Discovery Of Antibiotics Generally Accredited Alexander Flemming Biology Essay

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"It is time to close the book on the problem of infectious diseases" (Steinfeld, J. 1969) Discuss and analyse how the initial optimism following the discovery of antibiotics was dissipated. One of the top 10 great public health achievements in the twentieth century have been the detection and progression of antimicrobial agents. It is considered to be a significant medical advancement in modern history and has played an essential role in the management and control of infectious diseases (Centres for Disease Control and Prevention 1999).

The discovery of antibiotics is generally accredited to Alexander Flemming, who by accident discovered penicillin on a contaminated laboratory plate (Levy 1992). The first reported clinical use of penicillin was in 1941, and then became widespread in 1944 after work carried out by Florey and Chain (Levy 1992). Fleming had made a prediction on antibiotic resistance, concluding that inadequate forms of antibiotic therapy could assist in resistance (Levy 1992). However, Flemings forewarning was ignored and from the 1940's onwards antibiotics were used in great quantity and without controlled measures, (Porter 1997).

The initial optimism following the discovery of the antibiotic began to wane from the 1970's onwards with the emergence of more multi-resistant microbes (Levy 1992). A prime public health concern effecting hospitals and the other health care settings is the materialization of antibiotic-resistant organisms. Treatment options have become limited due to antibiotic-resistant organisms appearing to be biologically robust which enables them to cause critical, life threatening infections. The incidence of drug-resistant pathogens is increasing especially when the detection and expansion of innovative antibiotics is decreasing radically (Spellberg, B et al 2008).

Diagnostic testing advancements have been slow to emerge, which has resulted in antibiotic treatment based on empirical prescribing and generalised practice guidelines (Peterson et al 2004). A number of antibiotic-resistant pathogens have been recognized in the past ten years as one of the main causes of infections among patients in the health care setting. These organisms are frequently resistant to multiple classes of antibiotics and are often referred to as multidrug-resistant organisms. The great principle of antimicrobial resistance is "survival of the fittest" (Darwin 1859). 

The expectations of society today, together with the physician's fundamental aspiration to help, have contributed to the prevalent overuse of antibacterial agents in most countries. A study undertaken in Spain discovered that 67% of patients were given antibiotic treatment by their doctor, while only 22% were actually diagnosed with an infection (Baquero et al 1996). Some studies are also looking at outpatient use of antimicrobial treatment which accounts for 85% of usage in the community setting (Cars et al 2001).

Bacteria are able to adapt to their environment by means of genetic information borne on extra chromosomal elements identified as plasmids. Some bacteria are capable of recombination with their host cells chromosome (Glenn et al 2005). During cell division the plasmids are capable of replication and transmission. Plasmids are able to transfer vertically to daughter cells during binary fusion and can also transfer horizontally from infected cells to uninfected cells through conjugation (Thomas 2000).

Plasmids exist outside the chromosome and can encode for multi drug resistance. Through selection, they have become prevalent in many species. R-plasmids carry the genes for resistance to several antimicrobials and can code for a number of proteins useful to bacteria (Playfair 1995). In 1963 broad spectrum penicillin was introduced for the first time. It initially had a good response to most gram-negative bacteria, including  Escherichia coli, Haemophilus influenzae and Neisseria gonorrhoeae.

However, by 1965, ampicillin-resistant Escherichia coli were recorded and found to have a plasmid-mediated ampicillin degrading enzyme. In the subsequent 33 years this enzyme has spread to 40-60% of isolates of Escherichia coli and closely related species (Livermore 1995).Sometimes a protein is coated around the plasmid DNA is able to transmit as an extra cellular virus. In some cases the transmission would require direct contact between the cells carrying the plamisd and cells that are free from plasmids (Levin et al 1980).

Plasmids can also replicate copies and transfer themselves to bacteria which are plasmid free at an incredible rate. The extended-spectrum ß-lactamase gram-negative bacilli are plasmid mediated and are rapidly ever-increasing in the health care setting (Jacoby et al 2005). With interaction with specific bacterial targets, antibiotics can inhibit nucleic acid replication, protein synthesis and bacterial cell-wall synthesis. In order to achieve this, the antibiotic binds to the available bacterial target site.

Whether antibiotic resistance is intrinsic or acquired, the genetic determinants of resistance encode specific biochemical resistance mechanisms that may include enzymatic inactivation of the drug, alterations to the structure of the antibiotic target site, and changes that prevent access of an adequate concentration of the antimicrobial agent to the active site (Nue 1992). For antibiotics to have an effect, they must connect to a specific bacterial target site, which varies depending on the class of the antibiotic. A change in the structure of the target may result in the inability of the antibiotic to bind to its target.

Another strategy that has evolved to work against antimicrobial activity is to inhibit the drugs access to the target site. This may arise because of a permeability barrier or because of the existence of an efflux pump mechanism. In the House of Lords report (1998), it evaluates the opinions of a number of scientists. Professor David Reeves argues that by removing selective pressure, bacteria will revert back to being susceptible to certain antibiotics; conversely one scientist suggests that this is not the case and if resistance was not related to use then mankind would have no chance of controlling antibiotic resistance. However, by controlling the use of antibiotics within hospitals and carrying out infection prevention and control practices, MRSA bacteraemia rates have been reduced by 57% (HPA 2008).  

Levin (2006) suggests that there may be other factors which contribute to antibiotic treatment failures, suggesting that one major factor is non-inherited resistance, he suggests that genetically sensitive bacteria given an antibiotic may survive in its presence. If Levin (2006) is correct, then antibiotic prescribing polices may not prevent the spread of resistance and would therefore support the arguments made against Professor David Reeves.

The gram-negative cell wall has inner and outer membranes which work as a permeability barrier. Outer membrane proteins are produced by the bacterial cell to allow the movement of vital compounds through the outer membrane; this allows the diffusion of molecules, including antibiotics into the cells cytoplasm. The outer membrane proteins can have their structure altered by mutations which impede the access of antimicrobial agents via the permeability barrier to their active site (Livermore 2001).

A number of organisms have developed an active efflux mechanism which prevents infiltration of antibiotics to the active site. The efflux mechanism works by pumping the antibiotic from the cytoplasm before they can connect to their target (Webber et al 2003). The gram-positive and gram-negative organisms have been found to have the efflux pump. Some pumps may be specific to only one l class of antibiotic, whilst other pumps may possibly be associated with resistance to multiple drugs due to their capability of exporting many different classes of antimicrobials (Webber et al 2003).

There may be many different factors that can implicate the emergence and transmission of antibiotic resistance within the health care setting. Antimicrobial resistance is for the most part determined and magnified by the selective pressure of antimicrobial use within the health care facilities and the community (Gaynes 1995).  Exposure to an antibiotic may inhibit or kill the majority of the bacterial population who are susceptible.

However, a resistant subset of organisms may not be inhibited or killed by the antibiotic. These bacteria may be intrinsically resistant to the antibiotic, or they may have acquired resistance. As a consequence, antimicrobial use selects for the emergence of resistant strains of organisms then proliferate and become predominant (McGowan 1985). A number of studies have identified the direct relationship between antimicrobial uses, whether it's appropriate or inappropriate, and antimicrobial resistance. A major association was found between macrolide consumption and macrolide resistance rates for group A  Streptococcus in Finland (Seppala et al 1997). In the United States, similar associations were identified for macrolide use and resistance in S. pneumoniae (Hyde et al 1997).

In health care settings, an increased use of fluoroquinolones is linked with a significant incidence of ciprofloxacin resistance in gram-negative bacilli (Neuhauser et al (2003). Prior exposure to antimicrobials has been recognized as a considerable risk factor for subsequent acquisition of an antibiotic-resistant organism. The acquisition of vancomycin-resistant enterococci and organisms that produce extended-spectrum ß-lactamases have been connected with the prior exposure to broad spectrum cephalosporins (Paterson et al 2004).The relationship between resistance and antimicrobial use is intricate.

In one study involving 8 hospitals in the United States, it was discovered that the high intensity use of antimicrobials was not necessarily related to high rates of resistance (Monnet et al 1998). Furthermore, different health care settings and individual risk factors for antibiotic resistance may be different, in particular with regards to antimicrobial exposure. In an analysis of individual and aggregated data on antibiotic exposure and resistance, different results were obtained with facility-level and individual patient level analysis (Harbarth et al 2001).

In the facility wide analysis, there was no apparent relation between intensity of antibiotic use and rate of resistance. But when the same data was analysed at the individual patient level, there was a significant associations between antibiotic exposure and resistance (Harbarth et al 2001).

In the health care settings, bacterial resistance to antimicrobial agents can be spread from patient to patient, usually by contamination of the health care professional hands, contaminated equipment or the innate environment. This type of spread is referred to as clonal, involving the transmission of a single strain of the antibiotic resistant organism. This has been commonly reported for been reported for Methicillin-resistant  Staphylococcus aureus (MRSA), Vancomycin-resistant enterococci, C. difficile and multi drug resistant gram-negative bacilli (Loo et al 2005).

MRSA is one of the commonly identified pathogens resistant to antibiotics in the health care setting (Grundmann et al 2006). Older patients with co morbidities in the hospital or long term settings were considered a primary nosocomial pathogen. However, in recent year's, community acquired MRSA, which also includes a small number of unique MRSA strains has emerged (Gilbert et al 2006). Patients with community acquired MRSA; often do not have any health care related risk factors. They are often linked with skin and soft tissue infections. Community acquired MRSA has been associated with hospital acquired bacteraemia and surgical site infections (Otter et al 2006). 

Multi drug resistance in gram-negative bacilli is usually defined as resistance to more than two classes of antimicrobial agents (Mulvey et al 2009). Multidrug-resistant gram-negative bacteria are typically resistance to penicillin's, cephalosporins, fluoroquinolones, trimethoprim-sulfamethoxazole and aminoglycosides (Mulvey et al 2009).  Acinetobacter baumannii is a nosocomial pathogen normally acquired in intensive care. The pathogen normally causes infections of the unrinary tract, respiratory system, bloodstream and wounds. It is commonly resistant to many classes of antimicrobials, leaving carbapenems and possible glycylcyclines as the only effective drugs.

However the surfacing of carbapenem-resistant A. baumannii thoughout the world very alarming and poses a threat to the successful management of these infections (Maragakis et al 2008). To manage antibiotic resistances guides for prescribing have been produced (Gonzales et al 2001) and pharmacodynamic concepts have been developed to maximise therapeutic response, prevent the emergence of resistance and minimise adverse events (Preston et al 1998).

Conversely, to date interventions have been vague and ultimately arrive at the notion of "using antibiotics wisely" to resolve the problem (Burke 2003). Prudent prescribing of antibiotics to reduce the risk of further infections, like C. difficile, and the need for narrow spectrum antibiotics results in it being not financially viable for pharmaceutical companies (Finch et al 2006). Postgate (2000) appears to be optimistic in the development of next generation antibiotics, that will control the resistant microbes given the financial investment required.

Vaccines have been shown to be invaluable in controlling and eliminating a number of infections. This has also shown to have an impact on the age groups that are not being vaccinated. When children were given the pneumococcal vaccine there was also a reduction in  the infection rates in older age groups and an associated reduction in macrolide resistance was discovered (Stephens et al 2005).

 The burden of antimicrobial resistance continues to increase and is accepted to be a major risk to the treatment of infectious diseases. The resistance rates are varied around the world; this may be related to differences in infection control prevention and control practices, antimicrobial use or diagnostic procedures. It also remains uncertain about how specofoc mechanisms or resistance may lead to the identification of novel targets for mew antimicrobial drug development.

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