<<

African Journal of Biomedical Research, Vol. 11 (2008); 235 - 250 ISSN 1119 – 5096 © Ibadan Biomedical Communications Group

Review Article Antimicrobial and Sustainable Development: The past, The Current Trend, and the future

*1Okonko I.O, 2Fajobi E.A, 3Ogunnusi T.A, 3Ogunjobi A.A. and 3Obiogbolu C.H. Full-text available at http://www.ajbrui.com 1Department of Virology, Faculty of Basic Medical Sciences, College of Medicine, http://www.bioline.br/md http://www.ajol.com University of Ibadan, University College Hospital (UCH), Ibadan, Nigeria 2 Department of Basic Sciences, Federal College of Wildlife Management, New Bussa, Niger State, Nigeria 4Microbiology Unit, Department of Botany and Microbiology, University of Ibadan, Ibadan

ABSTRACT Antimicrobial chemotherapy is a highly valued medical science which has shaped modern humanity in a phenomenal fashion. Within the past half century, a wide variety of antimicrobial substances have been discovered, designed and synthesized; literally hundreds of have been successfully used in some fashion over the years. Today, the world wide anti-infective market exceeds $20 billion dollars annually and overall antimicrobial agents comprise the bulk of this trade. A number of general classes of antimicrobial drugs have emerged as Received: mainstays in modern infectious disease chemotherapy. Regardless of a better August 2007 understanding of infectious disease pathogenesis and the importance of sanitation, most individuals will become infected with a microbial pathogen many times, Accepted (Revised): throughout their lives and in developed countries, anti-infective chemotherapy July 2008 will be periodically administered. Antibacterial amount for the majority of anti- infective agents in comparison to , antivirals and agents. Published An antimicrobial is a chemical substance produced by that can Septemeber 2008 inhibit the growth of, or kill other microorganisms. The goal of antimicrobial in disease such as gastroenteritis is to decrease stool water and electrolyte losses, thus limiting the morbidity resulting from dehydration. Most antiretroviral only suppress the pathogen and boast the immune status but does not provide cure. To date, several drugs have been tried in the treatment of acute diseases such as diarrhea, HIV/AIDS but none has met the requirements enumerated above. They are therefore of very limited value in the department of diarrhea, especially in children as well in department of HIV/AIDS (Afr. J. Biomed. Res. 11: 235 - 250 )

Key Words; Antimicrobials, microbial resistance, diseases

*Corresponding author: [email protected]

Abstracted by: African Index Medicus (WHO), CAB Abstracts, Index Copernicus, Global Abstracts, Asian Science Index, Index Veterinarius, Bioline International , African Journals online

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

BACKGROUND BC, Sumerian physicians treated ailing patients with a beer soup heavily laced with ground snake Most antimicrobial are called , literally skins and turtle shells. About 1,500 years later, meaning "against life". This is an ironic label for a Assyrian and Babylonian doctors used a salve group of drugs that have saved millions of lives made of frogs' bile and sour milk for healing over the last half century. They attack the infected eyes, but only after the patient took a swig microorganisms that have threatened humankind of beer and ate a sliced onion (Magner, 1992). Of for thousands of years. While antibiotics have won course, many ancient remedies had sound many battles, they have not won the war by any scientific foundations. Those same beer-soup- means. The clever enemy keeps changing and dispensing Sumerians knew the value of pain- coming back stronger than ever. Antibacterial killing opium. The Greeks had a substantial herb- chemotherapy is a highly valued medical science based pharmacopoeia, and the Romans outdid which has shaped modern humanity in a themselves with purgatives. But it wasn't until the phenomenal fashion. Within the past half century, mid-19th century that observed that a wide variety of antibacterial substances have some microorganisms could destroy others-a been discovered, designed and synthesized; phenomenon Pasteur believed could be useful in literally hundreds of drugs have been successfully medicine. Little did he know (Hoel and Williams, used in some fashion over the years. Today, the 1997). world wide anti-infective market exceeds $20 The last days of the 19th and the first decades billion dollars annually and overall antibacterial of the 20th centuries saw the birth of aspirin and agents comprise the bulk of this trade. A number barbiturates. In 1909, German bacteriologist Paul of general classes of antibacterial drugs have Ehrlich discovered the first chemical cure for emerged as mainstays in modern infectious disease disease-salvarsan, an arsenic compound that cured chemotherapy (Lorch, 1999; Murray, 1985; early syphilis. The medical profession dubbed it Chadwick and Goode, 1997 Chalker, 1995; "the magic bullet" because it killed the specific Lansang, 1990). germs that caused syphilis. Regardless of a better understanding of Next came the era of wonder drugs. In a few short infectious disease pathogenesis and the importance decades, from the 1930s to the late 1960s, medical of sanitation, most individuals will become science discovered antibiotics, sulfa drugs, infected with a microbial pathogen many times, cortisone, and a stunning collection of other throughout their lives and in developed countries, lifesaving . Death rates for dozens of anti-infective chemotherapy will be periodically diseases plummeted, and medical science won administered. Antibacterial amount for the unprecedented victories (Hoel and Williams, majority of anti-infective agents in comparison to 1997). antifungals, antivirals and antiparasitic agents. The The golden age of medicine actually began in concept of (against life) substance was 1934. That's when Gerhard Domagk, a 38-year-old put forth by Vuillemin in 1889, but the formal German pharmacologist, discovered that a dye definition as recognized today, would not be used to tint cloth seemed to cure streptococcal introduced until 1942 by Waksman. Thus, in mice (Robinson, 1976). Domagk's antimicrobial such as antibiotics is a chemical young daughter was dying of a streptococcal substance produced by microorganisms that can , and in desperation, he injected the dye inhibit the growth of, or kill other microorganisms into the child. Her fever dropped immediately, and (Prescott et al., 2005). her recovery was nothing short of miraculous. Next was Daniel Bovert, a Swiss-born scientist, THE PAST who identified the active compound as For about five millennia, give or take a few sulfanilamide, a white crystalline amide that was centuries, human beings have treated their aches deadly to many streptococci and staphylococci. and pains with mind-boggling creativity. In 3500 This led to the subduing of pneumonia and a

236 Antimicrobial Chemotherapy and development

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

number of other bacterial infections. Domagk was is history. In 1945, Fleming, Florey, and Chain awarded the Nobel Prize for Medicine in 1939, but were awarded the Nobel Prize for Medicine (Hoel Adolf Hitler forbade him to accept it. Hitler had and Williams, 1997). been outraged because the Nobel Peace Prize for 1935 had gone to an anti-Nazi. He had the gestapo The Emergence of drag Domagk off to prison for a week (Hoel and Streptomycin hits the stage in 1942, when another Williams, 1997). great scientist, Selman A. Waksman, a Russian- Jewish immigrant to the United States, gave the The Advent of name "antibiotics" to chemicals produced by soil- Antibiotics were actually discovered before sulfa borne fungi and microorganisms that destroy or drugs, but for 12 years no one showed any interest. slow the growth of other microbes. Inspired by the In 1928, , a shy Scottish potential of penicillin, Waksman spent his lifetime bacteriologist, left a culture of staphylococci hunting for friendly microorganisms that would do uncovered in his laboratory at St Mary's Hospital battle against the unfriendly germs (Hoel and in London while he went off on vacation Williams, 1997). When penicillin proved useless (Robinson, 1976). When he returned, Fleming for tuberculosis patients, Waksman decided to go noticed in the petri dish--along with a sizable after an antibiotic that could quell that ancient vacant space between the staphylococci and the scourge. He and his students investigated more blue-green, spotted mold. As he examined the than 10,000 soil cultures. Only 1,000 of them specimen under his microscope, he noticed that destroyed in preliminary tests, and only something in the mold was attacking the bacteria. 100 of these showed promise in later tests. Just 10 It was the classic instance of what Pasteur had could be isolated, but amazingly one of the 10 referred to as fortune accommodating a willing carried the mother lode (Hoel and Williams, mind. Fleming identified the mold as Penicillium 1997). notatum, very much like the mold that grows on It was 1943 when Waksman's group came stale bread. He cultured it in broth, filtered it, and across a clump of dirt containing a peculiar mold. discovered in the filtrate an amazing substance The dirt and mold had been taken from the neck of that ravaged bacteria. He named his discovery a sick chicken. When Waksman pitted the mold penicillin (Hoel and Williams, 1997). against the feisty tubercle bacilli, the mold won Fleming was not able to purify the penicillin out. He called his discovery streptomycin. himself, and he could not get much help from Physicians from the Mayo Clinic in Rochester, anyone else. One American university rejected an Minnesota, administered streptomycin to a young application for $100 to investigate the and woman with advanced pulmonary tuberculosis on threatened to fire a professor who offered to pay November 20, 1944. Her right lung had been for research out of his own pocket (Robinson, removed surgically, and now her remaining lung 1976). was being eaten away. The streptomycin saved her It took the wounded and -ridden life. In less than 10 years, deaths from all forms of troops and civilians of World War II to awaken the tuberculosis in the United States dropped money holders to penicillin's potential. Howard W. dramatically (Hoel and Williams, 1997). Florey, a 42-year-old pathologist from Australia, was given funds to study penicillin at Oxford Lunching in to the possibilities of Antibiotics University. He selected Ernst B. Chain, a 29-year- The discoveries of Fleming and Waksman old chemist who had fled Nazi Germany, to help awakened science to the wonders of antibiotics. him. In the spring of 1940, they were able to Soon, more broad-spectrum and extract a tiny morsel of a yellowish-brown powder were found, followed by other from Fleming's mold. This first sample of landmark antibiotics. Brucellosis, typhoid fever, penicillin was a million times more powerful than amebic dysentery, and undulant fever all but Fleming's original filtrate and, as they say, the rest disappeared. In these early days, antibiotics were

Antimicrobial Chemotherapy and development 237

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

often given indiscriminately, sometimes with resistant organisms emerged, and more drugs were tragic consequences. Resistant strains developed discovered in a seemingly inexhaustible cycle. quickly, and tenacious bugs seemed almost to Many of the diseases that had infested the earth for flaunt their immunity (Hoel and Williams, 1997). thousands of years were subdued. The medical establishment predicted an end to plagues and Table 1: Historical Events of Antibiotics pestilence. Date Major events 1500 Egyptian doctors dispense exotic THE CURRENT STATUS BC concoctions, some of which are based on Today some 5,000 antibiotics are known. Only sound medical practice. about 1,000 of these have been carefully 1654- When plague strikes, physicians don - investigated, and about 100 are currently used to 1661 filled masks to cover the stench of death. treat infections (Dixon, 1994). Most are produced 1822- Louis Pasteur recognizes that some by actinomycetes and bacteria. Throughout 1895 microorganisms destroy others. 1928- Alexander Fleming discovers penicillin in the last 50 years, a lot of scientific journals have 1940 1928, but no one pays much attention until been disseminating information on drug discovery 1940. and evolution. Hundreds of articles on infectious 1943- Antibiotics allow unprecedented victories disease management have kept physicians abreast 1949 over scourges of the past. of both advancements and problems. A new 1950- The medical establishments predict an end to vocabulary has emerged: plasmids, transposons, 1969 plagues and pestilence. promiscuous DNA, mutator alleles, Cairnsian 1970- New threats, such as Lyme and legionnaires' mutation, and many other esoteric terms. It is a 1979 diseases, shake up the scene whole new ball game (Hoel and Williams, 1997). 1980- Medical science recognizes the mechanisms Also, the discovery and development of the beta- 1989 and risks of antibiotic resistance. lactam antibiotics are among the most powerful 1990- Fewer and fewer drugs maintain potency and successful achievements of modern science 1997 against rapidly mutating bacteria. and technology. Since Fleming's accidental 1998- Bacterial resistance to antibiotics became a 2000 serious medical problem and is of serious discovery of the penicillin-producing mold, global concern now. Then the advent of seventy years of steady progress has followed, and bacteriophage as an alternative to antibiotics today the beta-lactam groups of compounds are as well as advent of antiretroviral drugs. the most successful example of natural product A Public health Action Plan to combat application and chemotherapy. was established. Immediately after the penicillin production by 2001- Emergence of totally new and stubbornly Penicillium chrysogenum came the discoveries of till obscure infectious agents was not part of the formation by Cephalosporium date long-range plan and more drugs are being acremonium, Cephamycin, Clavam and discovered in a seemingly inexhaustible Carbapenem production by actinomycetes, and cycle. More Multi- as well as antiretroviral drug resistance among monocyclic beta-lactam production by HIV/AIDS patients. actinomycetes and unicellular bacteria. Each one of these groups has yielded medically-useful According to Meleney (1947), people have to get products and has contributed to the reduction of experience all over again on the behavior of pain and suffering of people throughout the world. infection under treatment with these new drugs. Research on the microbiology, biochemistry, There is a temptation to use them promiscuously, genetics and chemistry of these compounds have and yet certainly if results are to be improved, continued up to the present with major people must use them with discrimination. The contributions being made by both individual and next three decades saw exponential growth in collaborative groups from industry and academia pharmaceutical research and manufacturing. Drugs (Demain and Elender, 1999). were discovered, diseases were conquered, According to Demain and Elender (1999), the

238 Antimicrobial Chemotherapy and development

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

discovery of penicillin not only led to the era of According to Appelbaum (2005), clinical the wonder drugs but provided the most important resistance to penicillin in Streptococcus antibiotics available to medicine. Continued pneumoniae was first reported by researchers in efforts have resulted in the improvement of these Boston in 1965; subsequently, this phenomenon compounds with respect to potency, breadth of was reported from Australia (1967) and South spectrum, activity against resistant pathogens, Africa (1977). Since these early reports, penicillin stability and pharmacokinetic properties. Major resistance has been encountered with increasing advances are being made on structural and frequency in strains of S. pneumoniae from around regulatory biosynthetic genes and metabolic the world. In South Africa strains resistant to engineering of the pathways involved on the penicillin and chloramphenicol as well as research front. multiresistant strains have been isolated. Similar Presently, new semi synthetic compounds patterns of resistance have been reported from especially those designed to combat resistance Spain. Preliminary evidence points to a high development are being examined in the clinic, and of resistant pneumococci in Hungary, unusual non-antibiotic activities of these other countries of Eastern Europe, and some compounds are being pursued. Although seventy countries in other areas of Europe, notably France. years of age, the beta-lactams are not yet ready for In the United States most reports of resistant retirement. Approximately half of the world’s pneumococci come from Alaska and the South, antibiotic production is not used as human but resistance is increasing in other states and in medicine but for animals. Some antibiotics for Canada. Pneumococcal resistance has also been industrialized husbandry are sold freely over the described in Zambia, Japan, Malaysia, Pakistan, counter as growth promoters. Several of these Bangladesh, Chile, and Brazil; information from antibiotics are known for cross-resistance to those other African, Asian, and South American used in human medicine. It has been shown that countries is not available. antibiotic resistant bacteria are present in The onset of drug resistance however products and can also be found in humans who threatens virtually all classes of antibacterial have not received these substances in the course of agents. Resistant bacteria have been known a medical treatment (Davies, 1994; Lansang, 1990; virtually since modern antibacterial chemotherapy Jacoby, et. al., 1991, Murray, 1985). Although so became an accepted medical practice. Only a few far there is no evidence for a causal relationship, years after the penicillin’s were introduced, this potential spread of resistance adds to the resistant staphylococci (S. aureus) were problems with antibiotics for future medical recognized. Since this time (1944), most applications (Lorch, 1999). Staphylococci have acquired resistance to conventional penicillin’s and many Streptococci The Onset of Antimicrobial Resistance have followed this trend (Davies, 1994; Murray, Bacterial resistance to antibiotics has become a 1985; Macaden, 1985; Wenzel, 1995; Prescott et serious medical problem and is of serious concern al., 2005). now (Lorch, 1999). Just a decade or two ago, However since the 1980’s, there has been a Lyme disease, toxic shock syndrome, legionnaires' complacency regarding antibacterial disease, Ebola and Marburg , Lassa fever, chemotherapy; many believed that humanity had hepatitis C, hantavirus, and of course HIV/AIDS forever gained ‘the upper hand’ in the battle startled scientists and physicians lulled by the against microbes. The past decade alone has been successes of the past. Emergence of totally new a very alarming ‘wake-up’ to battle once again; the and stubbornly obscure infectious agents was not emergence of a resistant and exceptionally virulent part of the long-range plan. Resources, limited as bacterial strains are once again causing outbreaks they were, had been directed elsewhere. Many and deaths, and unfortunately, this trend is likely experts felt hopelessly ill-prepared for the future to continue except for the advent of (Hoel and Williams, 1997). (Lorch, 1999).

Antimicrobial Chemotherapy and development 239

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

All over the world, the resistance of bacteria to provided an explanation of plasmid exchange as a antibiotics is becoming a grave medical problem. cause of the epidemic of drug failure. As he Independent of the resources of the medical pointed practitioners toward the future, Welch system, whenever antibiotics are used the (1984) stated that the microbiologist views development of resistance is a logical antimicrobial prescribing as excessive and consequence; like all other living organisms, particularly implicates empiric and prophylactic bacteria adapt to changing environmental therapy. The clinician feels that the benefits of conditions in a continuous process of evolution early therapy and of are (Lorch, 1999). In industrialized countries, bacteria underrated by basic science colleagues. The are developing multiple resistances to a range of microbiologist necessarily takes the long-term antibiotics, which threatens to make the view (the prospect of multiple resistance), while achievements of modern medicine futile (Lorch, the clinician is more concerned with the short-term 1999). Without the protection against bacterial effect (the patient's immediate welfare). Unless infections, for instance, large-scale operations and these two views are reconciled, plasmid treatments that weaken the patients’ immune will become common place. system, such as chemotherapy or organ Along with the new threats, some of the old transplantation, would not be possible (Lorch, scourges of humankind were reemerging in the 1999). In developing countries basic medical care 1980s. Under funded prevention programs and is already endangered by single resistance to drug resistance were allowing diseases like yellow inexpensive common generic antibiotics. fever, cholera, , bacterial meningitis, According to the World Health Organization dengue fever, tuberculosis, and even plague to report (WHO, 1993, 1999), a great number of the spring back with renewed vengeance. By the early population of developing countries will not be able 1990s, panicky investigators were realizing they to afford the replacements. In these countries, had very few resources to combat these stronger, dosage often appears to be too low or treatment is smarter foes (Welch, 1984; Hoel and Williams, not carried out over the whole course; resistance is 1997). encouraged because even if the patient is cured, According to Hagman, and Strausbaugh, those bacteria that are best adapted to low doses of (1996), in the May issue of Postgraduate these antibiotics survive. Cases of reported Medicine, of Oregon Health Sciences University antibiotic resistance comprise tuberculosis, in Portland, sounded yet another alert. They pneumonia and dysentery (World bank, 1995; pointed out that the antibiotic arsenal is dwindling Lorch, 1999). quickly. Specifically, vancomycin, generally Although the spread of antibiotic resistance considered the last stronghold against many life- has long been known as a worldwide phenomenon, threatening gram-positive infections, is losing research seems to have reached a dead end. During ground. While discussing vancomycin-resistant the last 30 years, no new classes of antibiotics enterococci, Hagman and Strausbaugh (1996), have been found, even with the help of modern warn that new antimicrobial pathogens resistant to biotechnology such as genetic engineering vancomycin are wreaking havoc in medical (Prescott et al., 2005). Pharmaceutical companies centers throughout the nation. Their tendency to have mainly focused on the development of new colonize or infect severely ill, hospitalized patients products derived from the known classes of who have undergone invasive procedures and antibiotics. The spread of drug resistant pathogens received prolonged courses of antimicrobial is one of the most serious threats to the successful therapy is alarming. The most potent weapon in treatment of microbial disease. the physician's arsenal against these enemies is Welch (1984), writing in the November 1, familiarity with their key features, with the issue of Postgraduate Medicine, of the US Public guidelines for prudent use of drug therapy, and Health Service, based in Bethel, Alaska, addressed with the precautionary measures necessary to limit the problems of antibiotic resistance. He also contact and spread (Hoel and Williams, 1997).

240 Antimicrobial Chemotherapy and development

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

Mechanism of the Antimicrobial Resistance development and spread of antibiotic resistant Bacteria become drug resistant in several ways. It strains because the antibiotic destroys normal, should be noticed at the beginning that a particular susceptible bacteria that would usually compete type of mechanism is not confined to a single class with drug resistant strains (Chadwick and Goode, of drugs. Two bacteria may use different resistant 1997). The result may be the emergence of drug mechanism to withstand the same resistant pathogens leading to a super-injection. A chemotherapeutic agent (Prescott et. al., 2005, possible effective alternative way of combating Jacoby et al., 1991). Furthermore, resistant these resistance mechanisms is that of phage mutants arise spontaneously and are then selected. therapies, which are, viruses that live on bacteria Mutants are not created directly by exposure to a and this offer a better advantages (Lorch, 1999). drug. According to Strohi (1997) and Prescott et The goal of antibiotics in disease such as al. (2005), Pathogens often become resistant gastroenteritis is to decrease stool water and simply: electrolyte losses, thus limiting the morbidity a. By preventing entrance of the drug into the resulting from dehydration. To date, several drugs envelope’s membrane. have been tried in the treatment of acute diarrhea b. By pumping the drug out of the membrane but none has met the requirements enumerated after it has entered (translocases). above. They are therefore of very limited value in c. By inactivating drugs through chemical the department of diarrhea, especially in children modification (hydrolysis). (Strohi, 1997; Prescott et al., 2005). It is time for a d. By modification of target enzyme or organelle new game plan. so that is no longer susceptible to the drug. e. They may either use an alternate pathway to Trends in Antimicrobial Resistance bypass the sequence inhibited by the agent or According to White et al. (1999) antibiotic- increase the production of target metabolite. resistant pathogens in animals pose a concern not only with respect to the health of animals but The Origin of Drug Resistance and Its because of possible to humans as Transmission food-borne pathogens. The problem is Ironically, resistance is promoted by both the compounded by the growing number of pathogens overuse of antibiotics as well as insufficiency of that are resistant to multiple, structurally unrelated dose (Lansang, 1990, WHO, 1993, 1999; Chalker, drugs, leading to the concern that there are likely 1995; World Bank, 1995). The gene for drugs to be few effective antimicrobials available by the resistant are present as both the bacteria end of the decade. Accordingly, more attention is chromosome and plasmids, small circular DNA now being paid to the ease with which resistance molecules that can exist separate from the to both single and multiple antimicrobials can chromosome or be integrated into it. Also, develop among bacterial pathogens. If the current spontaneous mutations will make bacteria drug trends continue, we may see bacterial pathogens resistant (Chadwick and Goode, 1997). that are resistant to all currently available Frequently, a bacteria pathogen is drug resistant antimicrobials. The Food and Drug Administration because it has a plasmid bearing one or more and the United States Department of Agriculture resistant genes, such plasmids are called R- are currently implementing strategies to address plasmids. They often code for enzymes that this threat. destroy or mortify drugs. Once a bacterial In the past few years, strains of E. coli have process an R-plasmid, the plasmid may be become increasingly resistant to most first-line transferred to other cells quite rapidly through antibiotics, including third-generation normal gene exchange processes, such as , aminoglycosides, and even conjugation, transduction and transformation fluoroquinolones. Infections caused by drug- (Prescott et al., 2005). resistant organisms are a major and costly problem Extensive drug treatment favors the in animal health. These infections prolong illness

Antimicrobial Chemotherapy and development 241

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

and, if not treated in time with more expensive, involved in pathogenesis. All 18 strains were alternative antimicrobial agents, can cause loss of negative for lt, sta, and stb. Six strains were stock. This potential problem will continue to be positive for slt-I, five were positive for slt-II, and scourge and have a large impact on the animal three strains were positive for slt-I and slt-II. Four industry and humans, across the countries of the strains were positive for eae, and five strains world if not investigated and solved. carried the cs31a fimbriae gene. Although the K- For instance, in a study by White et al. (1999) 99 antigen was found in 56% of strains, none of on the prevalence of multiple-antibiotic resistance the strains positive for enterohemolysin expressed among E. coli strains implicated in bovine calf this antigen. Four strains were positive for cnf-I, scours in North Dakota was determined by and one strain was positive for cnf-2. Two strains studying E. coli isolates from scouring calves, they were positive for slt-II and cnf-I, and one strain hoped to identify trends in antibiotic resistance was positive for slt-I and cnf-I. All strains positive and to track several virulence factors that have for slt-I and slt-II were also positive for shiga-like recently been identified in pathogenic E. coli toxins production. strains. Susceptibility testing for amikacin, According to him, isolates submitted to their ampicillin, ceftiofur (Naxcel; Upjohn, Kalamazoo, laboratory are usually the "worst of the worse," MI), gentamicin, tetracycline, sulfachlorpyridazine being unresponsive to all other treatments. Their (Vetisulid; Solvay Animal Health, Mendota testing showed that the most available drugs have Heights, MN), sulfonamides, enrofloxacin the highest rates of bacterial resistance. (Baytril; Miles Animal Health, Shawnee Mission, Unfortunately, these drugs are often the first line KS), lincomycin, neomycin, spectinomycin, and of defense in combating calf scours. Amikacin, trimethoprim/sulfadiazine (Tribissen; Mallinckrodt enrofloxicin, or ceftiofur continue to be effective Veterinary, Mundelein, IL) was performed using and with electrolyte fluid therapy constitute the standard disk-diffusion assays. E. coli strains are best treatment options for calf scours at the present screened for several virulence factors: F-5 (K-99) time. However, enrofloxacin is not approved for fimbriae, enterotoxin genes (lt, sta, stb), shiga-like large animal use; amikacin and ceftiofur are only toxins (slt-I, slt-II), enterohemolysin gene (Ehly), approved for extra-label use. the E. coli attaching and effacing gene (eae), cytotoxic necrotizing factor genes (cnf-I, cnf-II), THE FUTURE and cs31a, a fimbriae gene. While we are been reminded daily how quickly The result of their study showed that more disease can spread from jungles to urban centers, than 280 isolates of E. coli, obtained from clinical at present there is virtually no way to predict what cases, submitted to the North Dakota State will happen where. According to Lemonick University Veterinary Diagnostic Laboratory in (1996), in a recent article on emerging infection 1996. The resulting antibiograms of antibiotic that appeared in a special edition of Time, the susceptibilities have illustrated patterns of challenge for the near future undoubtedly lies in resistance among the strains and changes in quickly identifying and isolating outbreaks and resistance over time. Preliminary results show that limiting damages. Lemonick (1996) states that it is resistance to fluoroquinolones (enrofloxacin, guerrilla warfare, but for the next few years at which currently is not approved for use in large least, it may be the best we can do (Hoel and animals) and to cephalosporins (ceftiofur) are Williams, 1997). Morse (1996), head of the emerging among these E. coli strains. The level of infectious disease program at Columbia resistance to the antimicrobials tested ranged from University, adds that the current system is a less than 1% of isolates to 100% of submitted reactive one. Our ability for prediction will remain strains. Eighteen of the 280 strains were positive limited for quite some time. for enterohemolysin and were further Garrett (1994), in her riveting and frightening characterized by polymerase chain reaction for book, the Coming Plague: Newly Emerging virulence factors previously reported to be Diseases in a World out of Balance recounts some

242 Antimicrobial Chemotherapy and development

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

of the recent disease outbreaks that have triggered HIV/AIDS, Chlamydial infections, and other dramatic attention around the world. From the sexually transmitted diseases (STDs). Programs to mysterious outbreak of Bolivian hemorrhagic provide sterile needles to drug users certainly fever in 1962 to the recent Reston Ebola scare, seem likely to be effective, if controversial, Garrett narrates the sequence of events she alternatives to spreading disease through needle believes will become more common as new and sharing. Improved surveillance and strictly more virulent microbes surface (Hoel and enforced protocols for preventing spread of Williams, 1997). infections in hospitals and clinics are also As Garrett (1994) presents her case, she talks extremely important. And, of course, judicious use about the "soupy existence" of microbes stating of antibiotics is crucial, including veterinary and that wherever there may be an ideal soup for a farming applications (Hoel and Williams, 1997). microbe, it will eagerly take hold, immediately Much as we might hate to admit it, joining in the local microbial pushing-and- antibiotics/antiretroviral have been over prescribed shoving. The most sophisticated of their species and sometimes provided on demand, greatly have the ability to outwit or manipulate the one diminishing the strength of the arsenal. Patient microbial sensing system Homo sapiens possess, education about judicious use of drugs, about not that is, our immune systems. By sheer force of sharing antibiotics, and about compliance should numbers they overwhelm us. And they are be a regular part of physicians' instructions to the evolving far more rapidly than Homo sapiens, patients. According to Hoel and Williams (1997), adapting to changes in their environments by a small but extremely important step for a mutating, undergoing high-speed natural selection, practicing physician might be the simple practice or drawing plasmids and transposons from the vast of using and teaching patients to use proper hand mobile genetic lending library in their washing as a means of slowing down the spread of environments (Hoel and Williams, 1997). disease. A better understanding of the true problem is What is the next line of Action? also at the top of the list of what needs to be From many literatures cited in this review, we achieved next as pointed out by Osterholm (1996). strongly suggest that resistance to first-line Minnesota state epidemiologist Osterholm (1996) antibiotics/antiretroviral used for many infectious assisted the Centers for Disease Control and diseases is emerging at an alarming rate. Prevention (CDC) in surveying the policies and Multidrug resistance and the presence of several capability of all 50 state health departments. The virulence factors in the strains of many pathogens survey showed that after years of budget cuts, responsible for different diseases pose an most local and regional disease reporting systems increasing threat to the successful management of were sadly deficient, if not completely unreliable. disease scourge. Also, the rising prevalence of Unusual deaths were going unreported. drug resistance such as penicillin-resistant Contagious outbreaks were ignored. The pneumococci worldwide mandates selective of HIV/AIDS was underreported by at least 20% susceptibility testing and epidemiological at any given time. Officials could only guess about investigations during outbreaks (Appelbaum, the real incidences of penicillin-resistant 2005). gonorrhea and vancomycin resistant enterococcus, According to many authors, the time for action E coli food poisoning, multiple-drug resistant is now. What can physicians, health workers and tuberculosis, Lyme disease, and many other NGOs do to improve this picture? Primary problems. When the CDC asked that reporting be prevention and disease containment are crucial expanded, there were loud protests. Local health steps, according to many experts. Sex might be a departments simply can not keep up with what good place to start as suggested by Garrett (1994), they are already required to do (Hoel and pointing to limited but nonetheless encouraging Williams, 1997). results with sex education programs for The national, international and global

Antimicrobial Chemotherapy and development 243

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

situations are also disheartening. Laboratories unusual or puzzling outbreaks of infectious continue to be sadly behind the times in terms of diseases (Berkelman (1997; Hoel and Williams, equipment and skills for diagnosing the emerging 1997). pathogens as can be readily observed in this According to the WHO (1999) in developing nation-Nigeria. With the overwhelming increase in countries infections and parasitic diseases are high-intensity local conflicts among political, responsible for the death of twenty million people ethnic, and religious rivals, government-based per year. Every year about eight million children disease-surveillance systems have little or no under five die of acute respiratory tract infections chance of success. of bacteria such as Streptococcus pneumonia, According to Ogundipe et al. (1989), in their Haemophilus influenza type B or of diarrhea study the development and efficiency of the related diseases caused by bacteria such as animal health information system in Nigeria as Shigella sp., Vibrio cholera and several types of E. well as the completeness and immediacy of data coli ( Lorch, 1999; Macalden, 1985). supply by the system for the period between In Africa, dysentery caused by Shigella January 1977 and December 1984 revealed that dysenteriae is common. Since the late 1970s, the system was found to be characterized by: late, drug-resistant strains of S. dysenteriae have caused inaccurate and gross under reporting. And these epidemics in various parts of Central and Southern constraints in reporting include inadequate Africa. By 1990, several of these epidemics were personnel, poor diagnostic and reporting facilities. caused by strains resistant to all antibiotics used in Some steps are being taken. The worldwide those countries. The availability of advanced communications networks have made inroads with antibiotics is often limited by their higher costs SatelLife and ProMED online services. Physicians (Lorch, 1999; Macalden, 1985). in developing nations can consult colleagues, The situation in developing countries like libraries, or data banks for help with puzzling Nigeria has not really improved during the past cases. Promising as they are, though, these decade, state and local support for infectious "electronic conference tables" represent only a disease surveillance has diminished because of small piece of the solution. At present, the budget restrictions. For example, until recently a networks do not address the underlying causes of number of states had no foodborne disease new and reemerging infectious diseases. And they surveillance programs despite dramatic evidence probably can do little to get to the heart of the real that disease caused by contaminated food may be issues: educating the public, immunizing the increasing. Moreover, there has been little or no children, improving sanitation, cleaning up the federal support to states for the notifiable disease water, housing the homeless, feeding the starving surveillance system, and many state health (Hoel and Williams, 1997). laboratories receive no federal funding. For now, as Lemonick (1996) points out that In developed countries, this picture is the best that health professionals can hope to do is beginning to change. The CDC has already taken react quickly to an endlessly resourceful, sneaky, steps needed to implement a preventive strategy. and relentless enemy as well as the ability to Over 15 states are strengthening their infectious recognize that a successful holding action is the disease programs, and five more are establishing next best thing to victory. such programs in addition to the effort of the CDC The health care workers must recognize the (Berkelman, 1997; Hoel and Williams, 1997). pivotal role they play in our national notifiable Though, Berkelman (1997) stresses that while the disease system. The system breaks down if any debate on healthcare reform has focused intensely one step, such as appropriate diagnostic testing, on providing individual medical care; discussions reporting by health care workers to public health have not adequately addressed the equally agencies, or follow-up investigation, is not important topic of public health concern. The costs accomplished. In addition, we can not stress of preparedness through vigilance are far lower strongly enough how important it is to report than those needed to respond to unanticipated

244 Antimicrobial Chemotherapy and development

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

public health crises. borders and requires a global approach to its prevention and control, Part II of the plan, to be Public Health Action Plan to Combat developed subsequently, will identify actions that Antimicrobial Resistance more specifically address international issues. The When it comes to keeping an eye on emerging Action Plan, Part I (Domestic Issues), includes diseases, agencies of the Centers for Disease four focus areas: Surveillance, Prevention and Control and Prevention (CDC) are on the front Control, Research, and Product Development. A lines. According to Berkelman (1997), we once summary of the top priority goals and action items believed we could eliminate infectious diseases as in each focus area follows: Surveillance, public health problems but the emergence of Prevention and control, Research, as well as HIV/AIDS, the resurgence of tuberculosis, and the Product development. specter of increasing antimicrobial resistance have raised new challenges. Still, we have learned a lot Surveillance in the last few years about what it will take to get Unless AR problems are detected as they emerge the job done. and actions are taken quickly to contain them the This Public Health Action Plan to Combat world may soon be faced with previously treatable Antimicrobial Resistance (Action Plan) was diseases that have again become untreatable, as in developed by an interagency Task Force on the pre-antibiotic era. Priority Goals and Action Antimicrobial Resistance that was created in 1999. Items in this focus area address ways to: Develop The Task Force is co-chaired by the Centers for and implement a coordinated national plan for AR Disease Control and Prevention, the Food and surveillance; Ensure the availability of reliable Drug Administration, and the National Institutes drug susceptibility data for surveillance; Monitor of Health and also includes the Agency for patterns of antimicrobial drug use; and Monitor Healthcare Research and Quality, the Health Care AR in agricultural settings to protect the public's Financing Administration, the Health Resources health by ensuring a safe food supply as well as and Services Administration, the Department of animal and plant health. Agriculture, the Department of Defense, the Department of Veterans Affairs, and the A coordinated national surveillance plan for Environmental Protection Agency. The Action monitoring AR in microorganisms that pose a Plan reflects a broad-based consensus of federal threat to public health will be developed and agencies on actions needed to address implemented. The plan will specify activities to be antimicrobial (a) resistance (AR). Input from state conducted at national, state, and local levels; and local health agencies, universities, define the roles of participants; promote the use of professional societies, pharmaceutical companies, standardized methods; and provide for timely health care delivery organizations, agricultural dissemination of data to interested parties, e.g., producers, consumer groups, and other members public health officials, clinicians, and researchers. of the public was important in developing the plan. Needed core capacities at state and local levels While some actions are already underway, will be defined and supported. When possible, the complete implementation of this plan will require plan will coordinate, integrate, and build on close collaboration with all of these partners (b), a existing disease surveillance infrastructure. All major objective of the process. The plan will be surveillance activities will be conducted with implemented incrementally, dependent on the respect for patient and institutional confidentiality. availability of resources. The Action Plan provides a blueprint for The availability of reliable drug susceptibility specific, coordinated federal actions to address the data is essential for AR surveillance. The emerging threat of antimicrobial resistance. This accuracy of AR detection and reporting will be document is Part I of the Action Plan, focusing on improved through training and proficiency testing domestic issues. Since AR transcends national programs for diagnostic laboratories and by

Antimicrobial Chemotherapy and development 245

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

promoting and further refining standardized Appropriate drug-use policies will be methods for detecting drug resistance in important implemented through a public health education pathogens, including bacteria, parasites, fungi, and campaign on appropriate antimicrobial drug use as viruses. Public and private sector partners will a national health priority. Other actions in support address barriers to AR testing and reporting, e.g., of appropriate drug use will include reducing barriers due to changes in health care delivery. inappropriate prescribing through development of clinical guidelines and computer-assisted decision A plan to monitor patterns of antimicrobial support, considering regulatory changes, drug use will be developed and implemented as supporting other interventions promoting an important component of the national AR education and behavior change among clinicians, surveillance plan. This information is essential to and informing consumers about the uses and interpret trends and variations in rates of AR, limitations of antimicrobial drugs. improve our understanding of the relationship between drug use and resistance, identify and Improved diagnostic practices will be promoted anticipate gaps in availability of existing drugs, by encouraging the use of rapid diagnostic and identify interventions to prevent and control methods to guide drug prescribing, facilitating AR. direct consultation between clinicians and laboratory personnel with appropriate expertise Improved surveillance for AR in agricultural and authority, and promoting the use of settings will allow early detection of resistance appropriate laboratory testing methods. trends in pathogens that pose a risk to animal and Guidelines, training, and regulatory and plant health, as well as in bacteria that enter the reimbursement policies will be utilized to promote food supply. Agricultural surveillance data will improved diagnostic practices. also help improve understanding of the relationship between antimicrobial drug and Reduced rates of infection transmission will be use and the emergence of drug addressed through public health campaigns that resistance. promote and hygienic practices such as , safe food handling, and other Prevention and Control of Antimicrobial behaviors associated with prevention of infection Resistance (AR) transmission. Infection control in health care The prevention and control of drug-resistant settings will be enhanced by developing new infections requires measures to promote the interventions based on rapid diagnosis, improved appropriate use (c) of antimicrobial drugs and understanding of the factors that promote cross- prevent the transmission of infections (whether infection, and modified medical devices or drug-resistant or not). Priority Goals and Action procedures that reduce the risk of infection. Items in this focus area address ways to: Extend the useful life of antimicrobial drugs through The prevention and control of AR in appropriate use policies that discourage overuse agriculture and veterinary medicine requires 1) and misuse; Improve diagnostic testing practices; improved understanding of the risks and benefits Prevent infection transmission through improved of antimicrobial use and ways to prevent the infection control methods and use of ; emergence and spread of resistance; 2) Prevent and control emerging AR problems in development and implementation of principles for agriculture, human and veterinary medicine; and appropriate antimicrobial drug use in the Ensure that comprehensive programs to prevent production of food animals and plants; 3) and control AR involve a wide variety of improved animal husbandry and food-production nonfederal partners and the public so these practices to reduce the spread of infection; and 4) programs become a part of routine practice a regulatory framework to address the need for nationwide. antimicrobial drug use in agriculture and

246 Antimicrobial Chemotherapy and development

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

veterinary medicine while ensuring that such use of AR emergence, acquisition, spread, and does not pose a risk to human health. persistence; and on the effects of antibiotics used as agricultural growth promotants on microbes that Comprehensive, multifaceted programs live in animals, humans, plants, soil and water. involving a wide variety of nonfederal partners Further study is also required to determine and the public are required to prevent and control whether variations in drug use regimens may AR. The AR Task Force agencies will ensure stimulate or reduce AR emergence and spread. ongoing input from, review by, and collaboration Improved understanding of the causes of AR with nonfederal partners. The appropriate agencies emergence will lead to the development of tools will support demonstration projects that use for reducing microbial resistance, as well as for multiple interventions to prevent and control AR predicting where AR problems are likely to arise. (e.g., through surveillance, appropriate drug use, optimized diagnostic testing, immunization A comprehensive research infrastructure will practice, and infection control). The Task Force help ensure a critical mass of AR researchers who agencies will encourage the incorporation of will interact, exchange information, and stimulate effective programs into routine practice by new discoveries. This aim will be achieved implementing model programs in federal health through the appropriate strategies and scientific care systems and promoting the inclusion of AR conferences that promote research on AR. The AR prevention and control activities as part of quality Task Force agencies will work with the academic assurance and accreditation standards for health and industrial research communities to attract AR care delivery nationwide. researchers, prioritize needs, identify key opportunities, and optimize the utilization of Research resources to address AR problems. Understanding the fundamental processes involved in antimicrobial resistance within microbes and the The translation of research findings into resulting impact on humans, animals, and the innovative clinical products to treat, prevent, or environment forms an important basis for diagnose drug-resistant infections is an area in influencing and changing these processes and which the federal government can play an outcomes. Basic and clinical research provides the important role, focusing on gaps not filled by the fundamental knowledge necessary to develop or by other appropriate responses to antimicrobial resistance nongovernment groups. Special efforts will be emerging and spreading in hospitals, communities, placed on the identification, development and farms, and the food supply. Priority Goals and testing of rapid, inexpensive, point-of-care Action Items in this focus area address ways to: diagnostic methods to facilitate appropriate use of Increase understanding of microbial physiology, antimicrobials. The AR Task Force agencies will ecology, genetics and mechanisms of resistance; also encourage basic research and clinical testing Augment the existing research infrastructure to of diagnostic methods, novel treatment support a critical mass of researchers in AR and approaches, new vaccines, and other prevention related fields; and Translate research findings into approaches for resistant infections. clinically useful products, such as novel approaches to detecting, preventing, and treating Product Development antimicrobial resistant infections. As antimicrobial drugs lose their effectiveness, new products must be developed to prevent, Needs in the field of AR research will be rapidly diagnose, and treat infections. The Priority identified and addressed through a government- Goals and Action Items in this focus area address wide program review with external input. ways to: Ensure that researchers and drug Additional research is needed, for example, on the manufacturers are informed of current and epidemiology of resistance genes; on mechanisms projected gaps in the arsenal of antimicrobial

Antimicrobial Chemotherapy and development 247

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

drugs, vaccines, and diagnostics and of potential inhabitant of the human intestinal tract, is the most markets for these products (designated here as thoroughly studied of all organisms. Studies of the "AR products"); Stimulate the development of mechanisms of genetic exchange and the biology priority AR products for which market incentives of plasmids and bacteriophages of E. coli have are inadequate, while fostering their appropriate been crucial in understanding many aspects of use; and Optimize the development and use of DNA replication and the expression of genetic veterinary drugs and related agricultural products material. These studies have led to the ability to that reduce the transfer of resistance to pathogens insert DNA from unrelated organisms into E. coli that can infect humans. plasmids and bacteriophages, and to have that DNA replicated by the bacteria, with the genetic Current and projected gaps in the arsenal of information it contains expressed by the bacteria AR products and potential markets for these (Dimmock et. al., 1993; Karam, 1994; Prusiner, products will be reported to researchers and drug 1996; Prescott et. al., 2005). manufacturers through an interagency working In recent biotechnology development, DNA group convened to identify and publicize priority analysis is assisting with precise identification of public health needs. outbreaks and with rapid diagnosis of new cases. Molecular biology breakthroughs allow The development of urgently needed AR identification and tracking of organisms so products will be stimulated throughout the surveillance teams can quickly link related cases. process from drug discovery through licensing. Genetic engineering is helping us understand how The regulatory process for AR products will resistance takes hold and what might be done to continue to be streamlined, and incentives that suppress it. promote the production and appropriate use of However, new antibiotics have been priority AR products can be evaluated in pilot developed recently, including some that are programs that monitor costs and assess the return effective against S. pneumoniae and vancomycin- on the public investment. resistant organisms. The threat of epidemics has The production of veterinary AR products that triggered unprecedented Cooperation among reduce the risk of development and transfer of scientists, government agencies, physicians, and resistance to drugs used in human clinical drug manufacturers. Fast-track research is medicine will be expedited through a streamlined encouraging development of critically needed regulatory and approval process. As with drugs for therapeutic agents. Still, the cost of bringing a new the treatment of human infections, pilot programs antibiotic from discovery to market (estimated at can be initiated to evaluate incentives that between $100 million and $350 million for the encourage the development and appropriate use of United States) is a serious concern for the priority products that meet critical animal and manufacturers who must recoup their investment plant health needs. Private and public partners will (Gold and Moellering, 1996; Hoel and Williams, also evaluate ways to improve or reduce the 1997). agricultural use of particular antimicrobial drugs, According to Benjamin Schwartz, MD, Chief as well as ways to prevent infection, such as the of the CDC's Childhood and Preventable use of veterinary vaccines, changes in animal Diseases Section, Division of Bacterial and husbandry, and the use of competitive exclusion Mycotic Diseases in a recent report by Hoel and products (i.e., treatments that affect the intestinal Williams (1997) said that Primary care health care of food animals). workers will also play a critical role in controlling antibiotic resistance in the future. Health care Biotechnology's promises workers can help a great deal by closely In recent years, bacteriology has been greatly monitoring how antibiotics are used. Cutting back expanded from its concentration on disease- on the 50 million or so courses of unnecessary causing pathogens. , a normal antibiotic therapy prescribed each year will have a

248 Antimicrobial Chemotherapy and development

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

major effect on slowing down the development of resistance. And that culturing infectious organisms REFERENCES and testing for sensitivity also are crucial for controlling resistance. The primary health care Chadwick, D.J. and Goode, J. 1997. Antibiotic workers can help bring the problem under control resistance: Origins, evolution, selection and spread. though everyone is trying to keep costs down, but Ciba Foundation symposium. Chister, UK: John Wiley eliminating lab tests for antibiotic sensitivity will & Sons. 207:1-10 only cause more problems and cost more money in Chalker, J. 1995. Effect of a drug supply and cost sharing system on prescribing patterns and on the long run. utilization of health facilities, a controlled trial from Improved awareness is leading, slowly but heath posts in the hills of Nepal. Health policy and surely, to an appreciation of what meaningful planning.10 (4):423-430 prevention programs should include and what they Davies, J. 1994. Inactivation and the dissemination of will cost. There is a subtle and tentative resistance genes. Science 264: 375-82 resurgence of confidence in our ability to wrestle Demain, A.L. and Elander, R. P. .1999. The beta- control over our microbial future. But for those of lactam antibiotics: past, present, and future. us on the front lines of disease management, Antonie Van Leeuwenhoek.75(1-2):5-19. Dimmock, N.J. and Primrose, S.B. 1993. An vigilance continues to be the watchword. Our th individual small steps can make a difference as Introduction to Modern Virology, 4 edition. Blackwell, Oxford. Pp 564. revealed by Hoel and Williams (1997). Dixon, B. 1994. Power unseen: how microbes rule the Although, in recent time, World Health world. New York: WH Freeman. Organization (WHO) and AIDS Prevention Garrett, L. 1994. The coming plague: newly emerging Initiative in Nigeria (APIN) of Harvard University diseases in a world out of balance. New York: Penguin in collaboration with the Federal Ministry of Books. Health have really intensified on their front line of Gold, H.S. and Moellering, R.C. Jr.1996. disease surveillance and disease management in Antimicrobial-drug resistance. N. Engl J Med; Nigeria as in the case of Polio eradication 335(19):1445-53 programme and HIV/AIDS prevention programme Hagman, H.M. and Strausbaugh, L.J. 1996. but the inadequate availability of diagnostic Vancomycin-resistant enterococci: the 'superbug' scourge that's coming your way. Postgrad. Med; facilities and competent personnel in some part of 99(5):62-71 the country could result in considerable time being Hoel, D. and Williams, D. N. 1997. Antibiotics: Past, lost before outbreak or reemergence of present, and future-Unearthing nature's antimicrobial resistant pathogens as well as magic bullets. Postgraduate Medicine, Vol 101:1 notifiable diseases is confirmed and reported. January 1997 There is therefore an urgent need to improve Holzman, D. (1998). Phage as antibacterial tool. the use of antibiotics and the medical system by Genetic Engineering News. 15 October, pp48. adopting the various recommendations already Jacoby, G.A., and Archer, G.L. 1991. New made. It must be noted that improvement in mechanisms of bacterial resistance to diagnostic and diseases reporting facilities as antimicrobial agents. New England Journal of Medicine, 324 (9): 601-9. recommended will really help in the resurgence of Karam, J.D. 1994. Molecular biology of bacteriophage confidence in our ability to wrestle control over T4. Herridon, Va: ASM Press our microbial future. It is our hope that this review Knudson, M., 1998. The Hunt is on: For New Ways will stimulate the examination of antibiotic to Overcome Bacterial Resistance novel antibiotics and resistance in some of the states that are lagging phage therapy as answers to this problem IACFA behind as this bacterial resistance to antibiotics has Newsletter: May, Issue 52. Reprinted from MIT's become a serious medical problem of global Technology Review on the mechanism of antibiotic concern now. resistance Jan/Feb 1998, Vol 100:9 Lansang, M. 1990. Purchase of antibiotics without prescription in Manila, the Philippines, in appropriate choices and doses, Journal of Clinical Epidemiology

Antimicrobial Chemotherapy and development 249

African Journal of Biomedical Research 2008 (Vol. 11) / Okonko, Fajobi, Ogunnusi, Ogunjobi and Obiogbolu

43:61-67 Osterholm, M.T. 1996. Emerging infectious diseases: Lemonick, M.D. 1996. Guerrilla warfare. Time. Fall a real public health crisis? (Guest editorial) Postgrad Special Issue: 59, 62 Med; 100(5):15-26 Levy, S.B. 1995. Antimicrobial resistance, a global Prescott, L.M., Harley, J.P. and Klein, A. D. 2005. perspective in Antimicrobial resistance, a Crisis in Drug Resistance, WCB McGraw-Hill, Microbiology 6th Health care, Jungkind et al.,(Eds), International Edition, pp 1212. biology.(390),Plenum press. Prusiner, S.B. 1996. Molecular biology and Levy, S.B. 1998, The Challenge of Antibiotic Pathogenesis of Prion diseases. Trends In Biochemical resistance, Scientific American, New York 278(3):46- Sciences, 21: 482-7. 53. Robinson, D. 1976. The miracle finders: the stories Lin, E.C.C.; Goldstein, R.; and Syvanerr, M. 1984. behind the most important breakthroughs in medicine. Bacteria, Plasmids and phages. An Introduction to New York: David McKay. Molecular biology. Cambridge, Mass: Harvard Univ. Welch, H.G. 1984. Antibiotic resistance: a new kind of press. Pp 538. epidemic. Postgrad. Med; 76(6):63-6 Lorch, A. 1999. "Bacteriophages: An alternative to Wenzel R. 1995. Control of Antibiotic resistant antibiotics?" Biotechnology and Development Organisms, Journal of Infectious Disease and Monitor, 39:14-17. Antimicrobial Agents, 12 (1): 47-48. Macaden R, and Bhat P. 1985. The changing pattern White David G, Michael Moen and Darren Huber of resistance to ampicillin and cotrimoxazole in (1999) Trends in antibiotic resistance associated with E. Shigella serotypes in Bangalore, South India. J. coli calf scours. Alliance For The Prudent Use Of Infectious Diseases, 152:1348. Antibiotics Department of Veterinary and Magner, L. A. 1992. History of medicine. New York: Microbiological Sciences, North Dakota State Marcel Dekker. University, Fargo, North Dakota, USA Meleney, F.L. 1947. Treatment of surgical infections World Bank 1995. Vietnam, poverty assessment and by chemical and antibiotic agents. Postgrad. Med; strategy, World Bank Country Operation Division, 1(2):87-96 Country Department East Asia and Pacific Regions, Murray, B. 1985. Increasing resistance to January 1995. trimethroprim-sulphamethoxazle among isolates of World Health Organization (WHO).1993. How to Escherichia coli in Developing Countries, J. Infectious investigate drug use in health facilities, Diseases, 152: 1107-1113. WHO/DAP/93.1 Ogundipe, G.A.T., Oluokun, S.B. and Esuruoso, World Health Organization, WHO (1999). G.O. 1989. The development and efficiency of the Combating the growth of resistance to antibiotics. animal health information system in Nigeria. Preventive http://www.who.int/dap-icium/posters/2E1_txtf.html Vet. Med., 7:121-135.

250 Antimicrobial Chemotherapy and development