In an environment containing vast numbers of micro-organisms saturated with or repeatedly exposed to antibiotics, Darwinian theory predicts the inevitable selection of resistant organisms. Following the introduction of a new antibiotic, resistant strains may be reported within as little as 1 year, and after a latent interval of some years,resistance increases dramatically and the value of the antibiotic for empirical therapy is reduced. Staphylococcus aureus is now almost universally resistant to penicillin – a phenomenon first observed in hospital outbreaks of surgical sepsis in the late 1940s. This organism has shown a remarkable facility to become resistant to every antibiotic introduced, even vancomycin. Reduced sensitivity tovancomycin (vancomycin-intermediate S. aureus) is associated with a thick peptidoglycan cell wall. The complex gene cassette for vancomycin resistance in Enterococcus spp. (vanA) can easily be transferred to S. aureus in vitro and has now been detected in methicillinresistant S. aureus (MRSA), making the organism fully resistant to glycopeptides. It is only a matter of time before strains are seenthat are sensitive to only a small number of novel antibiotics in development and perhaps some of the older antibiotics (e.g. tetracycline, chloramphenicol). In contrast, some organisms have not yet acquired resistance despite huge pressures; these include Streptococcus pyogenes, Gram-positive anaerobes such as Clostridium spp. and Peptostreptococcus spp. and Neisseria meningitidis (to penicillin).Almost all anaerobes were considered to be sensitive to metronidazole until recent reports from Spain, France and the USA suggested that resistant Bacteroides fragilis will soon become a serious problem.
and depends on the ease with which a resistance mechanism can arise. Novel resistance is usually detected in different places in the world at about the same time, implying that antibioticpressures are similar worldwide and that bacteria have limited means of dealing with the problem of survival. Following the appearance of one mutant resistant progeny, rapidly replicating bacteria can recolonize carrier sites in less than 24 hours. A resistant mutant of Mycobacterium tuberculosis, which replicates once every 24 hours, can recolonize diseased lung within 2 weeks. Once resistance has beenselected, organisms transferred from person to person continue to be resistant. When the antibiotic pressure is removed, novel colonizing and infecting flora tend to revert to the sensitive phenotype. Some bacteria containing large resistance plasmids are considered unfit and seem to disappear from the clinical environment more easily than others.
Resistance and choice of antibiotics
The term‘antibiotic resistance’ implies that a particular antibiotic is ineffective in a clinical infection. This may be because the organism is inherently resistant to the antibiotic or because it is inaccessible. In vitro, resistance is defined by measuring the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the antibiotic against an organism, under ideallaboratory conditions, using appropriate controls to define the cut-off points between ‘resistant’, ‘intermediate’ and ‘sensitive’. Methods of testing in the laboratory are problematic, however, and any result that does not correlate with clinical experience should be challenged. Low MIC and high MBC imply that an antibiotic is bacteristatic; that is, it inhibits the growth of an organism but isunable to kill it. Even with bactericidal antibiotics, killing in vivo normally requires an intact immune system. Thus, though bacteristatic antibiotics are ineffective in neutropenic sepsis, bactericidal antibiotics may suppress infection only for it to recrudesce when the antibiotic is removed. This observation governs strategies for the management of such infections. Paradoxically, even when an...