by high antibiotic concentration, or a ribosomal target change Erm(B), which can cause very high MICs and lead to clinical failure.

These resistance rates are being driven by overuse of antibiotics for upper RTIs. Pneumococcal macrolide resistance rates over 30% are reported in many parts of the US, driving increased use of respiratory fluoroquinolones for patients who have communityacquired pneumonia (CAP) with risk factors for resistance. Risk factors include recent antibiotic therapy, previous stay in a risk area (day care, prison, homeless shelter, or nursing home), alcoholism and previous RTI.9 If an isolate is penicillin resistant, only 20% of the isolates will be macrolide susceptible.

Susceptibility rates of S. pneumoniae to the respiratory fluoroquinolones, levofloxacin, gemifloxacin and moxifloxacin have been stable at about 99%, but rates for ciprofloxacin are much lower reported at 82%.9 In the US, ciprofloxacin has recently become a generic product, raising concern, since therapeutic substitution for the respiratory FQs may drive overuse of ciprofloxacin, increasing S. pneumoniae FQ resistance rates, and risking the utility of this important class of antibiotics.

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World-wide bacterial resistance rates continue to increase and national resistance rates reflect overall antibiotic use in each country.1 Over 60% of all antibiotics consumed in the US are used in the animal industry both as anabolic agents to increase animal growth and to prevent the spread of infections, as animals are crowded into confined living spaces. The farming of fish and seafood has also led to the increased use of antibiotics, since a dense population facilitates the spread of infectious agents. A recent study of fish and shrimp in Canada showed that many contain veterinary drug residues, including antibiotics. 2 Bacterial resistance is increasingly seen as a public health threat since few new antibiotics options are being introduced. The Infectious Diseases Society of America (IDSA) education campaign of “Bad Bugs, No Drugs” was begun to raise public awareness of this problem.3

Hemophilus influenzae resistance is due to the production of a βlactamases, which destroy penicillin derivatives and firstgeneration cephalosporins. Rates of resistance from sinus isolates are about 30% for penicillin and 40% for macrolides in the US and β-lactamase production was almost 50% in a study in Bangkok, Thailand.10-11 Sinus infections are similar to an abscess or an undrained collection with poor perfusion into the infected area. Resistance may have more significance in sinusitis than in lung infections, where high concentrations of antibiotics can typically be achieved due to high blood flow.12 S. aureus resistance has long been a hospital problem and 70% of all hospital isolates are MRSA. Recently, community-acquired MRSA is also becoming common, and may produce the toxin Panton-Valentine leukocidin (PVL). These strains are typically resistant to oxacillin, macrolides and fluoroquinolones, but sensitive to doxycyline and TMP/SMZ, in addition to the drugs that treat health care strains: vancomycin, linezolid and daptomycin. Originally seen in athletes, infants, IV drug users

There are three main mechanisms of antibiotic resistance: 1.

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and prisoners, the community strain is now reported in patients without identifiable risk factors. It most commonly causes skin infections such as furunculosis, but may also produce more serious infections including necrotizing pneumonia. Treatment of skin infections frequently includes surgical drainage and oral antibiotics and washing linens and towels in the in hot water to prevent re-infection.

Gram-negative bacteria resistance

Antibiotic Resistance

Finally, gram negative resistance remains an increasingly serious problem, and the most common mechanism is βlactamase production, with over 700 β-lactamases having been described.13 Resistance in community acquired enterobacteraciae is being reported with E. coli and Klebsiella pneumoniae due to extended-spectrum β-lactamase (ESBL) production of the CTX-M type and these isolates may be MDR with FQ, aminoglycoside and sulfonamide resistance. E. coli resistance to levofloxacin and ciprofloxacin is now reported to be about 10% of isolates in the US, and being driven by widespread use of FQs for various infections including URIs and UTIs. Enterobacter cloacae hyper-production of Amp C βlactamase causing third generation cephalosporin resistance is also being reported among hospitalized patients.

ESBL production may be missed unless specific tests are performed by the microbiology lab to detect it and bacteria may test susceptible to cephalosporins by conventional breakpoints, although clinical failure is possible if they are ESBL producers.13 Pseudomonas aeruginosa and Acinetobacter baumannii are two ICU pathogens associated with higher mortality in HAP. P. aeruginosa is the most common causative ICU pathogen for HAP and UTI. Resistance is due to multiple mechanisms including ESBL production targeting cephalosporins, and both an Opr-D porin protein change and up regulation of efflux pumps to cause carbapenem resistance. A. baumannii causes sporadic outbreaks and although not a highly pathogenic organism, it is persistent on environmental surfaces and causes HAP or other hospital acquired infections. It is being reported in returning US soldiers from the Middle East due to the presence of this soil organism in wounds and hospitals.

Frequently it is only sensitive to polymyxin and tigecycline, and colistin is being nebulized for pulmonary infections to limit renal and CNS toxicity. Infection control practices are crucial to prevent spread of this organism and local outbreaks.

Practices to help maintain susceptibilities: The major hope to limit bacterial resistance rates is to promote the appropriate use antibiotics. First, they should be used in cases of suspected bacterial infection only. Newer methods of achieving microbiologic eradication and clinical cure should be employed: use of prolonged infusions of β-lactam antibiotics to take advantage of time dependent killing pharmacodynamics (PD), and the FQs as HDSC regimes to take advantage of concentration-dependent killing PD. Also, use of the most potent antibiotic for the shortest duration should be employed, instead of long courses which promote permissive growth of resistant bacteria. De-escalation of antibiotics in the ICU is recommended by the ATS/IDSA guidelines for the treatment of HAP/VAP and HCAP and should be extended to all ICU infections.7 This includes stopping antibiotics if infection is not apparent after antibiotics are initiated, and changing to narrow-spectrum agents if resistant pathogens are not isolated or if a susceptible pathogen is identified. All antibiotic classes should continue to be prescribed, so that resistance pressure for any one antibiotic class is limited. Finally, we should continue infection preventive measures, including 4 International Pharmaceutical Students’ Federation

administering vaccines and adhering to hand washing along with other infection control practices. In the ICU, simple techniques, such as elevating the head of the bed, daily sedation vacation to accelerate extubation of mechanically ventilated patients and identification and isolation of patients infected with resistant pathogens are important. In this way, we hope to maintain our antibiotic susceptibilities, as best we can, until new antibiotic classes are developed which can add to our armamentarium against the ever evolving pathogens we confront on a daily basis.

References: 1. Granizo JJ, Aguilar L, Casal J, Garcia-Rey C, Dal-Re R, Baquero F. Streptococcus pneumoniae resistance to erythromycin and penicillin in relation to macrolide and beta-lactam consumption in Spain (1979-1997). J Antimicrob Chemother.

2000;46(5):767-73.

2. Tittlemier SA, Van de Riet J, Burns G, Potter R, Murphy C, Rourke W, et al. Analysis of veterinary drug residues in fish and shrimp composites collected during the Canadian Total Dieg Study, 1993-2004. Food Addit Contam. 2007;24(1):1420.

3. Infectious Diseases Society of America. Bad bugs, no drugs.

As antibiotic discovery stagnates…a public health crisis brews.

Alexandria, VA: Infectious Diseases Society of America; 2004.

4. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis. 2001:33(6):757-62.

5. Bent S, Saint S, Vittinghoff E, Grady D. Antibiotics in acute bronchitis: a meta-analysis. Am J Med.1999;107:62-7.

6. Schrag SJ, Peña C, Fernández J, Sánchez J, Gómez V, Pérez E, Feris JM, Besser RE. Effect of short-course, high-dose amoxicillin therapy on resistant pneumococcal carriage: a randomized trial. JAMA. 2001;286(1):49-56.

7. American Thoracic Society/Infectious Diseases Society of America. Guidelines for the treatment of adults with hospitalacquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171(4):388416.

8. Ruhe JJ, Myers L, Mushatt D, Hasbun R. High-level penicillinnonsusceptible Streptococcus pneumoniae bacteremia: identification of a low-risk subgroup. Clin Infect Dis. 2004;38(4):508-14.

9. TRUST study (Tracking Resistance in the US Today), Postgraduate Med (Suppl), In Press.

10. Critchley IA, Brown SD, Traczewski MM, Tillotson GS, Janjic N. National and redional assessment of antimicrobial resistance among communigy-acquired respiratory tract pathogens identified in a 2005-2006 U.S. Faropenem surveillance study.

Antimicrob Aents Chemother. 2007;51(12):4382-9.

11.

Srifuengfung S, Chayakulkeeree M, Chokephaibulkit K, Tribuddharat C. Five-year study of antimicrobial susceptibility and beta-lactamase production in Haemophilus infuenzae.

Southeast Asian J Trop Med Public Health. 2007;38(4):732-6.

12. Siegel RE. The significance of serum versus tissue level of antibiotics in the treatment of penicillin-resistant Streptococcus pneumonia and community-acquired pneumonia.

Are we looking in the wrong place? Chest 1999;116(2):535-538.

13. Perez F, Endimiani A, Hujer KM, Bonomo RA. The continuing challenge of ESBLS. Curr Opin Pharmacol. 2007;7(5):459469.

ESBL producing bacteria: Growing problem for antibiotic resistance Dr. Malay Ranjan Sen, Professor and Amitabha Bhattacharjee, Senior Research Fellow Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, INDIA email: mr_senbhu@yahoo.com and ab_0404@rediffmail.com

In recent years, there has been a growing prevalence of Gram negative organisms which have almost replaced Staphylococcus aureus in nosocomial infections. It is also observed that Gram negative bacteria were the most common blood stream pathogens. Moreover fatalities among patients infected with Gram negative bacilli are higher than those among patients who have Gram positive cocci as causative agents. The situation complicates more with the isolation of the organisms that are resistant to multiple antibiotics especially against beta lactam antibiotics.

The β-lactamases are the major defense of Gram negative bacteria against β-lactam antibiotics. These enzymes contain an active site consisting of a narrow longitudinal groove, with a cavity on its floor (the oxyanion pocket), which is loosely constructed in order to have conformational flexibility in terms of substrate binding. Close to this lies the serine residue that irreversibly reacts with the carbonyl carbon of the β-lactam ring, resulting in an open ring (inactive β-lactam) and regenerating the β-lactamase. β-Lactamases, serine residue at the active site, similar to bacterial penicillin binding proteins, is estimated from current sequence diversity to have evolved with bacteria over past 2 billion years. Since β-lactam antibiotics came in to clinical use, these enzymes coevolved with them. Around 20 years ago, agents resistant to common β-lactamase enzymes were introduced, which include third generation cephalosporins and the monobactam. Bacteria responded with a new β lactamase called “extended spectrum β-lactamase” (ESBL) with variable success, can confer resistance to the latest third and fourth generation cephalosporins and monobactam. Today more than hundreds of ESBL variants have been described and have been given variety of names on the basis of their substrate spectrum and functional groups. The selection pressure that drives ESBL evolution has usually been attributed to the intense use of oxyimino cephalosporins, mainly third generation cephalosporins.

What are ESBLs? There is no consensus of the precise definition of ESBLs. A commonly working definition is that the ESBLs are capable of conferring bacterial resistance to the penicillins, first, second, and third generation cephalosporins and aztreonam (but not the cephamycins or carbapenems) by hydrolysis of these antibiotics, and which are inhibited by β-lactamase inhibitors, such as clavulanic acid, sulbactam and tazobactam.

ESBLs are usually described as acquired β lactamases that are encoded mostly by plasmid located genes. Though, the first clinical isolates expressing acquired ESBLs were identified in Germany, the first nosocomial outbreaks caused by ESBL producers started to occur in France in 1985 and then in USA. The number of ESBL variants identified has been constantly growing since 1983, demonstrating a rapid ESBL evolution.

More than 150 different natural ESBL variants are known at present, and the list seems to be far from complete (http://www.lahey.org/studies/webt.htm). They have been classified in to nine distinct structural/evolutionary families based on comparisons of their deduced amino acid sequences e.g. TEM, SHV, CTX M, OXA, PER, VEB, GES, TLA, BES. Spectrum of ESBL producing organism: So far ESBL activity is observed only in Gram negative organisms. They are mainly found in Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, however, also occur in other members of Enterobacteriaceae family as well as in non fermenting Gram negative rods like Pseudomonas and Acinetobacter species. Recently it was also reported in Haemophilus influenzae.

Genetic environment of ESBL gene The increasing pattern of antibiotic resistance of these organisms prompted the genetic environment studies. The gene pool might already be firmly studied, and besides, the procurement and expression of new genetic material, even antibiotic resistant genes might be influenced by other factors other than antibiotic challenge. The widespread clinical use of commercial antibiotics has mobilized latent mechanisms to neutralize their impact. This process has been further facilitated by the variety of genetic elements that can harbor resistance genes, including the bacterial chromosome, transferable plasmid and transposons.

The dominance of a single genetic entity or piece (gene or series of genes) appears to be more influenced by its surrounding DNA than the gene itself, either by facilitating rapid mobilization and/or encoding other functions. The mobile genetic elements like plasmids and transposons reported to contain genetic units named integrons, contain genes for site specific recombination system, capable of capturing and mobilizing genes called gene cassettes. Although there could be independent existence of both the gene cassette and ESBL gene in a particular organism, ESBL genes are also reported to be located on integrons, which facilitate their horizontal transfer to other related as well as unrelated microbes.

Epidemiology

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Introduction The evolution of bacteria through time has permitted the elaboration of a range of diverse species. These many species have generated a corresponding diversity of resistance mechanisms that fight naturally occurring antibiotic challenges, such as those generated by molds, yeasts and actinomycetes.

As a result, even bacteria that have never been exposed to commercial antibiotics can nonetheless bear resistance genes to these drugs.

Large-scale surveillance studies, such as the SENTRY Antimicrobial Surveillance Program, have been a source of useful data regarding the regional prevalence of ESBL-producing isolates. The estimated prevalence of ESBL-producing strains of E. coli and K. pneumoniae in the United States was relatively low whereas, it was quite high in the Asia-Pacific region and in Latin America. In a survey almost 2800 Klebsiella species isolates recovered from more than 30 US medical centers from 1997 through 2000 found that 6-7% were phenotypically ESBL positive. In a survey of 2000 E. coli and K. pneumoniae isolates from the Asia-Pacific and South Africa region, a relatively larger proportion of potential ESBL producers (25% in Klebsiella pneumoniae and 10% in E. coli) were confirmed. In Latin America and Europe the survey showed 44-46% and 23% of Klebsiella species respectively and 5% of E. coli were positive for ESBL production. In India prevalence of ESBL producers in Enterobacteriaceae varies grossly from 12.6 to 86.6% among different centers.

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Impact on Antimicrobial therapy ESBL producing isolates are frequently resistant to other kinds of antimicrobials, aminoglycosides, quinolones and cotrimoxazole. What is especially frustrating is that genes coding for ESBLs and, and for example aminoglycoside modifying enzymes (AMEs) often reside within the same conjugative plasmids and therefore are transmitted together from one strain to another. This means that resistance to two different kinds of drugs may be co selected by the use of either one. Bell and Turnidge demonstrated that, in 1998 99 in Western Pacific countries and South Africa, the frequency of resistance in ESBL producing Enterobacter cloacae to gentamicin, ciprofloxacin and co trimoxazole could reach values of approximately 65%, 60% and 20% respectively.

In recent years, ESBLs have become more prevalent in species characterized by inducible class C cephalosporinases (AmpC), such as Enterobacter spp., Citrobacter freundii and Serratia marcenscens, which frequently segregate mutants with high level constitutive production of AmpC enzymes.Strains that are both ESBL producers and AmpC de repressed mutants have been already identified in studies, despite the masking of the ESBL phenotype by the inhibitor resistance of AmpC-β lactamases.

Antibiotic Resistance

In vitro, the carbapenems (imipenem and meropenem) and the cephamycins have the most consistent activity against ESBL producing organisms, given their stability to hydrolysis by ESBLs. Indeed, published reports of carbapenems resistance in organisms such as K. pneumoniae are exceedingly rare. The plasmid harboring genes encoding ESBLs frequently also contain genes encoding mechanisms of resistance to aminoglycosides and trimethoprim sulfomethoxazole. There is also strong association between quinolone resistance and ESBL production.

In vitro synergy may be achievable between cefepime and amikacin against ESBL producing organisms but cefepime should not be used as a therapy against ESBL producing organisms. Based on in vitro studies, the cephamycins appear an attractive option for use against ESBL producers. However, published clinical experience with these drugs is almost lacking.

The only reports describe in vivo selection of porin deficient mutants during therapy. In general cefotetan has lower MICs than cefoxitin, and should be preferentially used. However, cephamycin therapy leads to emergence of plasmid mediated AmpC resistance.

As per with the cephalosporins, combinations of β-lactam with β-lactamase inhibitor are also subject to rising MICs as inoculum rises. Treatment with β-lactam/β-lactamase inhibitor combination was shown to be inferior to the treatment with imipenem or piperacillin/tazobactam plus aminoglycoside combination in an animal model. Piperacillin/tazobactam was found to be an attractive option with high susceptibility and was also recommended for treatment to control ESBL producing Enterobacteriaceae.

Carbapenems should be regarded as the drugs of choice for serious infections with ESBL producing organisms. The basis for this statement is not just the almost uniform in vitro susceptibility but also increasingly extensive clinical experience. The choice between imipenem and meropenem is difficult. Published experience is greatest with imipenem, but MICs for meropenem is slightly lower than for imipenem. In vitro studies with a new carbapenem (L 749, 345) capable of once daily administration showed that it shared the excellent activity against ESBL producing organism than imipenem and meropenem.

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Conclusion The relatively low level of accuracy in testing for ESBLs reported for many clinical laboratories suggests that clinical failures might be occurring at higher rates in the general population than what indicated by published clinical studies. In a study of ESBLmediated resistance in 220 Klebsiella species isolates recovered from 35 intensive care units in Europe, communicating laboratories incorrectly reported the susceptibilities of a large proportion of isolates. In a study, 28.9% of the ESBL-producing isolates tested were reported to be susceptible to ceftriaxone, and 36.6% were reported to be susceptible to cefotaxime. A discrepancy of this kind is quite disturbing, because even low levels of in vitro resistance can lead clinical failure. Such an occurrence was also reported during a nosocomial outbreak of multidrug-resistant K. pneumoniae. The isolates exhibited a mode MIC for cefotaxime of 2 mg/L, indicating a low level of resistance. Although a regimen that included cefotaxime or ceftriaxone proved to be effective in treating cases of uncomplicated urinary tract infection, these antimicrobials failed to treat major infections at other sites.

The complexity of resistance development is still evolving and further investigation should be continued regarding their mechanism of resistance supported by genetic data to design novel antibiotic classes against these pathogens. Beside these, continuous surveillance studies should be under taken on region basis so as to help clinicians, pharmacologists and researchers.

References: 1. Bradford, P. A. Extended spectrum β-Lactamases in the 21st Century: Characterization, Epidemiology and Detection of this important resistance threat. Clin Microbiol Rev 2001; 14: 933 951.

2. Bhattacharjee, A., Sen, M. R., Prakash, P., Anupurba, S. Role of ß-lactamase inhibitors in enterobacterial isolates producing extended-spectrum b-lactamases. Journal of Antimicrobial Chemotherapy 2008; 61: 309 314.

3. Trevino, S., Mahon, C. R., Bacteremia (2000). In Mahon C R., Manuselis, J. Text book of Diagnostic Microbiology, 2nd edition. Philadelphia: W B Saunders company 998 1008.

4. Bush, K., Jacoby, G A., Medeiros A A. A functional classification scheme for β-lactamases and its correlation with molecular structure. Antimicrob Agents Chemother 1995; 39: 1211 33.

5. Palucha, A., Mikiewicz, B. et al. Concurrent outbreaks of extended spectrum β-lactamase producing organisms of the family Enterobacteriaceae in a Warsaw hospital. J Antimicrob Chemother 1999; 44: 489 99.

6. Paterson, D. L. Recommendation for treatment of severe infections caused by Enterobacteriaceae producing extended spectrum β-lactamases (ESBLs). Clin Microbiol Infect 2000; 6: 460 463.

Emergence And Spread Of Antibiotic Resistance In Bacterial Pathogens With Special Emphasis On Nosocomial Infections Prof. Dr. W. Witte Robert Koch-Institut, Bereich Wernigerode, BurgstraĂ&#x;e 37, D-38855 Wernigerode, Tel.: 49 3943 679-246, Fax: 49 3943 679206, email: wittew@rki.de

In the following prominent examples for different resistance mechanisms are described.

Target alteration due to mutation: Mykobacteria: resistance to rifampicin due to amino acid exchanges of the -subunit of RNA polymerase, resistance to streptomycin due to amino acid exchanges in the small unit of the ribosome.

Enterobacteriaceae, staphylococci, pneumococci: fluoroquinolones resistance due to amino acid examples in DNA gyrase (preferentially gram-negatives) and in topoisomerase IV (preferentially in gram-positives).

Target alteration due to modification: macrolide, lincosamide, streptogramin B resistance in gram-positives and methylation of 23S ribosome glycopeptides resistance in enterococci is due to splitting of the end standing D-Alanyl from N-acetyl-muraminic acid and replacing it by D-lactate.

An example for target modification reading to broad resistance against antibiotics belonging to different compound classes is the cfr-gene wwhich encodes methylation of 23S rRNA in posittion A2503 leading to resistance against flofenicol, chloramphenicol, linezolid, to macrolides, streptogramin B and tiamulins in staphylococci.

Synthesis of an alternative target: additional penicillin binding protein PBP2a (low affinity to all beta lactam antibiotics) in methicillin resistant Staphylococcus aureus (MRSA) and coagulase negative staphylococci.

Prevention of uptake: deletion, missense mutations in porin genes in enterobacteriaceae (above alls Klebsiella spp.) and in Pseudomonas aeruginosa leading to carbapenem resistance.

Efflux of antibiotics: specific porters (protein pump) conferring tetracycline resistance; ABC porters with expanded spectrum (extruding macrolides and streptogramines in staphylococci and enterococci).

Detoxification of antibiotics by hydrolysis or modification: Ă&#x;-lactamases in all aerobic gram-negatives, in staphylococci, Neisseria gonorrheae, Haemophilus influenzea, aminoglycosides modifying enzymes in enterobacteriaceae, pseudomonads, staphylococci and enterococci (high level resistance).

Genetic events leading to resistance: with low frequencies (1 per 10-9 bacterial cells) resistance mutations occur in every natural population of bacteria.

Acquisition of other resistance mechanisms needs the acquisition of resistance genes coding for them. Many resistance genes very likely originate from natural antibiotic producers such as streptomycetes of from in bacteria which have to protect themselves against antibiotics in their natural micro ecological habitates such as soil.

Mobilization of resistance genes is mediated by integrons, insertion sequences, transposons, and finally plasmids. Via their 59 base sequences integrons can accumulate several resistance gene cassettes, thus forming multiresistance aggregates. The same can be achieved by mobilization of resistance genes by insertions sequences and formation of multiresistance transposons which are known from both gram-positive and gram-negative bacteria. Via integrons and transposons

resistance genes are integrated into conjugative plasmids and this con reach a wide dissemination.

Genetic events rendering bacteria antibiotic resistant always take place at more or less low frequencies. Whether this results in emergence and spread of a resistant bacterial colonizer or pathogen is largely dependent upon antibiotic selective pressure in natural habitates as well as in the microflora of humans and other animals treated with antibiotics.

Dissemination of resistance takes place in different ways, most simply by clonal spread of the bacteria (bacterial strains) which have acquired a resistance gene(s). A second dimension is between different strains of a particular bacterial species, between different families and even among gram-negative and gram-positive bacterial (prominent example: tetM mediating resistance to tetracyclines by modification of a ribosomal protein). As mentioned above, in addition there is frequent exchange of mobile elements containing resistance genes.

Important examples for antibiotics resistant nosocomial pathogens: Methicillin-resistant Staphylococcus aureus (MRSA): MRSA are virtually resistant to all -lactam antibiotics. This is based on formation of an additional penicillin-binding protein (PBP2a) with low affinity for beta-lactams, which is coded by the mecA gene. This determinant is cont5ained by chromosomal located SCCmec elements.

Methicillin-resistant Staphylococcus aureus (MRSA) are a common cause of nosocomial infections worldwide. Hospitalassociated MRSA (haMRSA) are often resistant to multiple antibiotic classes, which limits treatment options. Since the end of the 1990s, however, MRSA infections in the general population without the risk factors known for acquisition of haMRSA have been described, first in the USA and later worldwide.

Hospital associated MRSA is remarkable for its clonal pattern of spread. There are 11 major MRSA clones within 5 groups of related genotypes, they account for approximately 70 % of >3,000 MRSA isolated obtained primarily from hospitals in the United States, South America, and Europe. The major mover of this sort of clonal spread is thought to be infection control lapses by healthcare practitioners-physicians, nurses, or other persons who become colonized with S. aureus and then have contact with hospitalized patients. MRSA, like any S. aureus, is known to colonize the skin and particularly the anterior nares; such colonization may be transient or persistent, and may spread faster during times of upper respiratory tract viral infections.

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Understanding of emergence of antibiotic resistance needs to know about the molecular mechanisms by which bacteria counteract their mode(s) of action.

In particular, fluoroquinolone resistance is a hallmark of nosocomial MRSA, although this was not always the case. When ciprofloxacin was first licensed, it was recommended as the first orally administered treatment effective against MRSA. However, within 1 year many hospitals observed dramatic increases in the rate of ciprofloxacin resistance in MRSA. For many years, vancomycin was the only effective treatment for serious MRSA infections. But in the past 6 years, 4 new agents with anti-MRSA activity have been introduced (quinupristindalfopristin, linezolid, daptomycin, and tigecycline). These new agents are most welcome, since the past decade has seen the emergence of vancomycin resistance in S aureus.

Beside MRSA with intermediate susceptibility to vancomycin (VISA) based on an altered cell metabolism acquisition of

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transferable vancomycin resistance from Enterococcus faecium became a matter of special concern (so far 6 cases known from the USA).

Antibiotic Resistance

Community-associated MRSA (caMRSA) are usually less broadly resistant to antibiotics; they often contain the genes lukS-PV lukF-PV coding for Panton-Valentine leucocidin (PVL) and SCCmec elements of types IV and V. Most of haMRSA are associated with 8 of the 10 major clonal lineages of the S. aureus population. caMRSA belong to various other clonal lineages than haMRSA. However, only a few of them are widely disseminated and therefore can be regarded as epidemic. In the USA, two lineages, namely multilocus sequence type (MLST) ST1 ("USA400" according to the PFGE pattern) and ST8 ("USA300"), are the most frequent and widely disseminated caMRSA. In Oceania, this is ST30 and in Europe St80.

Glycopeptide-resistant enterococci: Enterococci are commensal bacteria of the animal and human gut but con also serve as dreaded nosocomial pathogens of life-threatening infections especially among the elderly, immuno-compromised or seriously ill patients. E. faecalis still earmarks the majority of enterococcal infections, mostly urinary tract infections, endocarditis and bacteraemia. However, E. faecium attracts more and more attention due to its capacity of acquiring multiple antibiotic resistance determinants, especially those encoding glycopeptide resistance and its potential to spread among the nosocomial setting. The population structure of E. faecium has been disclosed by methods like amplified-fragment length polymorphism (AFLP), multi-locus sequence typing (MLST) and most recently comparative genomic hybridizations.

Within the clonal complex (CC) of human isolates a distinct subcluster (CC17 or C1) was identified by all these methods combining strains from clusters of infections and outbreaks among hospital patients from a representative worldwide collection. Characteristics of those so-called hospital-adapted, epidemic-virulent clonal types are, based on logistic regression models, (i) ampicillin resistance, (ii) high-level fluoroquinolone resistance, and (iii) possession of virulence markers.

Dissemination of isolates representing epidemic clonal types of the MLST CC-17 complex among the hospital setting possessing the above mentioned features and acquisition of determinants encoding vancomycin resistance as an indicator, to a later stage became a problem in hospitals world-wide.

Class B lactamases (preferentially of the VIM and the IMI types) at first became known from Pseudomonas aeruginosa and in Acinetobacter spp. Already in the mid 1990ties in South East Asia and later in South-East Europe. The corresponding genetic determinants were contained by class 1 integrons which more recently became integrated into broad host range plasmids and disseminated to Klebsiella pneumoniae with broad resistance to other antibiotics. This has lead to the emergence of isolates only susceptible to colistin in Central Europe and isolates completely resistant to all antibiotics in Greece.

Gram-negative bacteria with brad resistance against cephalosporines and carbapenems: The base mechanism conferring resistance against this classes of compounds are lactamases, the classification of these enzymes according to the active center of these enzymes is shown in figure 1. Most of the class A enzymes and class D enzymes represent the "classical" plasmid encoded enzymes, the gene(s) for class C enzymes are naturally contained in the core genome of nearly all enterobacteriaceae; class B enzymes are metallo-lactamases also capable of hydrolysis carbapenem.

Extended spectrum ß-lactamases in enterobacteriaceae. Soon after the introduction of ampicillin into human chemotherapy 8 International Pharmaceutical Students’ Federation

resistance due to hydrolysis by plasmid encoded ß-lactamases emerged. ß-lactamases in gram-negative bacteria can be grouped according to their active site (figure 1). During the 1960ties and 1970ties most of ampicillin-resistant enterics produced class A lactamases of type TEM-1, later of type SHV-1. About 10 years after the introduction of cefotaxim as the first 3rd generation cephalosporin resistance this group cephalosporin which had been regarded as refractory to hydrolysis by -lactamases emerged.

Surprisingly this was due to mutation(s) in TEM expanding the substrate spectrum. In TEM-derivatives of ESBL the site of the mutation decides about the hydrolysis spectrum with respect to 3rd and 4th generation cephalosporines. Many amino acid changes can lead to the ESBL phenotype, for most of them, however, complementory mutation in the enzyme protein age necessary for the stabilization of the protein structure.

Besides ESBL which have evolved from "classical" plasmid encoded class A enzymes by mutations the CTX-M -lactamases are particularly interesting as they originate from chromosomale blactxM-genes which are naturally chromosomal located in Kluyvera spp., a enterobacterial species for which plants are the natural habitate captured by an insertion sequence they are integrated into broad host range plasmids.

Besides a few enterobacterial species such as Klebsiella spp. the genomes of enterobacteria contain the ampC gene coding for a cephamycinase mediating broad spectrum cephalosporin resistance. The gene is normally reposed and only in a few species with an efficient promoter (Citrobacter spp., Enterobacter spp.), here constitutive mutants express clinically significant cephalosporin resistance. Via integrons of class I ampC genes can be mobilized and integrated into plasmids and widely disseminated (mobilized ampC).

Conclusion: The worldwide emergence of MRSA as a nosocomial pathogen and more recently also in the community followed by broad recently also in the community followed by broad resistance in gramnegative pathogen to all -lactamases currently available poses a threat to public health.

Rational use of antibiotics thus reducing selective pressure in favour of resistance and target infection control measures for prevention of further dissemination have to be brought into place.

Furthermore, there is an urgent need for development new antibacterial compounds refractory to resistance mechanisms bacteria have acquired so far.

β Laktamases

Active center

Serin

Metallo(Zn2+)

Classification according to A C D Amber Inhibition by clavulanic acid + + (Cefpodoxim) Hydrolysis by Cefpoxitin + Inhibition by EDTA TEM CMY-2 OXA Examples SHV-1

PAO

B IMP VIM

Fig. 1 Classification of ß-lactamases References: 1. Tenover FC. 2001. Development and spread of bacterial resistance to antimicrobial agents: an overview. Clin Infect Dis. 33 Suppl 3:S108-15.

2. Amabile-Cuevas CF (ed.). 2003. Multiple drug-resistant bacteria. 1st edition, Horizon scientific press, Norforlk, UK.

8. Andersson DI. 2006. The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol. 9: 461-5.

3. Hall BG. 2004. Innovation: Predicting the evolution of antibiotic resistance genes. Nature Reviews Microbiology 2, 430-435.

9. D'Costa VM, McGrann KM, Hughes DW, Wright GD. 2006.

Sampling the antibiotic resistome. Science 311: 374-7.

4. Kumar A, Schweizer HP. 2005. Bacterial resistance to antibiotics: active efflux and reduced uptake. Adv Drug Deliv Rev. 57: 1486-513.

10. Piddock LJ. 2006. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria.Clin Microbiol Rev. 19: 382-402.

5. Lambert PA. 2005. Bacterial resistance to antibiotics: modified target sites. Adv Drug Deliv Rev. 57: 1471-85.

11. Depardieu F, Podglajen I, Leclercq R, Collatz E, Courvalin P. 2007. Modes and modulations of antibiotic resistance gene expression. Clin Microbiol Rev. 20: 79-114.

6. Wright GD. 2005. Bacterial resistance to antibiotics: enzymatic degradation and modification. Adv Drug Deliv Rev. 57: 1451-70.

7. Woodford N. 2005. Biological counterstrike: antibiotic resistance mechanisms of Gram-positive cocci. Clin Microbiol Infect. 11 Suppl 3:2-21.

12. Woodford N, Ellington MJ. 2007. The emergence of antibiotic resistance by mutation. Clin Microbiol Infect. 13: 5-18.

13. Baquero F, Nombela C, Cassell GH, Gutierrez-Fuentes JA (eds.). 2008. Chapter III: Evolutionary biology of drug resistance. In: Evolutionary biology of bacterial and fungal pathogens. ASM Press, Washington, DC, USA.

National Antibiotic Policy in The Context of India Arati Sharma, BPharm, Sankaralingam Bhuvaneswari College of Pharmacy, Tamilnadu, India Antibiotic resistance is largely due to inappropriate use of antibiotics. The use of antibiotics is related to the prescription of antibiotics and self medication to some part. In order to reduce the resistance of antibiotic, hence, it is important to develop and follow antibiotic policy. In India, due to lack of national antibiotic policy, antibiotic resistance is one of the major problems for immature deaths. So, it is of utmost necessity to develop a national antibiotic policy in India and implement it to prevent and fight with antibiotic resistance.

Antibiotics are one of the most widely used classes of drugs in the world, accounting for over 25% of drug costs in many hospitals and for a higher proportion of prescriptions in the community, especially in the developing world.1 Many studies about the use of antibiotics from various countries, both developing and developed, have highlighted the widespread inappropriate use of antibiotics.1 Antibiotic resistance is the major cause of morbidity and mortality worldwide. It is the cause of increased healthcare cost. It should be prevented as much as possible or detected as soon as it emerges in order to prevent the spread of resistant strains. For the prevention and detection of resistance, a need of rational antibiotic therapy is obvious 2,3 and national policies or guidelines to address this issue are required.3 For the appropriate prescription and use of antibiotics, it is necessary to develop antibiotic policy. The aim of the policy is to improve the quality of prescribing leading to reduction of resistance and cost, and improvement in patient care. The antibiotic policy addresses to improve patient care by promoting the best practice in antibiotic prophylaxis and therapy, to make better use of resources by using cheaper drugs wherever possible, to retard the emergence and spread of multiple antibiotic-resistant bacteria, to improve education of junior doctors by providing guidelines for appropriate therapy, to eliminate the use of unnecessary or ineffective antibiotics and to restrict the use of expensive or unnecessary ones.

Need of antibiotic policy in India Information on the antibiotic resistance pattern of bacterial isolates is still not known in developing countries because the facilities for routine susceptibility testing are rare and limited to a few laboratories. Like most developing countries, India also lacks a national policy or guidance on the use of antibiotics.

Developing national policies is vital to combat the rise of resistance. Before getting on upon the development, dissemination and subsequent implementation of an antibiotic

policy, 4clinicians, pharmacists and key decision-makers are required to be clear on the ways to make plans for evaluating its impact. It is also important to know the patterns of antibiotic prescriptions and the surveillance about the prevalence of resistant strains in order to improve patient5 care. There is, however, lack of such surveillance data from India because there is no large scale, meta-analytic studies in India. Another serious concern is the lack of any strict adherence to the standard or recommended procedures in the microbiology laboratories across the country performing antibiotic susceptibility tests. This gives rise to different and inadequate performance and results.

The practice of indiscriminate dispensing antibiotics over the counter without any licensed prescriptions is another important issue that has to be critically addressed in India. Though an infection control committee exists in the hospitals of India, but the infection control committee is inactive and exists only in paper work just for a name. At the times of serious outbreaks of infection, this committee becomes a little bit active but the common cause of this outbreak is due to the unconcern towards infection control in the first place. In the mid-1990s, the use of 6 expired or 'resterilised' disposables such as intravenous infusion sets and catheters in a government hospital in New Delhi led to a serious outbreak of septicaemia that killed 26 people. In spite of such outbreaks, few, if any, Indian government hospitals have policies for using antibiotics, and they do not have an antibiotic monitoring system.

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Introduction

With the type of resistance patterns prevailing, there is an absolute and urgent need for nationwide-specific and standardoperating guidelines for the performance of antibiotic high-end susceptibility tests that should be strictly implemented in all laboratories across the country.

Conclusion Hence at the growing risk of antibiotic resistance worldwide, it has been extremely important for development of antibiotic policy in India in order to prevent further spread of resistance and Phuture - Antibiotic Resistetance2008

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treating the resistance in an isolated environment. To control the overuse, inappropriate prescription and early abandon of therapy, a national antibiotic policy should be developed in India. Such measures require political will, government commitment and significant levels of funding. Nevertheless, without these measures, the threat of antibiotic resistance in developing countries could grow uncontrolled.

References: 1. Smith A J, Aronson JK, and Thomas M. Antibiotics policies in the developing world. Eur J Clin Pharmacol,1991; 41:85-87 2. Joshi MC, Tariq K, Ejaj A. Restricted antibiotic policy: Rational approach towards antibiotic resistance - Policy Express Healthcare Management. Indian Express, Business

Publications Division, Issue dtd. 1st to 15th June 2005 3. El-Azizi M, Mushtaq A, Drake C, Lawhorn J, Barenfanger J, Verhulst S, et al . Evaluating antibiograms to monitor drug resistance. Emerg Infect Dis; 2005;11:1301-2 4. Binyon D. and Cooke RPD. Restrictive antibiotic policies - how effective are they? Hospital Pharmacist, 2000; 7: 183-187 5. Lakshmi V. Need for national/regional guidelines and policies in India to combat antibiotic resistance. Indian Journal of Medical Microbiology ;2008; 26: 105-107 6. Seth P. Antibiotic resistance calls for better diagnostic labs.

Science and Development Network. 26 March 2008

Preventing Antimicrobial Resistance: Role of Pharmacy Students Atmika Paudel, MPharm, University of Tokyo, Japan Binaya Sapkota, BPharm, Tribhuvan University, Nepal Antimicrobial resistance is a global problem that requires attention. There are several approaches to prevent the spread of resistant strains. Pharmacy students can play a vital role in combating resistance. Together with other organizations, pharmacy students' organizations, both national and international, can contribute to prevent and combat antimicrobial resistance by conducting various programmes. This article has summarized the roles that pharmacy students can play in reducing this growing problem.

Introduction

Antibiotic Resistance

The discovery series of antimicrobials began with the accidental finding of penicillin by Alexander Fleming in 1929. Then it was introduced into clinical medicine by Florey, Chain and associates at Oxford University in 1941.1 The antimicrobial agents were subsequently developed by Prof. Selman Waksman of Rutger University by discovering Streptomycin in 1944. Then chlortetracycline, macrolides and many other antimicrobials were introduced into the arena of pharmacotherapeutics.

However, being useful class of drugs, they are also leading group of widely misused drugs. The most important contributing factors of misuse are the complicated mode of diagnosis and prescribing for the prevention and treatment of infectious diseases. 2 Resistance to antimicrobials is currently a major health concern in treating infectious diseases because many bacteria that cause infections are becoming resistant to commonly-used antimicrobials leading to treatment failure.3 Antibiotic resistance is very much annoying, troublesome and costly for the general public and also imparts a serious problem in the therapeutics. The problems of such resistance have been found in case of tuberculosis, malaria, typhoid, etc. and many other drug resistant cases are also emerging especially in developing and under-developed countries. The rise of many resistant strains like Methicillin resistant Staphyloccus aureus (MRSA), Vancomycin-intermediate Staphylococcus aureus (VISA) and Vancomycin resistant Staphyloccus aureus (VRSA), Extended spectrum beta lactamase (ESBL) producing enterobacteria like Escherichia coli , multi drug resistant Pseudomonas aureginosa has given a scarcity for the effective antimicrobials and 4 scientists are exploring new ways to search new antimicrobials4 and methods to prevent the emergence of resistance in the first place.

Various factors contribute to antimicrobial resistance, some of which are the use of antimicrobials in animal feeds in low doses, availability of antimicrobials over-the-counter in many countries, misuse by health professionals, poor patient compliance, antimicrobial application in agriculture, aquaria and family pets and eating raw or undercooked foods. The most notable causes are improper antimicrobial use and inappropriate empiric therapy selection.5 10

International Pharmaceutical Students’ Federation

To check the occurrence of resistant microorganisms, there is a need of better education of the public, doctors, pharmacists and veterinarians in the appropriate use of the drugs. The antimicrobial use for inappropriate indications should be restricted, existing laws regarding over-the-counter drugs should be made strong to ensure rational sale and use of antimicrobials; judicious use of antimicrobials in hospitals should be done by intensive teaching of the principles of the use of antimicrobials and to establish better control measures for nosocomial infections.

Role of pharmacy students Pharmacy students can contribute to the prevention and control of antimicrobial resistance. In the present context, antimicrobial resistance needs a great attention and many researches are being conducted by scientists, antimicrobial usage guidelines are being formulated and many programmes for awareness are being carried out to which pharmacy students can add a brick.

With such a noble purpose that pharmacy students can be competent and knowledgeable regarding various aspects of pharmacotherapeutics like preventing or minimizing antimicrobial resistance problem, many universities and schools of pharmacy have incorporated Doctor of Pharmacy (Pharm D) program in their curricula. Likewise, some colleges have introduced Masters in Clinical Pharmacy or Pharmacology or Pharmaceutical Care. Moreover, many universities are now running Bachelor of Pharmacy program giving more preference to pharmacotherapy.

Students, by conducting campaigns, workshops and carrying out small scale studies about the pattern of prescription and susceptibility, most prevalent strain in a particular area, patient/physician satisfaction, the habit of people to selfmedicate antimicrobials etc. can help to know the status and ultimately to prevent the development and to improve the treatment of antimicrobial resistance.

They can carry out public awareness campaigns regarding the antibiotics resistance problem via media (radio, television), seminars, role-play, drama, conducting talk programmes, marching in some rally and interacting with other health sector

Conclusion Pharmacy students are one of the potential members, who can help in reducing the morbidity and mortality caused by antimicrobial resistance. They can make a difference by conducting different programmes that draw attention of community as well as health care professionals. International Pharmaceutical Students Federation (IPSF) is playing a crucial role in raising awareness about many health related issues by conducting several programmes and campaigns and by publishing newsletters, bulletins and supplements. It can further act in combating antimicrobial resistance by assessing the knowledge about antimicrobial resistance among pharmacy

students and evaluating and promoting a pharmacy school curriculum on appropriate use of antimicrobials, forming partnerships to harness the resources of collaborating organizations and conducting research in the field of antimicrobials.

References: 1. Nicholas WK. Remington: The Science and Practice of Pharmacy 20th edition: Lippincott Williams & Wilkins, USA, 2000; 87(2): 1514.

2. Barriere SL. Pharmacotherapy: A Pathologic Approach 3rd edition: Appleton & Lange, USA, 1997; 98(3): 1953- 1969 3. Essential Drugs Monitor No. 28-29 (2000). WHO/DAP, WHO/EDM; 2000 4. Tenover FC. Mechanisms of Antimicrobial Resistance in Bacteria. The American Journal of Medicine .2006; 119 (6A), S3S10 5. Weller TMA and Jamieson CE. The expanding role of the antimicrobial pharmacist. Journal of Antimicrobial Chemotherapy, 2004; 54: 295298

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colleagues etc. They can develop and distribute pamphlets and other educational materials to promote the appropriate antimicrobial use and importance of completion of therapy for preventing emergence of resistance. Such programmes will not only create and increase the awareness of general public about the importance of judicious use of antimicrobials, prevention of self medication of such medicines but also make the pharmacy students more competent and prepare themselves to handle their responsibilities when they become pharmacists.

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International Pharmaceutical Students' Federation P.O. BOX 84200 2508 AE Den Haag The Netherlands Tel: +31 70 302 1992 Fax: +31 70 302 1999 E-mail: ipsf@ipsf.org Website: www.ipsf.org