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Running head: ANTIBIOTIC USE IN BANGLADESH

Current Trends of Antibiotic Use in Bangladesh and Its possible Outcomes Arafat Siddiqui East-West University Author Note Arafat Siddiqui, Department of Pharmacy, East- West University. This assignment was instructed by Farjana Khatun, Lecturer, and Dept. of Pharmacy, Course: PHRM 306, East-West University. Correspondence concerning this assignment should be addressed to Arafat Siddiqui, ID: 2009-1-70-014, Department of Pharmacy, East-West University, Mohakhali, Dhaka. E-mail: mohammad_arafat@rocketmail.com

Running head: ANTIBIOTIC USE IN BANGLADESH Abstract This assignment is based on the use of antibiotic in Bangladesh. It was found that irrational prescribing is common in Bangladesh. Hence, bacterial resistances are observed in our country

like outside world. Here current type of antibiotic prescribing practice, its scopes, advantages and disadvantages, causes, role of pharmacists and doctors, public consciousness and possible outcomes are briefly described. Some data are of outside world are mentioned here for better understanding. Some lists of locally popular antibiotics with its manufacturer and brand names are also included. Key words: antibiotic, multi-drug resistance, infection

Running head: ANTIBIOTIC USE IN BANGLADESH Current Trends of Antibiotic Use in Bangladesh and Its Possible Outcomes Before 1900s thousands of people died of bacterial infections and other diseases which are caused by microbes. At the battle field hundreds of soldiers died due to bacterial infections on major injuries and cut. Mercury was used to treat syphilis as early as 1495. In 1798 Edward Jenner discovered vaccination for smallpox using cowpox vaccine. Louis Pasteur worked on rabies. In 1910 an arsenical compound having antimicrobial property known as Salvarsan was synthesized by Paul Ehrlich. But during 1929, there was a breakthrough. It was Alexander Fleming who discovered the first antibiotic Known as Penicillin, a metabolic product of Penicillium notatum (Pelczar, Chan, & Krieg, 2005). It was just the beginning of a new era.

Since then development of newer antibiotics has been a major interest for scientists all over the world. Thousands of lives are saved. Within in few decades antibiotics became one of the most common names in medical prescriptions. Unfortunately due to widely use of antibiotics and lack of rational practice of it, new headache has came for scientists. Like environment pollution, natural disaster, insufficient sources of energy, a new problem for future generation of mankind has been created. It is bacterial resistance against antibiotics. Day by day choices of antibiotics are reducing. Scientists are working hard to find new source and developing newer antibiotics. International communities are working to create consciousness among public. Our country is not safe from this disaster. It is necessary to get an overview of present situation of antibiotic prescribing practice in our country so that we can predict the fortune of our next generation and take preventive measures as early as possible. In the past few years lots of survey was done. National public health organizations and others are working on it. Here we have gathered available information to get an overview.

Running head: ANTIBIOTIC USE IN BANGLADESH Survey and Case Studies Bacterial Resistence Increasing spectrum in antimicrobial resistance of Shigella isolates in Bangladesh: resistance to azithromycin and ceftriaxone and decreased susceptibility to ciprofloxacin.

Antimicrobial resistance of Shigella was isolated in Bangladesh, during 2001-2002, was studied and compared with that of 1991-1992 to identify the changes in resistance patterns and trends. A significant increase in resistance to trimethoprim-sulphamethoxazole (from 52% to 72%, p < 0.01) and nalidixic acid (from 19% to 51%, p < 0.01) was detected. High, but unchanged, resistance to tetracycline, ampicillin, and chloramphenicol, low resistance to mecillinam (resistance 3%, intermediate 3%), and to emergence of resistance to azithromycin (resistance 16%, intermediate 62%) and ceftriaxone/cefixime (2%) were detected in 2001-2002. Of 266 recent isolates, 63% were resistant to > or =3 anti-Shigella drugs (multidrug-resistant [MDR]) compared to 52% of 369 strains (p < 0.007) in 1991-1992. Of 154 isolates tested by Etest in 2001-2002, 71% were nalidixic acid-resistant (minimum inhibitory concentration [MIC] > or =32 microg/mL) and had 10-fold higher MIC90 (0.25 microg/mL) to ciprofloxacin than that of nalidixic acid-susceptible strains exhibiting decreased ciprofloxacin susceptibility, which were detected as ciprofloxacin-susceptible and nalidixic acid-resistant by the disc-diffusion method. These strains were frequently associated with MDR traits. High modal MICs were observed to azithromycin (MIC 6 microg/mL) and nalidixic acid (MIC 128 micdrog/mL) and low to ceftriaxone (MIC 0.023 microg/mL). Conjugative R-plasmids-encoded extended-spectrum betalactamase was responsible for resistance to ceftriaxone/cefixime. The growing antimicrobial resistance of Shigella is worrying and mandates monitoring of resistance. Pivmecillinam or ciprofloxacin might be considered for treating shigellosis with caution (Rahman et al., 2003).

Running head: ANTIBIOTIC USE IN BANGLADESH Of 266 of Shigella isolates tested for antimicrobial susceptibilities by the disc-diffusion method in 2001-2002, S. flexneri (51%) was the predominant species, followed by S. boydii, S. sonnei, and S. dysenteriae. Overall, Shigellaisolates had high rates of resistance to tetracycline (79%), trimethoprim-sulphamethoxazole (72%), ampicillin (56%), nalidixic acid (51%), and chloramphenicol (42%). Moderate-to-low rate of resistance to azithromycin (16%), gentamicin

(4%), mecillinam (3%), and third-generation cephalosporins (TGC), such as cefixime (2%) and ceftriaxone (2%) was observed. Many isolates were intermediate to azithromycin (62%), amoxicillin-clavulanate (26%), ciprofloxacin (12%), and mecillinam (3%). No resistance to levofloxacin and moxifloxacin was detected. Resistance to azithromycin and third-generation cephalosporins was detected for the first time among recent (20012002) isolates in our study. None of the Shigella isolates had complete resistance to ciprofloxacin (Rahman et al., 2003). Overall, MDR strains defined as simultaneously resistant to 3 of eight useful antimicrobial agents (ampicillin, trimethoprim-sulphamethoxazole, nalidixic acid, ciprofloxacin, mecillinam, tetracycline, azithromycin, and ceftriaxone/cefixime) were detected in 63% of the isolates. It was significantly high (94%, p<0.01) in S. dysenteriae, followed by S. sonnei (60%) and S. flexneri (58%) and was low in S. boydii (27%, p<0.01). Resistance to ampicillin, trimethoprim-sulphamethoxazole, nalidixic acid, and tetracycline was most frequent (48%), followed by resistance to ampicillin, trimethoprim-sulphamethoxazole, and tetracycline (R-type ApSXTTe) (18%), nalidixic acid, trimethoprim-sulphamethoxazole, and tetracycline (R-type NalSXTTe) (14%). Resistance to one and two drug(s) was 8% and 19% respectively. Only 26 (10%) isolates were susceptible to all eight drugs tested (Rahman et al., 2003). Resistance frequencies of Shigella isolates of 2001-2002 was compared with those isolated during 1991-1992, which constituted part of our previous report. Resistance increased

Running head: ANTIBIOTIC USE IN BANGLADESH during the 2000s. Of note, the resistance to trimethoprim-sulphamethoxazole increased from 52% to 72% (p<0.01), resistance to nalidixic acid from 19% to 51% (p<0.01), and mecillinam

from 0.5% to 3% (p<0.01). Resistance to ampicillin, tetracycline, and chloramphenicol was high (range 49-79%) in 1991-1992 and remained almost unchanged in 2001-2002. Strains with MDR phenotype increased to 63% in 2001-2002 from 52% (p<0.007) in 1991-1992 (Rahman et al., 2003). The MIC results of 154 available isolates (2001-2002) to nalidixic acid, ciprofloxacin, levofloxacin, azithromycin, and ceftriaxone are shown in the. High modal MICs and MIC90 of nalidixic acid (modal MIC 128 g/mL and MIC90 256 g/mL) and azithromycin (modal MIC of 6 g/mL and MIC90 8 g/mL) and very low modal MIC (0.047 g/mL) and MIC90 (0.023 g/mL) of ceftriaxone were observed(Rahman et al., 2003). Of four Shigella isolates that were resistant to third-generation cephalosporins (TGC), two isolates of S. sonnei were highly resistant to ceftriaxone (MIC >256 g/mL), and S. flexneri and S. boydii were intermediate to it (MIC 24 g/mL). However, all but one ceftriaxone-resistant strain was susceptible to mecillinam (Rahman et al., 2003). MIC of ciprofloxacin-differentiated isolates having high MICs (0.064-0.38 g/mL) and MIC90 (0.25 g/mL) exhibiting decreased susceptibility to ciprofloxacin and nalidixic acid resistance (MIC 32 g/mL) from nalidixic acid-susceptible (MIC <32 g/mL) and ciprofloxacin-susceptible isolates having 10-fold lower MIC90 (MIC 0.023 g/mL) and low MIC (range 0.012-0.047 g/mL, Levofloxacin showed similar results as ciprofloxacin. Of 154 Shigella isolates, decreased susceptibility to ciprofloxacin and resistance to nalidixic acid were detected among 110 (71%) strains. All isolates having decreased susceptibility to ciprofloxacin by MIC were susceptible to ciprofloxacin by the disc-diffusion method and

Running head: ANTIBIOTIC USE IN BANGLADESH resistant to nalidixic acid by the MIC and disc-diffusion method. Of 105 MDR strains tested, 91% exhibited decreased susceptibility to ciprofloxacin compared to 29% of 49 non-MDR strains (relative risk=3.20, p<0.00001) (Rahman et al., 2003).

Three (two S. sonnei and one S. boydii) of four TGC-resistant strains were susceptible to amoxicillin-clavulanate and positive in DDST, indicating production of a class A ESBL, as described earlier. We were able to transfer -lactam resistance and ESBL production of these TGC-resistant strains to E. coli andShigella by conjugation, which was encoded by a 50-MDa autotrasferable R-plasmid. The fourth isolate (S. flexneri) was resistant to amoxicillinclavulanate but negative in DDST, thus exhibiting a class C (Amp C) -lactamase phenotype mediated by a 94-MDa autotrasferable R-plasmid (Rahman et al., 2003). Shigella causes invasive infection of the intestine that presents the most pressing challenge for providing effective antimicrobial therapy. Due to the emergence of resistance, antimicrobial agents, such as sulphonamides, tetracycline, ampicillin, trimethoprimsulphamethoxazole, nalidixic acid, and mecillinam have all in succession been used as first-line drugs in Bangladesh and many countries of the world. During the past several decades, the organisms have progressively become resistant to most useful and inexpensive antimicrobial agents. Our study demonstrates an increasing incidence and spectrum of antimicrobial resistance of Shigella isolates in Bangladesh in 2001-2002. Rates of resistance to ampicillin, trimethoprimsulphamethoxazole, and nalidixic acid increased to more than 50%. The resistance to tetracycline and chloramphenicol, which are not used currently for treating shigellosis, remained high and unchanged during the last decade. It is likely that the resistance rates observed in our hospitalbased microbiology laboratory reflect the prevalence of resistance that exists in the community since nearly all cases of shigellosis were community-acquired, and the cultures were obtained on

Running head: ANTIBIOTIC USE IN BANGLADESH

the day of admission. By analyzing the trends in the resistance patterns of various Shigella spp., we found that S. dysenteriae was at present significantly more resistant, followed by S. flexneri and other Shigella spp., in Bangladesh, especially to commonly-used antimicrobial agents. This finding is of special importance because S. flexneri is at present the predominant species in Bangladesh, like many other developing countries (Rahman et al., 2003). At present, pivmecillinam (oral form of mecillinam), fluoroquinolones, azithromycin, and third-generation cephalosporins (cefixime) are used in many countries for treating shigellosis caused by Shigella resistant to all first-line drugs. Pivmecillinam is currently used as an empirical antimicrobial therapy for shigellosis in Bangladesh with caution since resistance to it is emerging. The rate of mecillinam resistance, observed in the present study, is significantly lower than that observed in our earlier study in Bangladesh. This was due to lack of precise guidelines for determining susceptibility to mecillinam in the past that inherently overestimated the resistance rate. We used the CLSI (formerly NCCLS) methodology for the determination of mecillinam susceptibility that reflects the true resistance rate in the present study. Azithromycin was found to be effective in treating shigellosis both in children and adults, including multidrugresistant Shigella-associated infections. High modal MICs (6 g/mL) and MIC90 (8 g/mL) of azithromycin for Shigella isolates were observed in our study, and we detected in-vitro resistance to azithromycin in Shigellafor the first time in Bangladesh. It is not clear why Shigella exhibits high modal MIC values to azithromycin. It is surprising that a significant proportion of isolates are resistant to this drug, although the drug is not commonly used for treating shigellosis in Bangladesh. However, the frequent use of macrolides for other infections and high carriage rate of Shigella in the gut of apparently healthy humans in Bangladesh might contribute to the emergence and spread of azithromycin-resistant Shigella strains. The significance of in-vitro

Running head: ANTIBIOTIC USE IN BANGLADESH resistance of Shigella to azithromycin is still unknown since intracellular concentration of

azithromycin achieved in colonic cells and leucocytes exceeds serum concentration by 100-fold or more that could be fatal for intracellular bacteria. It should be mentioned that the two zones of inhibition produced by azithromycin by the disc-diffusion method and E-test sometimes caused difficulty in interpretation of results (Rahman et al., 2003). Quinolones are a good choice for the treatment of shigellosis in adults. Nalidixic acid was effective and approved for use in the treatment of shigellosis in children aged less than three months. However, >50% of our Shigella isolates were resistant to nalidixic acid like many other developing countries. Fluoroquinolones (ciprofloxacin and norfloxacin) are also effective in treating nalidixic acid-resistant shigellosis, but paediatric use is limited by concerns about arthopathy and chondrotoxicity. However, reported data suggest that they are generally safe for the treatment of shigellosis in children. In 1994, S. dysenteriae type 1, resistant to nalidixic acid having decreased susceptibility to ciprofloxacin (MIC >0.125 g/mL), was reported for the first time in Bangladesh by our group. The isolation rate of such strains of Shigella remarkably increased to 71% in 2001-2002 involving all species. The importance of strains having decreased susceptibility to fluoroquinolones was revealed recently by an outbreak of S. dysenteriae type 1 in 2002 in eastern India that affected 1,728 persons (attack rate of 25.6%), resulting in 16 deaths. Suboptimal clinical responses, therapeutic and microbiologic (positive culture after therapy) failures were associated with decreased ciprofloxacin susceptibilities of clinical isolates of Salmonella spp. and other bacteria in many countries, including India, the UK, Denmark, and the USA. To reduce such risks for humans, a recommendation has recently been made to lower breakpoint to 0.125 g/mL for fluoroquinolones for Salmonella. With the increasing prevalence of Shigella strains having decreased susceptibility to fluoroquinolones such as ciprofloxacin,

Running head: ANTIBIOTIC USE IN BANGLADESH

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there is a need for careful observation of the outcome of ciprofloxacin therapy for shigellosis to detect suboptimal clinical response or therapeutic failures, if any. However, the problem is that the strains having decreased susceptibility to ciprofloxacin are not reported as these appear susceptible when subjected to ciprofloxacin-susceptibility testing (disc-diffusion method or by current MIC breakpoints) by the CLSI guidelines. As suggested by our study, resistance to nalidixic acid appears to be a useful screening marker for decreased ciprofloxacin susceptibility. Hence, future studies should evaluate the clinical outcome of the treatment of shigellosis caused by strains having susceptibility to ciprofloxacin but resistance to nalidixic acid. Further, in our earlier study, we detected a single-point mutation at codon Ser83 (TGC) to Tyr83 (TTC) in the quinolone resistance-determining region of gyrA gene of S. dysenteriae type 1, resulting in resistance to nalidixic acid with decreased susceptibility to ciprofloxacin. Additional mutations in the same gene (codon 87) and/or parC (codons 80 and 84) are known to result in complete resistance to ciprofloxacin. Thus, the use of fluoroquinolones is likely to result in complete resistance in Shigella strains harbouring resistance to nalidixic acid by additional mutations that we have witnessed recently in Bangladesh and India. Interesting is the fact that the recent isolates of ciprofloxacin-resistant S. dysenteriae type 1 in Bangladesh and India appeared to originate by such mechanisms: a mutation in codon 87 of the gyrA and additional mutation in codon 80 of parC genes. Although R-plasmid-mediated quinolone resistance may occur on rare occasion, it is not unlikely that we will see more and more ciprofloxacin-resistant Shigella-associated infections in the near future (Rahman et al., 2003). Cefixime and ceftriaxone were active against 98% of our isolates in vitro, but there is some dispute regarding the clinical efficacy of cefixime in treating shigellosis. Recently, cefixime was found to be clinically effective in 78% of children with shigellosis, predominantly

Running head: ANTIBIOTIC USE IN BANGLADESH caused by S. flexneri. However, it is an re-assuring finding that no increase in the MIC of

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ceftriaxone was observed in susceptibleShigella strains, unlike for ciprofloxacin or azithromycin. On the contrary, ESBL-mediated TGC resistance in Shigella strains was detected for the first time in Bangladesh. Detection of R-plasmid-mediated ESBL in Shigella isolates, transferable to E. coli K 12 and Shigella by conjugation, suggests that ESBL could spread resistance to thirdgeneration cephalosporins among Shigella spp. and other pathogens in the community (Rahman et al., 2003). The limitation of our study is that we could not test all strains for antimicrobial susceptibility to detect exact rates of resistance to conventional and new useful antimicrobial agents. The isolates were from patients who came to the hospital for treatment or submitted faecal samples on the advice of physicians. Thus, strains might be associated with severe form of illnesses or from cases not responding to therapy reflecting high rates of resistance compared to those existing in the community. However, high rates of resistance among Shigella isolates have been reported in the community of Bangladesh (Rahman et al., 2003). Our study showed that Shigella strains developed resistance to many useful antimicrobial agents, including mecillinam, azithromycin, ceftriaxone, and cefixime in Bangladesh. Options for antimicrobial therapy for such MDR Shigella-associated infections are very limited leaving fluo-roquinoloes as the only option. Detection of decreased susceptibility to fluoroquinoloes in a high proportion of Shigella strains and complete fluoroquinolones-resistant S. dysenteriae type 1 clearly demands careful and judicial use of these drugs to avoid rapid emergence and spread of resistance (Rahman et al., 2003). In conclusion, physicians should be aware of the high rates of antimicrobial resistance and increasing spectrum of resistance of Shigella spp. in Bangladesh. Continuous monitoring of

Running head: ANTIBIOTIC USE IN BANGLADESH

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the resistance patterns is essential, and antimicrobial susceptibility testing should be carried out on clinical isolates, and empirical antimicrobial therapy need to change accordingly. In addition, reduced susceptibility of Shigella strains to useful drugs should be identified by determination of MICs of antimicrobial agents for the early detection of the emergence of resistance. When indicated, pivmecillinam or ciprofoxacin might be considered for treating shigellosis with caution in Bangladesh (Rahman et al., 2003). Antibiotic resistance and genetic diversity of Shigella sonnei isolated from patients with diarrhoea between 1999 and 2003 in Bangladesh. Talukdar et al. (2004) found that Shigella sonnei is a significant cause of diarrhoeal infection in both developing and industrialized countries. From 1999 to 2003, 445 strains of Shigella sonnei were isolated from patients admitted to the diarrhoea treatment centre of the International Center for Diarrhoeal Disease Research, Bangladesh. More than 60% of the isolates were resistant to nalidixic acid, 89% to sulfamethoxazole-trimethoprim and 9.5% to ampicillin. In addition, 4% of strains were resistant to multiple antibiotics (AmpR TetR SxtR StrR) and 4.2% of strains were sensitive to all antibiotics tested. Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. In 2006 Rubhana et al. study on this topic showed that Shigella is a major cause of morbidity, mortality, and growth retardation for children in developing countries. Emergence of antibiotic resistance among Shigellae demands the development of effective medicines. Previous studies found that the endogenous antimicrobial peptide LL-37 is down-regulated in the rectal epithelium of patients during shigellosis and that butyrate up-regulates the expression of LL-37 in colonic epithelial cells in vitro and decreases severity of inflammation in experimental shigellosis. In this study, Shigella-infected dysenteric

Running head: ANTIBIOTIC USE IN BANGLADESH

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rabbits were treated with butyrate (0.14 mmol/kg of body weight) twice daily for 3 days, and the expression levels of the rabbit homologue to LL-37, CAP-18, were monitored in the colon. Butyrate treatment resulted in (i) reduced clinical illness, severity of inflammation in the colon, and bacterial load in the stool, (ii) significant up-regulation of CAP-18 in the surface epithelium, and (iii) disappearance of CAP-18-positive cells in lamina propria. The active CAP-18 peptide was released in stool from its proform by butyrate treatment. In healthy controls, CAP-18 expression was localized predominantly to the epithelial surface of the colon. In infected rabbits, CAP-18 expression was localized to immune and inflammatory cells in the colon, whereas the ulcerated epithelium was devoid of CAP-18 expression. The combination of CAP-18 and butyrate was more efficient in killing Shigella in vitro than CAP-18 alone. Our findings indicate that oral butyrate treatment in shigellosis may be of clinical value because of induction of the endogenous cathelicidin CAP-18 in the colonic epithelium, stimulation of the release of the active peptide CAP-18, and promoting elimination of Shigella. Multiple drug-resistant Shigella dysenteriae type 1 in Rajbari district, Bangladesh. In 1997 Jahan, Hossain obtained twenty-one Shigellae isolates from bloody faecal specimens of diarrhoeal patients at Rajbari District Hospital from January 1994 to June 1995, and serogrouped. Fourteen (67%) isolates belonged to the Shigella dysenteriae serogroup and 7 (33%) to Shigella flexneri serogroup. Shigella dysenteriae strains were further serotyped; all were Shigella dysenteriae 1. Each strain was tested for resistance to 6 common antimicrobial agents. The two strains had different antibiotic susceptibility patterns. The 7 S. flexneri showed 6 different resistant patterns and the 14 S. dysenteriae 1 isolates had 4 resistance patterns. One of the S. dysenteriae 1 isolates was resistant to all 6 antimicrobial agents; 10 to 5, and twice to a different combination of 4 antimicrobials. The 14 (100%) S. dysenteriae 1 strains were resistant to 3 major antimicrobial agents: ampicillin, tetracycline, and chloramphenicol; 13 (93%) were

Running head: ANTIBIOTIC USE IN BANGLADESH

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resistant to 5 agents: ampicillin, tetracycline, chloramphenicol, trimethoprim-sulphamethoxazole, and nalidixic acid. Ciprofloxacin was the only drug active against all 7 S. flexneri and 13 of the 14 (93%) S. dysenteriae 1 strains. Antibiotic usage at a primary health care unit in Bangladesh. Fahad, Matin, Asish (2010) found that one of the most costly, frequently and commonly used categories of medications is antibiotics. Not only do these drugs have the potential for adverse effects but inappropriate use may also lead to resistant infections. For the past two decades antibiotic resistance has become a major problem in the public health as the prevalence of multi-drug resistant bacteria is growing and the availability of new antibacterial agents is limited. Bacterial resistance is one of the major causes of failure in the treatment of infectious diseases and results in increased morbidity, mortality, and costs. The literature suggests that this global phenomenon needs to monitored and tackled. Studies conducted in Bangladesh suggested that Pseudomonas aeruginosa responsible for wound, urine, ear, throat and other infections were more than 50% resistant to commonly used antibiotics used in Bangladesh(8) including ciprofloxacin, gentamicin, ceftriaxone, cefixime and azithromycin. Azithromycin was 100% ineffective in wound and urine infections, while ceftriaxone and cefixime was 100% ineffective in tracheal infections. Another study in Bangladesh also reports that E.Coli was resistant in 40% of cases to commonly used ceftriaxone, levofloxacin, ciprofloxacin, amoxicillin and ampicillin and 95% resistant to azithromycin. Klebsiella pneumoniae also showed similar patterns inappropriate prescribing and use of antimicrobial agents continues to be global problems; reasons include the demand for antibiotic treatment even when not indicated. Lack of understanding about the ineffectiveness of antibiotics against viral illness and the worldwide and uncontrolled availability of antibiotics are contributing factors. Moreover the clinicians desire to satisfy the patient, and

Running head: ANTIBIOTIC USE IN BANGLADESH

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pressure to address the wants of the individual rather than to consider the overall population. The problem of antibiotic resistance has also been linked with overuse of antibiotics in Bangladesh due to iself-prescribing and over-the-counter availability. But adequate data has not presented to provide robust evidence. Although some hospitals in Bangladesh have maintained records of their antibiotic usage this data is rarely reported in literature and there have been no studies to assess and examine the usage pattern of antibiotics in primary care units of Bangladesh. This pilot study aims to explore the prescribing patterns of antibiotics at one primary healthcare unit. Retrospective treatment and medication record data of 150 patients who were admitted as in-patients at a primary health Complex were collected from January 2009 to June 2009 with an average of 25 patient records per month. The first 150 cases were selected based upon availability of complete patient records with adequate documentation. However incomplete patient records were excluded. Records were maintained by the superintendent Nurse in charge. All diagnoses and treatment decisions were made by the Resident Medical Officer (RMO) or authorized physicians or surgeons at the hospital. The treatment record sheets included age, sex, diagnosis and medication prescribed. The number of antibiotics and their percentages prescribed in all patients were analyzed by age group and by gender. Also the cost of antibiotics, the types and number of antibiotics used, and details of antibiotics when used in combination were also noted. Finally the top 7 diagnoses where the antibiotic usage was the highest were identified and Comparing antibiotic usage pattern at various age groups. Table 1 and Figure 1 compares the amount of antibiotics prescribed at various age groups. It shows that antibiotics were most commonly prescribed in patients older than 65 years of age and also in young children between the ages of 5 to 11 years. Antibiotic prescriptions were relatively uncommon for people aged 35 to 49 and 50 to 65.

Running head: ANTIBIOTIC USE IN BANGLADESH Table 1 Antibiotic Usage in Different Age Groups

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Figure 1:Antibiotic usage in different age groups.

Comparing antibiotic usage pattern by gender. Table 2 shows the variations of the amount of antibiotics in females vs. males. The male group received 20% higher percentage of antibiotics.

Running head: ANTIBIOTIC USE IN BANGLADESH Table 2 Antibiotic Usage by Gender

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Comparing antibiotic usage pattern of various antibiotics. Table 3 and Figure 2 show the extent of usage of various antibiotics that are available in Bangladesh. Ceftriaxone, a third generation cephalosporin is by far the most used antibiotic (30.2%, 95%CI: 22.2 -39.5%). Following it is cefixime, another third generation cephalosporin and it was used 18.9% of the time (95%CI: 12.5-27.4%). Amoxycillin, ciprofloxacin, metronidazole and cefuroxime follows the list. The least used antibiotics were Cefepime and Erythromycin. Figure 2: Usage pattern of different antibiotics.

Running head: ANTIBIOTIC USE IN BANGLADESH Table 3 Anntibiotics Usage of Different Types of Antibiotics

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Comparing antibiotic usage pattern in the top 7 Diagnoses (based on highest antibiotic usage). Physical assault, general weakness, acute watery diarrhea, acute trauma, gastrointestinal distress (GID), respiratory diseases and post partum cases in descending order were the top seven classes of diagnoses which resulted in most frequent antibiotic prescriptions. Ceftriaxone, Cefixime and other cephalosporins were most frequently used in physical assaults, while in general weakness and acute traumas Amoxycillin usage was very prominent too in addition the previously mentioned antibiotics. Both Ciprofloxacin and Metronidazole were used in 50% (95%CI: 23.7to 76.3%) of all acute watery diarrhea cases while Ceftriaxone was used in 20% (95%CI: 4.6 to 52.1%) of the cases. In 28.6% (95%CI: 11.3 to 55.0%) of GID cases Ceftriaxone was used. Amoxycillin seemed to be the most commonly used antibiotic (57.4%, 95%CI: 25.0 to 84.2%) in respiratory diseases Australasian Medical Journal AMJ 2010, 3, 7,

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414-421 416 followed by Ceftriaxone (14.3%, 95% CI: 0.5 to 53.4%) and other cephalosporins (14.3%, 95%CI: 0.5 to 53.4%). Ampicillin was prescribed in all post partum cases (95%CI: 29 to 100%) while Amoxycillin, ciprofloxacin and metronidazole were prescribed in 50% (95%CI: 9.5 to 90.6%) of all cases. Analysis of amount of antibiotic used and detailed Analysis of combination antibiotic therapy usage. Table 4 shows the frequency of combination antibiotictherapy in various diagnoses. Antibiotic usage was highest in March 2009. This probably occurred because of the high prevalence of diarrhea in March (35). A combination of two antibiotics were prescribed for 12.7% of the total population of patients (95%CI: 8 19%) while 3 antibiotic combination were received by 0.01% (95%CI: 0.06 to 5%). These combinations were mostly generated in January and March 2009. Combination therapies were most common in patients diagnosed with physical assault with 22.7% (95%CI: 9.7 to 43%) of all combination therapies being prescribed in this class. Other cases where combination therapies were mostly used were acute watery diarrhea (95%CI: 6.7 to 39.1%), GID (95%CI: 3.9to 34.2%) followed by those with General Weakness and Partum cases. Analysis of Cost profile of antibiotic usage. Figure 3 shows the contribution of the cost of antibiotics on the total prescription costs at various time periods. On an average, antibiotics accounted for Tk.136.3, while the total cost for the total prescription were Tk.238.5. The prescription costs averaged around Tk.102 where antibiotics had not been prescribed. The cost of total prescription for the group of patients who were receiving antibiotics was compared with those who were not receiving antibiotics. Paired t-test analysis revealed that the difference in the two groups were Tk.105.9 (p value of 0.049) with the antibiotic group incurring a cost of Tk.241.9 (where antibiotic itself accounted for Tk.134.9) while the average prescription costs for the non antibiotic group were Tk.148.2 which is almost half of the antibiotic group.

Running head: ANTIBIOTIC USE IN BANGLADESH

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Table 4 Combination Antibiotic Therapy

Figure 3: Antibiotics cost.

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Drug resistance of Mycobacterium tuberculosis in selected urban and rural areas in Bangladesh. In 2005 Zaman et al. studied the drug resistance patterns of Mycobacterium tuberculosis in an urban and a rural area of Bangladesh. A tuberculosis (TB) surveillance system has been set up in a population of 106,000 in rural Matlab and in a TB clinic in urban Dhaka. Trained field workers interviewed all persons > or =15 y at Matlab to detect suspected cases of tuberculosis (cough >21 d) and sputum samples were examined for acid-fast bacilli (AFB). The first 3 AFB positive patients daily from the urban clinic were included. AFB positive cases diagnosed between June 2001 and June 2003 from both settings were cultured and drug susceptibility tests were performed. Of 657 isolates, resistance to 1 or more drugs was observed in 48.4% of isolates. Resistance to streptomycin, isoniazid, ethambutol and rifampicin was observed in 45.2%, 14.2%, 7.9% and 6.4% of isolates, respectively. Multidrug resistance was observed in 5.5% of isolates. It was significantly higher among persons who previously had received tuberculosis treatment of > or =1 month (15.4% vs 3.0%, adjusted OR: 6.12, 95% CI: 3.03-12.34). The magnitude of anti-tuberculosis drug resistance in Bangladesh is high. Further evaluation is needed to explain the high proportion of streptomycin resistant M. tuberculosis. Appropriate measures to control and prevent drug resistant tuberculosis in Bangladesh to reduce mortality and transmission are warranted. Emergence of high-level fluoroquinolone-resistantEscherichia coli in Bangladesh. Saha et al. isolated fifteen fluoroquinolone-resistant strains of Escherichia coli from different clinical specimens of paediatric patients, 2 years after introduction of the drugs into Bangladesh. However, none of these patients had any definite history of treatment with fluoroquinolones. MICs of these strains to different antibiotics were determined by the broth microdilution method recommended by the Working Party of BSAC. Strains were highly

Running head: ANTIBIOTIC USE IN BANGLADESH resistant to all drugs except ceftriaxone. Study indicates a high frequency of fluoroquinoloneresistant E. colistrains among the clinical isolates which is possibly related to fluoroquinolone introduction. Antibiotic Prescribing Practice

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Socioeconomic and Behavioral Factors Leading to Acquired Bacterial Resistance to Antibiotics in Developing Countries. Okeke (1996) found that in developing countries, acquired bacterial resistance to antimicrobial agents is common in isolates from healthy persons and from persons with community-acquired infections. Complex socioeconomic and behavioral factors associated with antibiotic resistance, particularly regarding diarrheal and respiratory pathogens, in developing tropical countries, include misuse of antibiotics by health professionals, unskilled practitioners, and laypersons; poor drug quality; unhygienic conditions accounting for spread of resistant bacteria; and inadequate surveillance. Risk factors of persistent diarrhea in children below five years of age. Karim (2001) found that most of the children (82%) were aged below 2 years. Among the risk factors, Grade III malnutrition (p<0.008), irrational antibiotic use during acute diarrheal episode (p<0.0000005), use of unsafe drinking water (p<0.004) and lack of exclusive breast-feeding up to the first four months of life (p<0.004) were significantly associated with persistent diarrhea. Logistic analysis showed irrational antibiotic use (p<0.0001) during an episode of acute diarrhea and lack of exclusive breast-feeding (p<0.05) during the first four months of life as independent risk factors associated with persistent diarrhea. Improvement of nutritional status, encouraging exclusive breast-feeding during the first four months of life, discouraging the irrational use of antibiotic for the treatment of acute diarrhea, and provision of safe drinking water may be

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important for the prevention of persistent diarrhea as these have been identified as risk factors in Bangladeshi children below five years of age. Current practices for treatment of dysentery in rural Bangladesh. Ronsmans et al. (1991) found that a rural area of Bangladesh with a population of 191,000 had 643 health care providers, of whom 324 (50%) practiced allopathic (Western) medicine, 152 (24%) were spiritualists, 109 (17%) were herbalists, and 58 (9%) were homeopaths. Two hundred eight (64%) of the allopaths had no formal training, and only 18 (6%) were graduates of medical school. In a community-based study of 480 children with bloody diarrhea and 480 children with nonbloody diarrhea, allopathic treatment was the most common care provided. Furazolidone and metronidazole were the two most commonly prescribed drugs, given to 26% and 23% of children, respectively, who were seen by a practitioner. Only 25% of children had received oral rehydration therapy. We conclude that in this region of Bangladesh care of acute diarrhea is provided mostly by private medical practitioners who have little or no training; that such care currently is largely irrational; and that the provision of rational care will require the development of simple algorithms that these practitioners can implement for treatment of this disease. Prescribing pattern in acute diarrhoea in three districts in Bangladesh. Since the irrational administration of drugs in diarrhea cases is a serious problem, a prescribing survey was made among 10 government health facilities (GHF) and private dispensaries (PD) in the Dhaka, Tangail, and Serajgong districts of Bangladesh. Using standard indicators on prescribing, patient care, and drug supply developed by the International Network for the Rational Use of Drugs, 12 prescriptions written for children under 5 years old with acute diarrhea were studied from each center (total = 120). It was found that the average number of drugs administered per encounter was 1.82 and 2.30 in the GHFs and PDs, respectively. Almost every prescription (0.79 and 0.96

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in the GHFs and PDs, respectively) had an antimicrobial component, with metronidazole used in most cases despite the fact that it is not indicated in acute diarrhea and treatment guidelines advise against its use in children under age 5 years in Bangladesh. Oral rehydration salt solution was used in each facility in about 80% of cases (vs. 11% of cases in the community). Because of the inclusion of the antimicrobial, standard treatment guidelines were followed in only 17 and 23% of cases in the GHFs and PDs, respectively. Patient care indicators revealed that 1.8% of patients were examined in the GHFs vs. 65% in the PDs. 50% of patients in both facilities could report the correct dosing schedule for the drugs they were given. The GHFs do not label prescriptions, but all the drugs administered by the PDs remain in manufacturer-labeled containers. The existence of an essential drugs list and the distribution of standard treatment guidelines have not ensured good prescribing habits among health professionals for this common disease. Additional efforts are required to improve this situation (Chowdhury, 1993). Antibiotic use in a rural community in Bangladesh. In 1982 Hossain studied on antibiotic use by 175 000 people in the Matlab rural surveillance area (MSA) of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) to identify practices which might affect microbial drug resistance. We surveyed a 3% sample of drug purchases from pharmacies in the MSA over a four-week period in August and September 1980. Fifty-seven drug purchases were made per thousand Matlab residents per week; 9% of these were of tetracycline and 26% were antibiotics. Forty-eight per cent of the antibiotic tablets or capsules for persons aged 15 years or more were purchased in quantities which represented less than a single day's dose and rarely was a full course of therapy purchased at one time. The rate of tetracycline purchase for young children--in whom it is usually contraindicated--equalled the rate for older children and young adults. These practices have probably not led to improvements in

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health and may have promoted the emergence and persistence of drug-resistant micro-organisms. To optimize antibiotic use, control measures at government, producer, prescriber and consumer levels need to be pursued. Gender difference in treatment seeking behaviors of tuberculosis cases in rural communities of Bangladesh. In 2004 this descriptive cross-sectional study was conducted by Ahsan to investigate gender differences in the epidemiological factors associated with the treatment seeking behaviors of TB cases in the rural communities of Bangladesh. The study reveals that there is significant gender difference in treatment seeking behaviors of rural TB cases and the majority of them (52%) have taken prior treatment from various traditional healers, 70% of them are females who attended health centers (UZHCs) as the other choice (adjusted OR: 4.2, 95% CI: 2.0-8.4). It was found that the mean patient delay was 63 days (range 14-210 days) where half of the females delayed more than 60 days while they were spreading their disease. The study findings reveal gender differences in treatment seeking behaviors associated with socio-cultural barriers, particularly among females in their access to TB care. Fifty-five percent of cases wanted the diagnosis of TB remain confidential to avoid being labeled as TB patients, where 82.7% were female, 85.6% of female TB patients had problems in their relationships with their spouse (61%) and family members (58%) after being diagnosed with TB. The results of the TB service factors found that 39% of females were not satisfied with their provider's behaviors, which was significantly associated with treatment seeking behavior (adjusted OR: 2.6, 95% CI: 1.0-6.6). The study findings strongly suggest that there was a significant gender difference in treatment seeking behavior in rural Bangladesh. Based on the study findings, we recommend developing an appropriate gender strategy for developing a TB control program, comprised of

Running head: ANTIBIOTIC USE IN BANGLADESH operational, socio-cultural and community awareness interventions aimed at treating undiscovered reservoirs of female TB cases in rural Bangladesh.

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Adherence to cotrimoxazole treatment for acute lower respiratory tract infections in rural Bangladeshi children. In 1998 De Francisco studied to evaluate compliance with taking oral cotrimoxazole in an ALRI control programme in rural Bangladesh. Health workers administered the first dose to children with moderate disease and entrusted relatives to give the remaining doses. A team of medical assistants visited the families of cases 3 to 5 days after initiating treatment and counted the remaining tablets. Medical assistants undertook 367 visits to families of children under treatment at a mean (SD) of 4.4 (0.99) days after treatment began. All children appeared to have been given the antibiotic, but one-quarter were being under-dosed on the day of the visit. Under-dosing did not correlate with any of the socio-demographic variables studied, and seemed to be homogeneously distributed in the community. Under-dosed children did not seem to have a higher risk of subsequent ALRI episodes during the study period. There was no indication of progression to severe disease or death in home-managed cases of moderate pneumonia in this study. These findings raise a question about the need for 5 days of oral antibiotic in the management of moderate pneumonia. Careful studies of the effect on subsequent morbidity, mortality and antibiotic resistance of providing briefer treatment for moderate episodes of ALRI are required. If a briefer course proves effective, this would have important implications for funding programmes of control of ALRI in the community. Antibiotic Resistant Bacteria in Hospitals: A Time for Action. Every few years there are reports of antibiotic resistant microbes that prompt a series of predictions about the end of antibiotics. Srinivasan (2011) found that it happened in the 90s with multi-drug resistant tuberculosis and then again earlier this decade with methicillin-resistantStaphylococcus aureus or

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MRSA. Its happening again with carbapenem-resistant Enterobacteriaceaeor CRE. Predictably, over time these bacteria have become resistant to more and more antibiotics. Almost just as predictably, they could be treated by a category of powerful antibiotics known as carbapenems until now. Today, 35 states have reported cases of CRE infection to the Centers for Disease Control and Prevention in Atlanta. And they are dangerous. In a recent study of almost 100 cases, more than a third of the patients died from the infection. The concern over these bacteria is compounded by the fact that there are no new antibiotics to treat them coming anytime soon. Most experts agree that even in the most optimistic scenario it will likely be about 10 years before effective new drugs are developed. A variety of efforts are being debated to speed the development of new antibiotics, but these discussions often overlook one critically important issue. One of the reasons our current antibiotics are losing their effectiveness is because we dont use them properly. Studies have shown, repeatedly, that up to 50% of antibiotic prescriptions are either unnecessary or inappropriate a statistic that is disappointingly consistent across both in-patient hospitals and out-patient clinics. Not only does this overuse reduce the effectiveness of our current antibiotics, it threatens the utility of any new antibiotics that come along in the future. While we work on new antibiotics for the future, there is much that must be done right now to both preserve the lifespan of the antibiotics we currently have and to pave the way to ensure prolonged usefulness of new antibiotics that are developed. The most important immediate need is to reducing the overuse of these drugs. Reducing antibiotic over-use is good for society as a whole but it is also good for individual patients. A recent study showed that

Running head: ANTIBIOTIC USE IN BANGLADESH exposure to a carbapenem antibiotic was the single greatest risk factor for getting an infection with CRE, increasing the risk by 15-fold. This week, the CDC and its partners have launched the Get Smart for Healthcareprogram to complement the existing Get Smart: Know When Antibiotics

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Work program. This is an expansion of CDCs existing Get Smart programs targeting outpatient clinics and pediatricians offices to include hospitals and nursing homes. Promoting appropriate antibiotic use, as basic as it seems, can carry our drugs a great deal further. It can be helpful to view antibiotics much like we view natural resources that benefit from concerted, coordinated conservation efforts. Conservation requires collaboration and recognition that individual actions have an impact on the common good. Reducing overuse means engaging everyone in the effortfor example, by urging the passage of innovative policies aimed at hospitals, other healthcare facilities, and even pharmaceutical companies, to encourage stewardship. By aligning incentives for hospitals and healthcare facilities to focus on infection control and prevention, we can reduce the prevalence of resistant infections that jump from healthcare facilities into the community. By motivating pharmaceutical companies to care about drug resistance, we can encourage them to stop overselling their drugs. Consumers also need to stop demanding antibiotics when they suffer from a viral infection. We do need new antibioticsurgently. But, in the meantime, we must focus on using the ones we already have in a sustainable fashion. Not only will this extend the utility of the drugs we have on the market today, but it will also ensure that drugs approved in the future will stay effective for longer periods. It is easy to make frightening predictions about the end of antibiotics. It is harder but no less possible, to take definitive steps to ensure that such a day never comes. It is time for action.

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Rational use of antibiotics is a serious issue in the context of Bangladesh. Bacteria are so well armoured that frequently they develop an array of biochemical mechanisms by which they can resist the antibiotic. Thus, the greater an antibiotic is in use the faster will be the development of resistance. With its 130 million people and a very heavy infectious disease load, in Bangladesh huge quantities of antibiotics are used annually. But a very large portion of this is used unfortunately under conditions of inadequate or no medical supervision and in most cases without prior tests on identification of the disease-causing organism and determination of its sensitivity to the antibiotic prescribed. The sale of antibiotics without proper medical prescription or on a quack 'prescription' or simply on verbal demand of the buyer is common both in cities and rural areas. Even in those cases where a qualified doctor prescribes an antibiotic, patient compliance regarding using the full course of the drug is not always satisfactory largely due to ignorance. All of these contribute to rapid emergence of resistant types of bacteria soon after a new antibiotic is introduced. This is happening even with the newer types of antibiotics against which laboratory studies indicate that there should not be rapid development of resistance (Rahman, 2000). Patients' Knowledge and Awareness towards Use of Antibiotics in Bangladesh: A Cross-sectional Study Conducted in Three Tertiary Healthcare Centers in Bangladesh. This study is aimed to estimate general knowledge and awareness of patients regarding use of antibiotics to find out possible reasons of irrational use of antibiotics in Bangladesh. It was a questionnaire based crosssectional health survey conducted on 350 subjects aged 18 or over who came to get service at three tertiary healthcare centers named Dhaka Medical College (DMC) Hospital, Sir Salimullah Medical College (SSMC) Mitford Hospital and Bangabandhu Sheikh Mujib Medical University (BSMMU) Hospital of Dhaka, Bangladesh. Saha found from

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the study that the general knowledge of the patients about the indication of antibiotics was very poor. Majority of the patients did not know the appropriate use of antibiotics. Only 26% respondents answered correctly that antibiotics are indicated for bacterial infections. In addition, 38.97% of them also did not know that an antibiotic is a prescription drug and should not be used without doctors prescription. The awareness about the patients towards use of antibiotics was also poor. A very high percentage of the patients (51.71%) answered that they do not complete the full course of therapy. Surprisingly, 39.14% of the patients replied that they stop antibiotics when the symptoms disappear and remarkably 14.29% just make the dose double if they forget to take due dose. On the other hand, 28.86% of the patients said that they do not maintain dosing schedule during the course of therapy. Moreover, prevalence of self-medication with antibiotics in cold and fever was also extremely high (60.86%). This study indicates that there is an urgent need of health education for the community to increase knowledge and awareness about use of antibiotics to decrease the self-medication and inappropriate use of antibiotics. News Coverage Bangladesh News line (BDNL) (2011) found that many antibiotics are losing effectiveness on patients because of their misuse, utterly ignoring the long term side effects. Different studies and surveys show people, irrespective of their social and financial status, seldom get doctors advice before taking antibiotics for treating common illness like flue, cold and food poisoning. A survey finds misuse of antibiotics is higher in the rural areas where people are less aware about proper use of drugs and urban people are also reluctant to follow prescription all the time.

Running head: ANTIBIOTIC USE IN BANGLADESH Another study reveals the misuse is increasing rapidly, ringing an alarm bell to the authorities who are surprisingly showing their indifference to the serious health threat.

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A bdnl.net query, however, finds severe manpower shortages in the drug administration to monitor the practices of doctors and drug sales procedures country-wide. Bangladesh Health Watch a non-government organization working in the field of health and nutrition- in a report said the misuse of antibiotics doubled in 15 years when it increased to 50 percent in 2009 from 25 percent in 1994. The increasing trend was comparatively higher in the rural areas as salesmen at medicine shops there often suggest patient antibiotic for flu or cold, the report said. According to the report, retail drug sellers in rural areas mostly advise people antibiotics, which is 60 percent of the total medicine they prescribe. The rate is 45 percent at urban clinics and 43 percent at upazilla health centers. The International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) conducted a survey in Mirpur area in the capital city in 2009 where it found that most patients first go to local pharmacies for medicine and take antihistamine and antibiotics for the disease like influenza. Some specialists even gave a dreadful scenario saying a large number of doctors prescribed antibiotics to bring quick relief to the patient without considering the consequence of the wrong prescription. They said the wrong uses of antibiotic have become very common in our society due mainly to noncompliance with doctors advice, self-diagnosis and self-medication.

Running head: ANTIBIOTIC USE IN BANGLADESH Associate Professor of Medicine Department at Bangabandhu Sheikh Mujib Medical University Dr Md Abul Kalam said people mostly misused antibiotics in cases of flu and cold related illness. But, he said fever is not a disease; rather it is only the symptom of a disease. Similarly, hepatitis-B, jaundice and dengue are virus-borne diseases, which cannot be treated with antibiotics though people take such medicine from a common perception that antibiotics cure everything, he said.

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Such misuse helps grow resistance to the respective antibiotic inside the patent body and as a result the same drug does not work in future for real cause, Kalam said. He said patients should be diagnosed properly before prescribing any antibiotic. Officer-in-charge of Upazilla Health Complex at Raipur in Norsingdi district Dr Sadiq Khan said he observed people in the rural area take antibiotics for virus-related sickness like common cold and flu without consulting doctors. He said antibiotics are usually prescribed for bacteria related diseases like tuberculosis, severe cold and pneumonia. On the other hand, virus-related sickness like common cold and flu require antiviral intake. These illnesses cannot be treated by antibiotics. Khan said some people are not aware that antibiotics take one to two weeks to work. So they switch to another antibiotic, which may cause serious side affect. Besides, he said some people stop taking the drug without completing the full course as per the doctors prescription, which also helps develop resistance like misuse of it. There are certain regulations, which prohibit selling prescription medicine without doctors written advice. But medicine shops hardly follow the regulation only to make more profit by selling as much medicine as they can.

Running head: ANTIBIOTIC USE IN BANGLADESH The drug administration does not have enough manpower to implement the regulation.

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Official sources said the regulator only has 25 staff for overseeing thousands of medicine shops across the country. Bangladesh gets tough with antibiotic use. Bangladesh is set to pass a new rule on the use of antibiotics such as nitrofurans and chloramphenicol in animal feeds after the EU detected the two drugs in freshwater prawn imported from the country. Bangladeshs livestock and fisheries departments have drafted the Fish and Animal Feed Law to regulate antibiotics use in animal feeds and prevent them from entering the food chain. Rafiqul Islam, Director General of the Department of Fisheries, said the Parliaments standing committee on fisheries has reviewed the draft and it is expected to be passed as a law soon. The detection prompted the EU to impose a ban on shrimp exports from Bangladesh. After tracing back the cause of contamination, authorities found that the drugs came from the feed and chicken manure in the water. (www. Zootechnicainternational.com, 2010) Prevention and Containment of Antimicrobial Resistance In 2010 a meeting by regional office for south east asia of WHO found that consequences of resistances are:

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Systematic studies to understand the status of antimicrobial resistance and its trends, and consumption of antimicrobial agents have been undertaken in the SEA Region. However, the data available from published reports from Member States of the Region provide an insight into the magnitude of the problem of resistance. The information available for selected diseases/organisms is briefly described below: Tuberculosis Resistance to first-line anti-TB drugs has become a concern for national TB control programmes. The population weighted mean of MDR-TB1 in the Region is 2.08% (1.9%-3.6%) among new cases and 18.8% (13.3%-24.3%) among previously treated cases. It is estimated that around 150 000 cases of MDR-TB reside in this Region with more than 80% of these being in Bangladesh, India, Indonesia, Myanmar and Thailand. 1 MDR-TB = Resistance in mycobacteria to isoniazid and rifamipicin. The level of multidrug-resistant TB however remains low (below 3%) reflecting the good quality of TB programmes. The need for preserving the efficacy of firstline antituberculous drugs has been widely felt since drugs used in the management of MDR-TB cases are not only expensive but also toxic. Extensively drug-resistant TB (XDR-TB) has been detected in mycobacteria isolated in Bangladesh, India, Indonesia and Thailand giving another serious dimension to managing resistance in TB. HIV and sexually-transmitted infections Emerging diseases continue to challenge public health as never before. An estimated 3.5 million people are currently living with HIV/AIDS; the Regions HIV/AIDS burden is next only to sub-Saharan Africa. The generic antiretroviral (ART) drugs produced by the pharmaceutical industry in the Region are contributing greatly to improve the survival rate of patients worldwide and in rendering HIV as a chronic but manageable condition. Although the response to ART

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drugs is excellent when they are delivered at health facilities, the emergence of resistance in HIV can destroy the hopes of survival for millions of people living with HIV. There has been a substantial change in the antimicrobial susceptibility of Neisseria gonorrhoeae. Thirty years ago, gonorrhoea used to respond effectively to penicillin. Now, the resistance to penicillin and fluoroquinolones is widespread across the Region. Malaria Resistant malaria has become a major issue for a population of 400 million living in areas that expose them to a high risk of contracting it. Artemisininbased combination therapies (ACT) have recently been introduced in virtually all countries in which malaria is endemic, thereby making such drugs the most essential class of antimalarial agents. However, recent data indicate that artemisinin resistance has emerged along the border between Cambodia and Thailand. Surveillance data from the Thai Ministry of Public Health indicate that clinical failures of artemisinin-based therapies exist in the ThaiCambodian 2 XDR-TB = MDR-TB + resistance to fluoroquinolones and at least one of the three injectable second-line drugs (capreomycin, kanamycin and amikacin). Sutrisna A, Soebjakto O, Wignall FS, Kaul S, LimniosEA, Ray S et al. Increasing resistance to ciprofloxacin and other antibiotics in Neisseria gonorrhoeae from East Java and Papua, Indonesia, in 2004-implications for treatment. Int J STD AIDS 2006, 17:810-12. border, whereas efficacy with artesunatemefloquine along the western borders of Thailand remains high. A global disaster could happen if malaria parasites worldwide developed resistance against the new artemisinin-based combination therapies (ACTs) that have become the gold standard. Large parts of the world would have no drugs to fall back on, and malaria cases and deaths could soar, erasing the hope that the world might be close to a huge

Running head: ANTIBIOTIC USE IN BANGLADESH reduction in the disease. Yet, resistance against ACTs is precisely what now seems to be developing in western Cambodia, along the Thai border. Kala-azar

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Kala-azar is a public health problem in Bangladesh, India and Nepal and is being targeted for elimination using miltefosine. Pentavalent antimonials have been successfully used for treatment of kalaazar since the last six decades. Since the 1970s, however, their conventional dosages have failed to achieve the desired results with 60% unresponsiveness being reported with the WHO regimen in Bihar (India). Pentamidine initially used as a second-line drug, acquired resistance (25%) even with prolonged dosage. The newer oral drug, miltefosine is a potent antileishmanial drug with a longer half-life, a property likely to delay resistance. The evolution of resistance to this drug will cause havoc to the regional efforts to combat this disease. Diarrhoeal diseases Cholera germs have acquired resistance to a number of antimicrobials. The resistance spectrum varies in different locales. In areas around New Delhi (India) extensive resistance to furazolidone, cotrimoxazole and nalidixic acid has been noted while tetracycline has remained effective. On the other hand, in Bangladesh, tetracycline resistance has also been found to be frequent. 4 Vijaykadga S, Rojanawatsirivej C, Cholpol S, et al. In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated P. falciparum malaria in Thailand in 2003. Tropical Medicine and International Health 2006;11:211-219. 5 Enserink M. . Malaria: signs of drug resistance rattle experts, Trigger bold plan. Science; 2008:322:1776. 6 Jha T.K. Drug unresponsiveness and combination therapy for kala-azar . Indian Journal of Medical Research 123,2006, 389-398. 7 Sharma NC et al.

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Changing profile of Vibrio cholerae O1, O139 in Delhi and periphery. Indian Journal of Medical Research 2007;125:633. Respiratory infections Streptococcus pneumoniae is the most common causative agent of pneumonias in children and adults in Asia8. Till the 1980s, almost all isolates of this organism used to be susceptible to penicillin. In 2006, in a hospital in Thailand, almost 69% isolates of this bacterium were found to be penicillin-resistant. Typhoid and paratyphoid fever Typhoid and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in the SEA Region where this disease is associated with poor sanitation and unsafe food and water. Published reports indicate that multidrugresistant Salmonella typhi are prevalent widely in India and Indonesia. Shortly after the emergence of multidrug-resistant Salmonella typhi in this Region, case fatality rates approaching 10% (close to 12.8% recorded in pre-antibiotic era) were reported. Wound sepsis due to Staphylococcus aureus More than 50% isolates of Staphylococcus aureus in hospital settings are now methicillin-resistant. In a study undertaken in a 1000-bedded hospital in Thailand, 48% patients with bacteraemia due to resistant Staphylococcus aureus died. Methicillin-resistant Staph. aureus (MRSA) is a major problem in hospital-associated infections in almost all countries in the SEA Region. Nosocomial infections Multiresistant klebsiellae, pseudomonas and Acinetobacter species have given new dimensions to the problem of hospital-associated infections. Acinetobacter baumannii has

Running head: ANTIBIOTIC USE IN BANGLADESH become an important pathogen in intensive care units. It 8 Song J.H. et al. Epidemiology and clinical outcomes of community acquired pneumonia in adult patients in Asian countries: a prospective study by the Asian network for surveillance of resistant pathogens. International Journal of Antimicrobial Agents 2008, 31:107-114. 9 Srifuengfung S et al. Antimicrobial susceptibility of Streptococcus pneumoniae isolated from patients with respiratory tract infections in Thailand. Southeast Asian Journal of Tropical Medicine and Public Health 2008;39:461. 10 Gupta A. Multidrug-resistant typhoid fever in children: epidemiology and therapeutic approach. Pediatr Infect Dis J 1994;13: 13440. 11 Tyagi A, Kapil A, Singh P. Incidence of methicillin resistant Staphylococcus aureus (MRSA) in pus samples at a tertiary care hospital. JIACM 2008, 9:33-35. produces a wide range of beta lactamases and has a formidable spectrum of intrinsic resistance mechanisms that can mean that some strains are resistant to almost all known antimicrobial agents. In a study done in Thailand, mortality in

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admitted patients due to imipenem-resistant Acinetobacter baumannii was 52% as compared to 19% in those who were infected with the sensitive variant. Country reports Bangladesh Antimicrobial resistance (AMR) is considered a national priority though there is no national alliance or regulations governing the use of antimicrobials and no national coordination mechanism on AMR. The Director-General of Drugs Administration is the proposed focal point for AMR in Bangladesh. Antimicrobials are also used extensively in the veterinary sector. There is no national surveillance and network of laboratories on AMR at present but it is being planned. Many medical colleges and NGOs have published several scientific papers in different technical journals highlighting the problem of AMR in Bangladesh.

Running head: ANTIBIOTIC USE IN BANGLADESH Many infectious diseases do not respond to conventional antimicrobial agents. While

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standard treatment guidelines are available at various levels of health care delivery and medical professionals are oriented on the rational use of antimicrobials, community awareness programmes are weak. Most of the antimicrobials are available over the counter all over he country and usually prescribed even by unqualified or unauthorized personnel. For surveillance of antimicrobial resistance, national authorities are planning to establish a national network of laboratories to be coordinated by a National Reference Laboratory. India Antimicrobial resistance in important disease pathogens has become a matterof great public health concern globally including India. The factors responsible for this are widespread use and availability of practically all the antimicrobials across the counter meant for human as well as animal consumption. Though there are definite policies/guidelines for appropriate use of antimicrobials at national level in specific national health programmes being run in the country, the same are not available for other pathogens of public health importance like enteric fever, diarrhoeal disease, respiratory infections etc. However, during the recent H1N1 pandemic, national guidelines were framed and implemented regarding restricted sale/use of oseltamivir in the country. Similarly, there is no national data base on antimicrobial resistance in different pathogens except for those where there is a specific national health programme. Though a large number of laboratories in the country (both in the private and public sector) are carrying out drug susceptibility testing of micro organisms, the data is either not analysed on a regular basis or not being disseminated for use of clinicians/public health experts/programme managers. There are also issues of quality control and data sharing with these laboratories. There are a few examples of successful networking of laboratories carrying out antimicrobial sensitivity testing of

Running head: ANTIBIOTIC USE IN BANGLADESH gonococcus in the country with the Regional STD laboratory Prevention and Containment of Antimicrobial Resistance 15 at S.J. Hospital, New Delhi being the referral laboratory. There is networking of such laboratories also in the Revised National TB Control Programme of the country generating some useful data on drug resistance in TB and recently a laboratory network has also been established for antimicrobial testing of HIV under National AIDS Control Organization. Meta analyses of the drug susceptibility results of various laboratories across the country reveal an increasing trend of development of resistance to commonly used antimicrobials in pathogens like salmonellae, shigellae, V.cholerae, Staph aureus, gonococcus, meningococcus, klebsiellae, Mycobacterium tuberculosis, HIV, malarial

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parasite and others. Though there is no national database on surveillance of use of antimicrobials in the community, there are a few studies in the country in this regard. Studies carried out in Delhi and Vellore, with support from WHO during 2003-2005 suggested a very high use of flouroquinolones in the community as compared to other antimicrobials. At present there are a large number of challenges that need to be addressed for effective containment of this problem. Available data suggest increasing drug resistance trends in the country. There is no national programme for the purpose, there is inadequacy of quality assured laboratories, insufficient data analysis and dissemination, absence of national guidelines on antimicrobial usage, no control on sale of these drugs for public consumption etc. In the last decade or so a large number of new initiatives have been launched by various agencies to contain this problem. These include IndiaClen (Indian Clinical Epidemiology Network) which has generated some quality data on AMR in pathogens like pneumococcus, H.influenzae across the country; IIMAR (Indian Initiative for Management of Antibiotic Resistance) launched in March 2008, with WHO support, by a consortium of NGOs to promote prudent use of antimicrobials, INSAR

Running head: ANTIBIOTIC USE IN BANGLADESH (Indian Network for Surveillance of Antimicrobial Resistance) a network of 20 laboratories in the private as well as public sectoracross the country to generate quality data on AMR, organization by the ICMR of an expert group meeting in December 2009 and an Indo-Swedish workshop held at New Delhi on 2 February 2010 to discuss a joint strategy for containment of AMR, recommendations of which are under consideration by the Ministry of Health & Family Welfare. Proceedings of the meeting Maldives Antimicrobial resistance is considered as a national priority as the resistance of

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antimicrobials is increasing over the years. There is no national policy or a guideline on AMR. There are no national programmes or alliances on use of antimicrobials with any country or nation. Since there are no animals in the country, there is no veterinary sector and hence antibiotics are not used in these areas. There is no national focal point, no national surveillance mechanism and no network of labs on AMR. Data collection has not been done nationwide. However, data is available with the Indira Gandhi Memorial Hospital (IGMH) Lab information system. The data that is available on AMR is taken from IGMH Lab information system from 2007 to 2009. Three organisms that are commonly isolated are selected along with the antibiotics tested for them. The three organisms are: Escherichia coli, Staphylococcus aureus and Klebsiella species. When the data are analyzed, it is seen that all the three organisms are showing more than 70% resistance to ampicillin and amoxacillin. Amikacin shows less than 3% resistance to E.coli and Klebsiella. Also, it is seen that the resistance of Klebsiella to all antibiotics is much more compared to that of E.coli. Based on the data, it is seen that the resistance has been increasing over the years to the antibiotics that we are using. This can be very useful information for the clinicians regarding

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AMR. There is some training for doctors and pharmacists about the rational use of drugs, but for nurses and dental professionals training is not being conducted regarding AMR. The mechanism for monitoring of rational use of drugs is under development and it is hoped to be completed in the near future. Most of the antimicrobials are not available over the counter and it can be taken only by a prescription from a qualified professional. There are no NGOs working on rational use of drugs. Community awareness programmes are coordinated through the media but no research has been done to analyze the impact of these programmes. Major issues with regard to prevention and containment of AMR are absence of a national guideline on AMR, availability/accessibility of data/ information nationally and also lack of resources to carry out sustainable assessments like not having enough microbiologists and also no funds for research. A plan of action is being proposed to the government on AMR advising on consideration for policy formulation, formation of guidelines and also action plans. Myanmar Myanmar needs to formulate a national policy on use of antimicrobials and national regulations related to the use of antimicrobials. A national policy on use of antimicrobials and a national co-ordination mechanism on AMR do not exist but are being developed. Although restrictions on the use of specific antimicrobials in therapeutic purposes (veterinary sector) is present, it needs to be implemented. It is the same for non-therapeutic purposes. A national network of laboratories on AMR needs to be developed for initiating quality national surveillance. There is a strong need to formulate standard treatment guidelines at the national level. CME is required for physicians, nurses, dental professionals and pharmacists. Community

Running head: ANTIBIOTIC USE IN BANGLADESH awareness programmes also need to improve. Major issues with regard to prevention and containment of AMR and future national plans are the following: Establish national alliance against AMR. Establish national policy on AMR. Promote public awareness on rational use of drugs. Improve national surveillance system on AMR. Improve infection control programme in health care practice. Nepal Public sector health institutions in Nepal are categorized in three levels: primary level constitutes the health post and sub-health post, where paramedical staff are available, the

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secondary level constitutes primary healthcare centre and district hospitals. There are zonal, subregional, regional, central and specialized hospitals at the tertiary level. In the non-governmental sector, there are 18 Proceedings of the meeting teaching, I/NGO, community and private sector hospitals. Antibacterial drugs are prescribed both by physicians and paramedical personnel. The National Drug Policy, 1995 addresses the issues regarding rational use of antimicrobials in human and animals. However, implementation status is far from satisfactory. The Drug Act has categorised antibiotics as a prescriptive drug, which cannot be sold without prescription, though there may be a gap between the legal provision and practice. Standard treatment protocol is available for some national programmes like tuberculosis, leprosy, HIV/AIDS and also for health posts and sub-health posts to treat common infections. For the surveillance of AMR, 11 laboratories are participating, coordinated by the National Public Health Laboratory. Data dissemination is done every year although there is no formal publication. Various journals and bulletins published by academic institutions and

Running head: ANTIBIOTIC USE IN BANGLADESH professional organizations include results of AMR surveillance. The organisms regularly

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monitored are: Neisseria gonorrhoae, Salmonella typhi, Shigella, Vibrio cholerae, Streptococcus pneumoniae, Haemophilus influenza and E. coli. Training on the rational use of drugs is normally conducted by NGOs, though recently the Ministry of Health has also started such training. The government has initiated the process for developing treatment protocols for various levels of health institutions. Antibiotics used for curative purposes are not allowed to be used in feed supplement or as growth promoters. Though policy guidelines and a legal framework is in place, there are lapses in practice due to inadequate monitoring and supervision. This results in over-the-counter sale of antibiotics, which may enhance the development of resistance. The laboratory findings suggest that the above-mentioned micro organisms have developed resistance of various degrees towards many antibacterials in use. Sri Lanka Monitoring of AMR is considered a national priority. Though presently there is no national programme, there is an on-going activity by the Sri Lanka College of Microbiologists that commenced in 2009 and involves seven surveillance centres to monitor AMR in gram negative organisms. It is proposed to expand this programme to three additional laboratories in 2010. AMR surveillance for gram positive organisms shall also commence in a few centres in August 2010. Data r elated to AMR in different settings are published in the Bulletin of the Sri Lanka College of Microbiologists and released annually. The Ministry of Health has constituted a Task Force on Microbiology that has recognized the need for an antimicrobial policy and it will be formulated on data generated by the aforesaid surveillance programme. There is no national policy for use of antimicrobials. There are no direct regulations on antimicrobial use, but indirect controls are exerted at the time of drug registration and in selecting prescribers. Legal

Running head: ANTIBIOTIC USE IN BANGLADESH restrictions on nontherapeutic use of antimicrobials in veterinary practice exist but the status of

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implementation remains unknown. Standard treatment guidelines are available nationally and in major hospitals but compliance is inadequate which is compounded by frequent shortages of antimicrobials. Monitoring of drugs at the community level is done through authorized officials belonging to the National Regulatory Authority. Professional bodies are working on rational use of antimicrobials and some of them are the Sri Lanka College of Microbiologists and the Sri Lanka Medical Association. There have been training programmes on rational use of drugs to different categories of healthcare providers but coverage remains inadequate. Availability of antimicrobials over the counter and their prescription by unauthorized personnel takes place in spite of laws against such practices. Thailand Antimicrobial resistance (AMR) is considered a national priority although not so prominently. This reflects that there is no national policy with only a draft policy for more than 10 years without adoption or action. There are two major national programmes regarding AMR, one on human health (Ministry of Public Health) and another covering animal health (Ministry of Agriculture and Cooperatives). National antimicrobial resistance surveillance in Thailand was set up by the National Institute of Health, Department of Medical Sciences, Ministry of Public Health in 1997. It started with 28 hospitals as members and increased to 60 hospitals in 2005. Data from routine laboratory isolation of bacterial pathogens 20 Proceedings of the meeting was collected, analyzed, and the information of resistance was disseminated annually through websites (http://narst.dmsc.moph.go.th), brochures and reports to all hospitals and relevant institutions. There are standard treatment guidelines for a few selected diseases both at the

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national level and at major hospitals but the updating system is not very clear. Implementation is unlikely to be followed in all settings. Training imparted on rational use of drugs both in the undergraduate curriculum and as continuing education are provided to all health professionals (physicians, nurses, dentists, and pharmacists). There are at least three official programmes that always have sessions on promoting the rational use of antibiotics. These are: the National Congress in Infection Control; secondly, the short training in infection control; and thirdly, the Annual Academic Meeting of the Infectious Disease Association of Thailand. All these activities are held annually aimed at physicians, pharmacists, nurses, and laboratory personnel. There is no national regulation related to the use of antimicrobials. Only some scattered activities in different organizations such as requirement for DUE (drug use evaluation) for some schedule IV and V of Essential Drug List (EDL). Mechanism for monitoring of rational use of drugs is not set as routinely but is covered by occasional observation or by research and by indirect approach such as Pay for Performance Programme. Antimicrobials are unfortunately available over the counter, allowed by law to be dispensed without prescription from pharmacies by pharmacists and illegally distributed via grocery by unqualified professionals. There are some academic programmes on rational use of drugs specifically with antimicrobials. The first is the Antibiotic Smart Use programme coordinated by the Thai FDA and IHPP. The second is DMD (Drug System Monitor and Development Programme) by Chulalongkorn University that works broadly on the drug system and supports the movement for AMR policy as one direction. Monitoring of drug use at the community level is observed but not systematically.

Running head: ANTIBIOTIC USE IN BANGLADESH

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Awareness of the community regarding AMR is low as observed by the high tendency of using antimicrobials in the community and poor understanding on antimicrobial use. Ten major issues for prevention and containment of AMR and future national plans are as follows: (1) National Policy on AMR. (2) National Monitor System on antibiotic use pattern and rationality at all levels of health facilities and the community. (3) Alert or signal system on AMR to stakeholders. (4) Linkage from monitoring data to policy implementation. (5) Regulatory strengthening of antibiotics registration. (6) Antimicrobial in vet and farm/fishery. (7) Pharmacy and therapeutic committee (PTC) strengthening on rational use of drugs (RUD) especially antimicrobials (8) Consumer knowledge and awareness on antimicrobial use and resistance. (9) Curriculum and continuing education in RUD of antimicrobial use and resistance. (10) Collaboration among countries in the Region for further AMR prevention and containment. Timor-Leste This important issue has not been discussed in any formal forum in Timor- Leste since there are many other priorities. This workshop on prevention and containment of AMR has highlighted the real problem being faced now globally including Timor-Leste. Limited data are available from the national laboratory. Available test results show high level (62%) of the isolates being resistant against cloxacillin among isolates of Staphylococcus aureus from patients in the national hospital Guido

Running head: ANTIBIOTIC USE IN BANGLADESH Valadares in Dili. At the same time, 13% resistance is recorded against amoxicillin plus

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clavulanic acid. The data as interpreted is likely to reflect that the difference between cloxacillin and amoxiclav resistance reflect Staph aureus carrying betalactamases, while the remaining proportion may be true mec gene dependent, so called MRSA resistance, e.g. resistance against all betalactam antibiotics. If this is the case, the available test data suggest that some 13 % of the Staphylococcal infections would need treatment with vancomycin. This issue needs to be addressed with the help of molecular biology, to assess the true mec gene positive Staph aureus rate. The rate of quinolone resistance in clinical isolates of Staph aureus is also considered to be surprisingly high. Likewise the Gentamicin resistance rate of 22% presents a cause for concern, which needs to be considered further also in the recommendations provided for treatment of pneumonia, in cases where Staph spp infection is suspected. Proceedings of the meeting Major issues for prevention and containment of AMR and future Timor- Leste national plans include: (1) Strategy plan for prevention and containment of AMR. (2) A national drug policy drafted. (3) A new Pharmacy Law with stronger prescribing rules drafted. (4) Standard Treatment Guideline for PHC and hospital care has been developed, to be launched and implemented as a tool for guiding patient treatment throughout Timor-Leste (5) Inspection of private pharmacies, including prescription handling and drug OTC sale practices. (6) Establish regulation and legislation for antibiotic use.

Running head: ANTIBIOTIC USE IN BANGLADESH Table 5 Penicillin Group of Drugs. Generic Penicillin G Brand Name PEN- G PRONAPEN Penicillin V OPEN ORACYN- K PENVIK Benzathine Penicillin BENZAPEN DIAMINE PENICILLIN BPEN Cloxacillin CLOXICAP CLOXIN FICLOX Dicloxacillin Flucoxacillin DICLOX FLUBEX FLUCLOXIX FLUX FLUXON PHYLOPEN Ampicillin AMPEXIN AMPICIN FICILLIN Manufacturer Opsonin Renata Opsonin Aventis Square Square Renata Opsonin Renata Opsonin Aventis Novartis Beximco SK+ F Opsonin Aventis Square Opsonin Square Aventis

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Running head: ANTIBIOTIC USE IN BANGLADESH Amoxycillin AMOXI AMOXIL AVLOMOX BITOXIL FIMOXYL MOXACIL MOXAPEN MOXILIN MOXIN SERVIMOX SK- MOX TYCIL CO-Amoxiclav FIMOXYCLAV MOXACLAV Carbenkillin PYOPEN Renata Glaxo-Smithkline ACI Aventis/ Unihealth Aventis Square Nipa Acme Opsonin Novartis SK+ F Beximco Aventis Square Beecham (Shahidi. 2004)

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Running head: ANTIBIOTIC USE IN BANGLADESH Table 6 Cephalosporins. Generic Cefadroxil Brand Name ADORA AROCEF CEDRIL Manufacturer Incepta SK+F ACI

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Cephalexin

ACELEX ALEXIN CEPHALEN CEPOREX CEPORIN KEFLIN NEOREX SELEX

Acme Renata Beximco GlaxoSmithkline Square Opsonin SK+F Orion ACI Opsonin Beximco GlaxoSmithkline Square Renata Incepta Orion

Cephradine

AVLOSEF CEPHRAN INTRACEF KEFDRIN LEBAC POLYCEF PROCEF SEFIN

Running head: ANTIBIOTIC USE IN BANGLADESH SEFRAD Aventis

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Cefaclor

BIOCEF CEFLON LORACEF

Novartis SK+F Square

Cefuroxime

AXET CEFOTIL CEROX-A FUROCEF KILBAC ZINNAT

Orion Square ACI Renata Incepta GlaxoSmithKline Roche Square ACI Opsonin SK+F Beximco Square Acme SK+F Aristopharma Incepta

Cefetamet Cefixime

GLOBOCEF CEF-3 CEFIM-3 CEFTID ROXIM TRIOCIM

Cefotaxime

MAXCEF TAXIM

Cefpodoxime

STERIN TAXETIL XIMEPROX

Running head: ANTIBIOTIC USE IN BANGLADESH Ceftazidime CEFTAZIM FORTUM TAZID Ceftibuten Ceftriaxone CEDAX ACIPHIN ARIXON CEFTIZON CEFTRON ENOCEF MEGION ORICEF TRAXON Aristopharma GlaxoSmithKline Square Janata Health Care ACI Beximco Renata Square Aventis Novartis Roche Opsonin (Shahidi. 2004)

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Running head: ANTIBIOTIC USE IN BANGLADESH Table 7 Tetracycline Group of Drugs. Generic Tetracycline Brand Name DECACYCLINE TETRACYCLINE TETRACYN TETRAX Oxytetracycline OXYCIN RENAMYCIN Doxycycline DOXACIL DOXICAP IMPEDOX MEGADOX SERVIDOSYNE Manufacturer Beximco Opsonin Renata Square Nipa Renata Square Renata ACI Beximco Novartis (Shahidi. 2004)

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Running head: ANTIBIOTIC USE IN BANGLADESH Table 8 Aminoglycosides. Generic Amikacin Gentamicin Brand Name KACIN GENACYN GENTIN INVIGEN Kanamycin KANTREX Manufacturer ACI Square Opsonin Beximco Bristol/ Myers (Shahidi. 2004)

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Running head: ANTIBIOTIC USE IN BANGLADESH Table 9 Macrolides. Generic Erythomycin Brand Name EROMYCIN ERYTHIN ERYTHROX ETROCIN FIRMAC MACROCIN SERVITROCIN Azithromycin AZICIN AZYTH ODAZYTH ZIMAX ZITHRIN ZITHROX Claithromycin BINOCLAR REMAC ROLACIN Roxithromycin Sipramycin PEDILID ROVAMYCINE Manufacturer Square ACI Renata Beximco Incepta Aventis Novartis Opsonin Novartis ACI Square Renata SK+F Novartis Square Beximco Incepta Aventis (Shahidi. 2004)

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Running head: ANTIBIOTIC USE IN BANGLADESH Table 10 Miscellaneous Antibiotics. Generic Chloramphenicol Brand Name CHLORPHEN OPSOMYCETIN Vancomycin VANCOMYCIN Manufacturer Nipa Opsonin DBL/ Globex (Shahidi. 2004)

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Running head: ANTIBIOTIC USE IN BANGLADESH Table 11 Sulphonamides and Trimethoprin. Generic Sulphasalazine Co- trimoxaxzole Brand Name SALAZINE AVLOTRIN BACTIPRONT BITRIM COSAT COTRIM COTS FISAT MEGATRIM OCTRIM SUPTRIM Manufacturer Opsonin ACI Renata Aventis SK+ F Square Opsonin Aventis Beximco Orion Incepta (Shahidi. 2004)

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Running head: ANTIBIOTIC USE IN BANGLADESH Table 12 Quinolone Groups Generic Ciprofloxacin Brand Name CIPROCIN CIPROX FIPROX FLONTIN FLOXABID MAPROCIN NEOFLOXIN QUINOX SERVIFLOX Levofloxacin LEFLOX LEVOX LEVOXIN TREVOX XENOXIN Lomefloxaci Moxifloxacin Ofloxacin Pefloxacine MEXLO MAXIMOX RUTIX PEFLACINE PIPROX Sparfloxacin ACIFLOX Manufacturer Square Opsonin Aventis Renata ACI Orion Beximco SK+ F Novartis ACI Opsonin Incepta Square SK+ F Square Orion Square Aventis Opsonin ACI

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Running head: ANTIBIOTIC USE IN BANGLADESH PARLOX SAGA SPACIN SPARLIN SK+ F Square Novartis Beximco (Shahidi. 2004)

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Running head: ANTIBIOTIC USE IN BANGLADESH Table 13 Anti tubercular Antibiotics. Generic Streptomycin Rifampicin Brand Name STREPTOMYCIN FIRIFAM REFANIN RIMACTANE Isoniazid INH SERVIZID Ethambutol FLAMBUTOL SERVAMBUTOL Pyrazinamide FIRAZIN TUBRANIN Manufacturer Opsonin Aventis Opsonin Novartis Aventis Novartis Aventis Novartis Aventis Opsonin

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References Ahsan, G. et al. (2004) Gender difference in treatment seeking behaviors of tuberculosis cases in rural communities of Bangladesh. Retrieved from: www.pubmed.com Bangladesh gets tough with antibiotic use. Retrieved from: http://www.zootecnicainternational.com/article-archive/focus/773-poultry-houseenvironment.html Bangladesh News line. Retrieved from: http://bdnl.net/en/2011/01/antibiotics-losingeffectiveness-for-utter-misuse/ Chowdhury, A.K. et al.(1993) Prescribing pattern in acute diarrhoea in three districts in Bangladesh. Retrieved from: www.pubmed.com De Francisco, A. et al. (1998) Adherence to cotrimoxazole treatment for acute lower respiratory tract infections in rural Bangladeshi children. Retrieved from: www.pubmed.com Fahad, B.M. Matin, A. Asish, K.D. (2010) Antibiotic usage at a primary health care unit in Bangladesh. Retrieved from: www.pubmed.com Hossain, M.M. et al. (1982) Antibiotic use in a rural community in Bangladesh. Retrieved from: http://ije.oxfordjournals.org/content/11/4/402.abstract Jahan, Y. Hossain, A. (1997) Multiple drug-resistant Shigella dysenteriae type 1 in Rajbari district, Bangladesh. Retrieved from: www.pubmed.com Karim, A.S. (2001) Risk factors of persistent diarrhea in children below five years of age. Retrieved from: www.pubmed.com Okeke, I. N. Socioeconomic and Behavioral Factors Leading to Acquired Bacterial Resistance to Antibiotics in Developing Countries. Retrieved from: www.cdc.com Prevention and Containment of Antimicrobial Resistance. Retrieved from: www.WHO.org

Running head: ANTIBIOTIC USE IN BANGLADESH Pelczar, M.J. Chan, E.C.S. Krieg, N.R.(2005). Microbiology. New Delhi: Tata McGraw-Hill. Ronsmans, C. et al. (1991) Current practices for treatment of dysentery in rural Bangladesh. Retrieved from: www.pubmed.com

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Rubhana, R. et al. (2006) Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Retrieved from: www.pubmed.com Rahman, M. et.al. Increasing spectrum in antimicrobial resistance of Shigella isolates in Bangladesh: resistance to azithromycin and ceftriaxone and decreased susceptibility to ciprofloxacin. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17985817 Shahidi, R.U.(2004). Quick Index of Medical Products & Problems.Bangladesh. Srinivasan, A. et al. Antibiotic Resistant Bacteria in Hospitals: A Time for Action. Retrieved from: www.pubmed.com Saha, S. K. et al. Emergence of high-level fluoroquinolone-resistantEscherichia coli in Bangladesh. Retrieved from: www.pubmed.com Saha, M. R. Patients' Knowledge and Awareness towards Use of Antibiotics in Bangladesh: A Cross-sectional Study Conducted in Three Tertiary Healthcare Centers in Bangladesh. Zaman, K. et al. (2005) Drug resistance of Mycobacterium tuberculosis in selected urban and rural areas in Bangladesh. Retrieved from: www.pubmed.com

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