Antibiotic resistance is now a major issue confronting healthcare providers and their patients. Changing antibiotic resistance patterns, rising antibiotic costs and the introduction of new antibiotics have made selecting optimal antibiotic regimens more difficult now than ever before. Furthermore, history has taught us that if we do not use antibiotics carefully, they will lose their efficacy

Antibiotic resistance

Antibiotic resistance is a form of drug resistance whereby some (or, less commonly, all) sub-populations of a microorganism, usually a bacterial species, are able to survive after exposure to one or more antibiotics; pathogens resistant to multiple antibiotics are considered multidrug resistant (MDR) or, more colloquially, superbugs.

Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has emerged as one of the pre-eminent public health concerns of the 21st century, in particular as it pertains to pathogenic organisms (the term is especially relevant to organisms that cause disease in humans). A World Health Organization report released April 30, 2014 states, "this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country. Antibiotic resistance–when bacteria change so antibiotics no longer work in people who need them to treat infections–is now a major threat to public health."

In the simplest cases, drug-resistant organisms may have acquired resistance to first-line antibiotics, thereby necessitating the use of second-line agents. Typically, a first-line agent is selected on the basis of several factors including safety, availability, and cost; a second-line agent is usually broader in spectrum, has a less favourable risk-benefit profile, and is more expensive or, in dire circumstances, may be locally unavailable. In the case of some MDR pathogens, resistance to second- and even third-line antibiotics is, thus, sequentially acquired, a case quintessentially illustrated by Staphylococcus aureus in some nosocomial settings. Some pathogens, such as Pseudomonas aeruginosa, also possess a high level of intrinsic resistance.

It may take the form of a spontaneous or induced genetic mutation, or the acquisition of resistance genes from other bacterial species by horizontal gene transfer via conjugation,transduction, or transformation. Many antibiotic resistance genes reside on transmissible plasmids, facilitating their transfer. Exposure to an antibiotic naturally selects for the survival of the organisms with the genes for resistance. In this way, a gene for antibiotic resistance may readily spread through an ecosystem of bacteria. Antibiotic-resistance plasmids frequently contain genes conferring resistance to several different antibiotics. This is not the case for Mycobacterium tuberculosis, the bacteria that causes Tuberculosis, since evidence is lacking for whether these bacteria have plasmidsAlso M. tuberculosis lack the opportunity to interact with other bacteria in order to share plasmids

Genes for resistance to antibiotics, like the antibiotics themselves, are ancient. However, the increasing prevalence of antibiotic-resistant bacterial infections seen in clinical practice stems from antibiotic use both within human medicine and veterinary medicine. Any use of antibiotics can increase selective pressure in a population of bacteria to allow the resistant bacteria to thrive and the susceptible bacteria to die off. As resistance towards antibiotics becomes more common, a greater need for alternative treatments arises. However, despite a push for new antibiotic therapies, there has been a continued decline in the number of newly approved drugs. Antibiotic resistance therefore poses a significant problem.

The growing prevalence and incidence of infections due to MDR pathogens is epitomised by the increasing number of familiar acronyms used to describe the causative agent and sometimes the infection; of these, MRSA is probably the most well-known, but others including VISA (vancomycin-intermediate S. aureus), VRSA (vancomycin-resistant S. aureus), ESBL (Extended spectrum beta-lactamase), VRE (Vancomycin-resistant Enterococcus) and MRAB (Multidrug-resistant A. baumannii) are prominent examples.Nosocomial infections overwhelmingly dominate cases where MDR pathogens are implicated, but multidrug-resistant infections are also becoming increasingly common in the community.

Cause

Although there were low levels of preexisting antibiotic-resistant bacteria before the widespread use of antibiotics, evolutionary pressure from their use has played a role in the development of multidrug-resistant varieties and the spread of resistance between bacterial speciesThe widespread use of antibiotics both inside and outside medicine is playing a significant role in the emergence of resistant bacteria

In some countries, antibiotics are sold over the counter without a prescription, which also leads to the creation of resistant strains. Other practices contributing to resistance include antibiotic use in livestock feed to promote faster growth. Household use of antibacterials in soaps and other products, although not clearly contributing to resistance, is also discouraged (as not being effective at infection control). Unsound practices in the pharmaceutical manufacturing industry can also contribute towards the likelihood of creating antibiotic-resistant strains. The procedures and clinical practice during the period of drug treatment are frequently flawed — usually no steps are taken to isolate the patient to prevent re-infection or infection by a new pathogen, negating the goal of complete destruction by the end of the courseCertain antibiotic classes are more highly associated with colonisation with "superbugs" compared to other antibiotic classes. A superbug, also called multiresistant, is a bacterium that carries several resistance genes. The risk for colonisation increases if there is a lack of susceptibility (resistance) of the superbugs to the antibiotic used and high tissue penetration, as well as broad-spectrum activity against "good bacteria". In the case of MRSA, increased rates of MRSA infections are seen with glycopeptidescephalosporins, and especially quinolones. In the case of colonisation with Clostridium difficile, the high-risk antibiotics include cephalosporins and in particular quinolones andclindamycin.

Of antibiotics used in the United States in 1997, half were used in humans and half in animals; in 2013, 80% were used in animals.

Natural occurrence

There is evidence that naturally occurring antibiotic resistance is commonThe genes that confer this resistance are known as the environmental resistome.These genes may be transferred from non-disease-causing bacteria to those that do cause disease, leading to clinically significant antibiotic resistance.

In 1952, an experiment conducted by Joshua and Esther Lederberg showed that penicillin-resistant bacteria existed before penicillin treatment. While experimenting at theUniversity of Wisconsin-Madison, Joshua Lederberg and his graduate student Norton Zinder also demonstrated preexistent bacterial resistance to streptomycin. In 1962, the presence of penicillinase was detected in dormant Bacillus licheniformis endospores, revived from dried soil on the roots of plants, preserved since 1689 in the British Museum. Six strains of Clostridium, found in the bowels of William Braine and John Hartnell (members of the Franklin Expedition) showed resistance to cefoxitin andclindamycin. It was suggested that penicillinase may have emerged as a defense mechanism for bacteria in their habitats, such as the case of penicillinase-richStaphylococcus aureus, living with penicillin-producing Trichophyton, however this was deemed circumstantial. Search for a penicillinase ancestor has focused on the class ofproteins that must be a priori capable of specific combination with penicillinThe resistance to cefoxitin and clindamycin in turn was attributed to Braine's and Hartnell's contact with microorganisms that naturally produce them or random mutation in the chromosomes of Clostridium strains. Nonetheless there is evidence that heavy metals and some pollutants may select for antibiotic-resistant bacteria, generating a constant source of them in small numbers.

Medicine

The volume of antibiotic prescribed is the major factor in increasing rates or bacterial resistance rather than compliance with antibiotics.[32] Inappropriate prescribing of antibiotics has been attributed to a number of causes, including people insisting on antibiotics, physicians prescribing them as they feel they do not have time to explain why they are not necessary, and physicians not knowing when to prescribe antibiotics or being overly cautious for medical and/or legal reasons. For example, a third of people believe that antibiotics are effective for the common cold, and the common cold is the most common reason antibiotics are prescribedeven though antibiotics are useless against viruses. A single regimen of antibiotics even in compliant patients leads to a greater risk of resistant organisms to that antibiotic in the person for a month to possibly a year.

Antibiotic resistance has been shown to increase with duration of treatment; therefore, as long as an effective lower limit is observed, the use by the medical community of shorter courses of antibiotics is likely to decrease rates of resistance, reduce cost, and have better outcomes due to fewer complications such as C. difficile infection and diarrhea. In some situations a short course is inferior to a long course.

BMJ editorial recommended that antibiotics can often be safely stopped 72 hours after symptoms resolve. Because patients may feel better before the infection is eradicated, doctors must provide instructions to patients so they know when it is safe to stop taking a prescription. Some researchers advocate doctors' using a very short course of antibiotics, reevaluating the patient after a few days, and stopping treatment if there are no longer clinical signs of infection.

Patients taking less than the required dosage or failing to take their doses within the prescribed timing results in decreased concentration of antibiotics in the bloodstream and tissues, and, in turn, exposure of bacteria to suboptimal antibiotic concentrations increases the frequency of antibiotic resistant organisms, however factors within the intensive care unit setting such as mechanical ventilation and multiple underlying diseases also appeared to contribute to bacterial resistance. These nosocomial pneumonia patients represented a situation where there was relatively little contribution of host defense to outcome, and therefore may not be applicable to otherwise healthy individuals taking antibiotics.

Poor hand hygiene by hospital staff has been associated with the spread of resistant organisms, and an increase in hand washing compliance results in decreased rates of these organisms.

The improper use of antibiotics and therapeutic treatments can often be attributed to the presence of structural violence in particular regions. Socioeconomic factors such as race and poverty affect the accessibility of and adherence to drug therapy. The efficacy of treatment programs for these drug-resistant strains depends on whether or not programmatic improvements take into account the effects of structural violence.

Veterinary medicine

The emergence of antibiotic-resistant microorganisms in human medicine is primarily the result of the use of antibiotics in humans, although the use of antibiotics in animals is also partly responsible.[

Since the last third of the 20th century, there has been extensive use of antibiotics in animal husbandry. Some of these drugs are not considered significant for use in humans, because of their lack of either efficacy or purpose in humans (such as the use of