1. INTRODUCTION:

Sir Alexander Fleming in 1928 discovered the first antibiotic Penicillin. In the early days of 1940’s antibiotics were prescribed only to treat serious infection. During the Second World War Penicillin was successfully employed in controlling bacterial infection. Unfortunately after a short period of time Penicillin resistance become a substantial clinical problem. It resulted in the discovery of new β-lactam antibiotics. But also that too had not become a permanent solution for the resistance threat¹. The newly discovered β-lactam antibiotics also had lost its action due to the resistant organism. A wide range of biochemical and physiological mechanism are responsible for resistance. Antibiotics were not only used for human purposes, but also for animal, agricultural purposes. These all renders the reason for antibiotics resistance². Increasing antibiotic resistance become a major threat to the public health all over the world as it reduces the effectiveness, of antibiotic treatment resulting in increased morbidity, mortality and health care costs.

Many resolutions and recommendations have been proposed, numerous reports were written regarding antibiotic resistance, but no avail the development of antibiotic resistance is relentless³.

2. MAJOR CAUSES FOR ANTIBIOTIC RESISTANCE:

2.1. Excessive use:

The discoverer of antibiotic himself had warned the public regarding the resistance of antibiotic in the period of 1945 itself .Over use of antibiotics clearly drives the evolution of resistance. Over the counter availability of antibiotics without prescription is the major reason for the effective use. This lack of regulation result in antibiotics that are easily accessible, cheap and plentiful, that promotes overuse. Now a day’s online purchasing of medicine also available, that made the situations worst. As a result of this over the counter availability the antibiotics were used unnecessarily for every small illness, that in finally result in resistance ¹.

2.2. Patient noncompliance:

Illiteracy is one major reason for patient noncompliance. Patient noncompliance includes skipping doses, stopping drugs without doctor advice, once when the disease was cured. Most of the people will stop the antibiotics once when they fell illness was cured, without completing the prescribed course of the medicine. If a course of antimicrobial drug is not fully completed then some microbes may survive and develop resistance to drug¹.

2.3. Inadequate diagnosis:

Sometimes doctor will diagnosis infection without all necessary information. This will lead to antimicrobial being prescribed “just in case”, or broad spectrum antimicrobials being prescribed when a specific drug would be more apt. Both situations accelerate antimicrobial resistance [AMR] ¹.

2.4. Agricultural uses:

Antibiotics which are used for animal agriculture will be ingested by human beings, when they consume food. Antibiotics used for agricultural use will affect the environmental microbes. About 90% of the antibiotics given to live stock are excreted in urine and stool, and then widely dispersed through fertilizer, ground water and surface run off ¹.

2.5. Availability of few new antibiotics:

Development of new antibiotic drug molecule by pharmaceutical companies had not essentially stalled due to economic and regulatory obstacles. And if once a new antibiotic is marked, physicians mostly hold this new agent in reserve only for the worst cases due to fear of promoting drug resistance. Regulatory barrier is on other important stage for the newly discovered drugs ¹.

3. MOST COMMON ANTIBIOTIC RESISTANT PATHOGENS:

Antibiotic resistance can be found in bacteria, virus, fungi, and parasites.

3.1. Mycobacterium tuberculosis:

Tuberculosis has become a worldwide threat, mainly due to the emergence of multidrug-resistance [MDR] and extensively drug resistance [XDR] strains of mycobacterium tuberculosis. To treat MDR-TB, second line drug including fluroquniolone [FQS], amikacin [AMK], kanamycin [KAN] and capreomycin [CAP] were employed. These drugs are administered for approximately 20 months and can be toxic, poorly tolerated, and difficult to produce. Approximately 95 % of MDR-TB is XDR-TB, having additional resistance to at least one FQS and one inject able drug [AMK, KAN or CAP] and for which treatment limited ^4.

3.2. Methicillin –resistant Staphylococcus aureus [MRSA]:

Methicillin resistant Staphylococcus aureus is a bacterial infection that most commonly acquired in hospitals. MRSA is resistant to penicillin like beta –lactam antibiotics, macrolides, fluroquniolones and aminoglycosides. MRSA infection can be very serious and are among the most frequently occurring of all antibiotics resistant threats ^5,
6.

3.3. Neisseria gonorrhea:

Gonorrhea is a sexually transmitted disease and the second most commonly reported infectious diseases. The drug resistance to N. gonorrhea became more wide spread .Cephalosporin resistant N.gonorrhea is often resistant to other types of antibiotics, such as fluroquniolones, tetracycline’s and penicillin. Infections caused by these bacteria will therefore likely fail empiric treatment regimens ³.

3.4. Pseudomonas aeruginosa:

Pseudomonas aeruginosa is a common cause of health care associated infections, including pneumonia, bloodstream, urinary tract and surgical site infections ^2,5. Some strains of multi drug resistant P.aeruginosa have been found to be resistant to nearly all antibiotics, including amino glycosides, cephalosporin’s , fluroquniolones , and carbapenems ^7,8.

3.5. Escherichia coli:

It is commonly referred to as E.coli, is a bacterium and commonly causes food- borne diseases community , nursing home-acquired urinary tract infection and severe hospital acquired infection. E.coli resistance drugs are cephalosporin’s, fluroquniolones, amino glycosides, and carbapenems. Carbapenems resistance involves the entire class of beta- lactam antibiotics and associated with resistance to unrelated antibacterial drug class. The consequence is the emergence of extensive drug resistance ⁹.

3.6. Enterococci

Enterococci are other examples of bacteria with a complex interacting resistance reservoir in humans, animals–from livestock to wild animals and even migrate bird, food and the environment. Enterococci primarily Enterococcus faecium are multi resistant pathogens that rapidly spread and are difficult to treat owing to a high resistance rate to the main antibacterial group like amino penicillin, amino glycosides and vancomycin ⁶.

3.7. Klebsiella pneumonia:

Klebsiella pneumonia belongs to the family of enterobacteriaceae. In addition to the ability to colonize gastrointestinal tract, nasopharynx and skin, K. pneumonia could cause various infection syndromes, including urinary tract infection, intra abdominal infection, skin and soft tissue infection. The presence of drug resistance in the infecting pathogen would adversely affect the treatment outcome one the major drug resistance mechanism of concern in K .pneumonia is the production of β–lactamase especially extended spectrum β–lactamases ¹⁰.

3.8. Acinetobacter baumanii:

Acinetobacter is a gram –positive bacterium that causes pneumonia or blood stream infection, especially in critically ill patient on mechanical ventilation ^11-13. Some acinetobacter species have become resistant to all or nearly all antibiotics, including carbapenems ^13-15.

3.9. Streptococcus pneumonia:

It is a major cause of bacterial pneumonia and meningitis as well as blood stream, ear, sinus infection. S.pneumoniae has developed resistance to drugs in the penicillin class and erythromycins such as amoxicillin and azithromycin respectively. It has also resistance to less commonly used drugs. In 30 % of severe S. pneumonia cases, the bacteria were fully resistance to one or more clinically relevant antibiotics ³.

3.10. Human immuno deficiency virus:

HIV treatment often requires different types of antiretroviral medicines, which can have unpleasant side effect, not fully adhering to drug regimens can create new strains of HIV that are drug resistant ^{17, 18}.

3.11. Candida:

Candida albicans is a fungus that can cause vaginal yeast infection. According to the Centre for disease control and prevention, nearly 75% of women experience a yeast infection at some point in their lives. Candida can become resistant to antifungal agent like fluconazole with resistant often observed in patients who also have HIV ¹⁹.

3.12. Malaria:

Malaria is a disease caused by a parasite and kills around one million people every year worldwide. In many parts of the world, the evolution of drug resistant parasite has lead to certain anti malarial drugs becoming ineffective²⁰. Especially chloroquines species of the malaria parasite cause disease in human namely, Plasmodium falciparum, Plasmodium vivax, Plasmodium malaria, Plasmodium ovale and Plasmodium knowlesi of this species Plasmodium falciparum cause the most severe disease ^{21, 22}.

3.13. Salmonella typhi and Salmonella paratyphi:

Salmonella typhi and Salmonella paratyphi were the bacteria that can causes enteric fever, which could be resistant to drugs like ampicillin, chloramphenicol, cortimoxazole and fluroquniolone ^{23, 24}.

3.14. Mycobacterium leprae:

Mycobacterium leprae has become resistant to various concentration of dapsone, rifampicin or clofazimine with 6.23 % being resistant to two drugs ²³.

3.15. Protozoa:

Plasmodium falciparum has become resistant to chloroquine and other antimicrobials. Only plasmodium vivax remained sensitive to antimicrobials for long time. Leishmania donovani has become resistant to the pentavalent antimonials, meglumine antimoniate and sodium stibogluconate, likewise pentamide unresponsiveness as well as its toxicity, has removed another therapeutic option. Amphotericin B, paramomycin and the recently introduced miltefosine are available but often unaffordable but are being used extensively in a programmed mode. E. histolytica has shown some drug resistance but the problem is not very serious ²³.

3.16. Clostridium difficile:

Clostridium difficile is the toxin producing anaerobe, which is increasingly found as the cause of severe, intestinal infection, recently hyper virulent toxin producing strain have been recognized. It is a renewed prominence considered the result of extensive use of antibiotics in hospitals such as extended- spectrum cephalosporin, the newer penicillin and fluroquniolones that cause significant depletion of the gram negative intestinal micro flora ²⁵.

3.17. Enterobacteriaceae:

Enterobacteriaceae resistance is an urgent threat to the medical science. Carbapenem resistant Enterobacteriaceae have become resistant to nearly all available antibiotics, Carbapenem resistance is mainly due to the presence of enzyme beta lactamase in the gram negative Enterobacteriaceae ^{5,26, 27}.

3.18. Haemophilus influenza:

Although that much resistance was shown by Haemophilus influenza. Recent studies revealed that in North India there are high prevalence of ampicillin resistant H. influenza was observed ^{28, 29}.

3.19. Vibrio cholera:

It has acquired resistance to a number of antimicrobials. Its resistance spectrum various in different locality. Tetracycline remained effective but furazolidone, cortimoxazole, are noted as resistant ³⁰.

3.20. Onchocerca volvulus:

Onchocerca volvulus is a nematode that cause to onchocerciasis (river blindness) and is the second largest cause to blindness after trachoma. This Onchocerca volvulus was found to be highly resistant to diethyl carbamazine³⁰.

3.21. Pneumocystis jiroveci:

Pneumocystis jiroveci (human derived Pneumocystis carinii ) is an opportunistic pathogenic fungus which cause pneumonia and is life threatening in immuno compromised individuals. Spontaneously acquired resistance to atovaquone , a hydroxyl naphthoquinone³¹.

3.22. Cryptococcus neoformans:

Cryptococcus neoformans is encapsulated yeast known to cause disease in both immune suppressed as well as seemingly immune competent hosts. Cryptococcal disease in both HIV-positive and HIV-negative hosts continues to be associated with significant morbidity and mortality. Successful treatment has historically relied on the use of amphotericin -B, flucytosine, and fluconazole .Despite the availability of new antifungal agents and HAART, treatment failures continue to occur for a Varity of reason including direct antifungal resistance^18,32,33.

3.23. Aspergillus:

Aspergillus is a fungal pathogen that cause infections on humans. Fluconazole and ketoconazole are inactive against aspergillus. Validation of testing procedures for the detection of itraconazole resistance in Aspergillus fumigatus and were further validated with posaconazole and voriconazole ³⁴.

3.24. Campylobacter jejuni:

Campylobacter jejuni is the most commonly recognized causes of bacterial gastroenteritis in United States . When antibiotics were indicated for the treatment of campylobacter gastroenteritis, erythromycin or a fluoroquinolone such as ciprofloxacin is the drug of choice. The resistance of campylobacter jejuni isolates quinolones has been reporte³⁵.

3.25. Human helminthes:

In recent years, several reports of apparent failures in the treatment of human schistosomes and nematodes have been reported due to the potential problem on anthelmintic resistance in the treatment and control of human helminthes³⁶. The main drugs used to treat human nematodes nowadays are mebendazole, albendazole, pyrantelpamoate, and levamisole for intestinal nematodes, ivermectinzole for onchocerciiasis, and diethylcarbamazine (DEC) alone or DEC-albendazole are combination treatment for filariasis^37-39.

4. CONCLUSION:

Medical science had developed in various branches, in various ways. But antibiotic resistance is a global issue and medical science still has to find out any reasonable measures to overcome that. Lives that many imponderables the best one can expect are that all physicians and health care centers provide their patients with environments that are resistance free by taking strider measures in infection control by antibiotic use. Despite of their own business missions pharmacy companies have to take interest on the research and development of new antibiotics. If not the pre antibiotic era awaits our descendants.

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Received on 08.04.2017 Modified on 20.04.2017

Research J. Pharm. and Tech. 2017; 10(6): 1886-1890.

DOI: 10.5958/0974-360X.2017.00331.6