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Antimicrobial chemotherapy 

Antimicrobial chemotherapy

Chapter:
Antimicrobial chemotherapy
Author(s):

R.G. Finch

DOI:
10.1093/med/9780199204854.003.070205_update_001

Update:

Addition of new treatments for HCV and HIV; addition of echinocandins; update on antimalarials; novel antituberculosis agents; emergence of drug-resistant organisms, e.g. XDR TB, VISA, and VRSA.

Updated on 31 May 2012. The previous version of this content can be found here.
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date: 29 April 2017

The practice of medicine changed dramatically with the availability of effective antimicrobial agents. Fatal diseases such as bacterial meningitis and endocarditis became treatable; much minor community infectious morbidity became readily controlled; many surgical procedures became much safer, and developments in solid organ and bone marrow transplantation became possible. However, the very success of antimicrobial chemotherapy has led to overuse, misuse and inappropriate pressures from the public to prescribe. In many countries, antibiotics are freely available to the public for purchase ‘over the counter’, with few controls or guidance to ensure their safe and effective use. The emergence and spread of antimicrobial resistance worldwide and the decline in development and licensing of new antimicrobials threaten the future successful treatment of bacterial infections.

Antimicrobial drugs

Pharmacological characteristics and antimicrobial spectrum—antibacterial drugs can be divided according to their mode of action into those that (1) inhibit cell wall synthesis—e.g. penicillins and cephalosporins; (2) interfere with protein synthesis—e.g. tetracyclines, aminoglycosides; (3) inhibit bacterial nucleic acid synthesis—e.g. fluoroquinolones; and (4) act on metabolic pathways—e.g. sulphonamides and trimethoprin. The antimicrobial spectrum of a drug is determined by the mode of action and ability to reach the relevant target site. Antibiotics active against a few particular bacteria are considered narrow spectrum (e.g. vancomycin), while others are active against many bacteria and are labelled broad spectrum (e.g. meropenem). Some antimicrobials are only active against anaerobically dividing bacteria (e.g. metronidazole).

Clinical effectiveness—to be effective clinically, sufficient drug must reach the infection site. The pharmacokinetic characteristics of absorption, distribution, metabolism and excretion are critical to defining dose, efficacy and often safety. Poorly absorbed agents are often administered parenterally, some topically. Hydrophobicity and hydrophilicity are important in defining tissue and extracellular fluid concentrations, as are factors such as molecular size and pH. Highly protein-bound drugs such as flucloxacillin may achieve lower tissue concentrations in selected body sites.

Excretion, metabolism and drug monitoring—many drugs are metabolically degraded in the liver and/or excreted by the kidney via glomerular filtration or tubular secretion. It should therefore be anticipated that dose modification may be necessary to avoid toxicity in patients with compromised hepatic or renal function. Therapeutic drug monitoring is important in ensuring therapeutic and nontoxic concentrations of some drugs, e.g. gentamicin and vancomycin.

Antiviral, antifungal, and antiparasitic drugs—the availability of drugs to treat herpesvirus infections (herpes simplex, varicella–zoster and cytomegalovirus), and the development of new drugs active against hepatitis viruses, influenza viruses, and HIV have revolutionized the treatment of viral infections. Advances in the management of invasive fungal disease have been slower: the reliance on polyenes, e.g. amphotericin, has only recently been eclipsed with the availability of potent azoles and triazoles and echinocandins. In the case of many parasitic diseases, advances have been extremely slow, but the importance of malaria has led to new compounds being developed (e.g. the artemisin derivatives), also new ways of using established drugs in combination.

Resistance to antimicrobial drugs

Resistance mechanisms—loss of efficacy through resistance mechanisms is unique to antimicrobial drugs. There are four main types: (1) drug inactivation or destruction, (2) target site alteration, (3) reduced cell wall permeability (porin mutation) or increased removal from the cell (efflux resistance); and (4) inhibition as a result of metabolic bypass. Individual drugs can be subject to one or more mechanisms of resistance, which may vary by infecting microorganism.

Spread of resistance—genetic mutations that confer resistance do not just affect the target pathogen in the treated individual. They can disseminate both horizontally and vertically as a result of person-to-person or indirect spread of the pathogen. Spread through genetic mechanisms via plasmids, transposons, integrons, and phages between bacteria of the same and different species are common, as is spread between genera. Likewise, resistance mechanisms can spread to organisms making up the normal flora of the gut and skin.

Clinical impact—antibiotic resistance is of increasing medical and public concern, and affects all aspects of medicine. Infections become unresponsive to initial therapy, sometimes with fatal consequences in the seriously ill. In others, reassessment and alternative therapy with agents are often more toxic and more expensive are required, leading to increased morbidity and increased costs through prolonged hospitalization. The spread of resistant pathogens within hospitals, nursing homes and the community is a very significant concern. High rates of meticillin-resistant Staphylococcus aureus (MRSA) infections are present in many countries, including the United States of America, the United Kingdom, and soutern Europe. Public confidence in health care has been eroded, leading to major government initiatives in the European Union, North America, and Australia in efforts to contain these resistant pathogens.

Prescribing of antimicrobial drugs

A set of principles has emerged to support safe and effective prescribing, covering issues of choice of drug, dose and route of administration, duration of therapy, strategies to minimize adverse reactions, and what factors need to be considered should initial treatment fail. The complexity of modern therapeutics has led to the development of formularies and practice guidelines, the latter increasingly being evidence based, with the twin goals of supporting cost-effective safe prescribing whilst minimizing the risks of emergence of antibiotic resistance.

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