wards. Antibiotic resistant organisms are more difficult to treat and there are increasing numbers of bacterial species for which there are no or few therapeutic choices.
Transmission of resistance determinants between bacteria
Transformation
Many bacterial species incorporate naked DNA into their genome, a process called transformation. For example, Streptococcus pneumoniae and Neisseria gonorrhoeae incorporate small sections of penicillin‐binding protein genes from closely related species to produce a penicillin‐binding protein that binds penicillin less avidly, so becoming more resistant. Such organisms are still able to synthesize peptidoglycan and maintain their cell walls in the presence of penicillin.
Conjugation
Bacteria contain plasmids, circular DNA structures that are found in the cytoplasm. Genes carried on plasmids encode metabolic enzymes, virulence determinants and antibiotic resistance properties. Plasmids can pass from one bacterium to another by conjugation allowing resistance to spread rapidly in bacterial populations in the same environment (e.g. the intestine). Antibiotic prescription in enclosed populations (e.g. in hospitals) may allow significant resistant populations to develop.
Transposons and integrons
Transposons and integrons are mobile genetic elements able to encode transposition and move between the chromosome and plasmids, and between bacteria. Many functions, including antibiotic resistance, can be encoded. Resistance to methicillin among Staphylococcus aureus and to tetracycline among N. gonorrhoeae probably entered the species by this route. Integrons are important in transmission of multiple drug resistance in Gram‐negative pathogens. Resistance genes can also be mobilized by bacteriophages (viruses that live in bacteria).
Multiple resistance
Multiple resistance can develop on mobile genetic elements because once a gene is established on the element, it can readily acquire resistance to another agent by one of the mechanisms above. Once there is more than one resistance gene, exposure to any of these agents will permit survival of the resistance encoding element with the risk that further resistance will be acquired.
Mechanisms of resistance
Antibiotic modification
Enzyme inactivation
Many antibiotics are degraded by bacterial enzymes. Many S. aureus strains make a β‐lactamase that breaks the penicillin β‐lactam ring inactivating it. In the face of newer β‐lactam antibiotics, many human pathogens have acquired a range of genes that encode broad‐spectrum β‐lactamases; these include Escherichia coli, Haemophilus influenzae and Pseudomonas spp.
Enzyme addition
Some bacteria become resistant by adding an inactivating chemical group. Aminoglycoside resistance develops by adding an acetyl, amino or adenosine group to the antibiotic molecule. Different aminoglycosides differ in their susceptibility to this modification, amikacin being the least susceptible. Aminoglycoside‐resistance enzymes are found in Gram‐positive organisms (e.g. S. aureus) and Gram‐negative organisms (e.g. Pseudomonas spp).
Impermeability
Some bacteria are naturally resistant to antibiotics because their cell envelope is impermeable to that particular antibiotic (e.g. Pseudomonas spp. are impermeable to some β‐lactam antibiotics). Aminoglycosides enter bacteria by an oxygen‐dependent transport mechanism and so have little effect against anaerobic organisms. Other bacteria may lose a porin protein, so creating a permeability barrier that stops antibiotics from entering the cell.
Efflux mechanisms
Bacteria, for example E. coli or streptococci, may become resistant to tetracyclines, macrolides or fluoroquinolones by the acquisition of an inner membrane protein that actively pumps the antibiotic out of the cell – an efflux pump. Over‐expression of naturally occurring pumps may cause resistance to multiple drugs (multi‐drug efflux pumps).
Alternative pathway
Bacteria may acquire genes that create an alternative pathway that can circumvent the metabolic block imposed by an antibiotic. S. aureus becomes resistant to methicillin or flucloxacillin when it acquires the gene mecA, which encodes an alternative penicillin‐binding protein (PBP2′) that is not inhibited by methicillin. Although the composition of its cell wall is altered, the organism is still able to multiply.
Alteration of the target site
Rifampicin acts by inhibiting the β‐subunit of RNA polymerase. Resistance develops when the RNA polymerase gene is altered by point mutations, insertions or deletions. The new RNA polymerase is not as easily inhibited by rifampicin and resistance occurs. Similarly, an alteration of the binding sites on DNA gyrase (the target of fluoroquinolones) can make an organism resistant. The genes responsible for these effects are often found in a small region of the target gene, for example in the rifampicin resistance‐determining region (RRDR).
Impact of prescribing
There is a link between antibiotic prescribing and the risk of resistance. Exposure to antibiotics not only favours the emergence of resistance through mutation, it gives resistant organisms a selective advantage. It is important, therefore, to manage antibiotic use at a local, national and international level (see Chapter 8).
10 Sources and transmission of infection
Sources of infection
Infection is caused either by organisms from the host’s normal flora (endogenous infection) or by organisms transmitted from another source (exogenous infection).
Endogenous infection
The normal flora will only invade if circumstances facilitate it, as in some of the following examples.
Enterobacteriaceae and non‐sporing anaerobes such as Bacteroides fragilis can invade the peritoneal cavity causing peritonitis and septicaemia following bowel perforation.
Inhalation of stomach contents may cause aspiration pneumonia, possibly followed by a lung abscess.
Staphylococcus aureus that is normally found in the nose may cause wound infection if inoculated into a surgical wound.
Neutropenic patients are especially prone to infection from organisms normally held in check by the body’s defenses and gut; neutropenia or damage by chemotherapy, radiotherapy can allow
