Chapter 15 Drug treatment of infections
After reading this chapter, you should be able to:
INTRODUCTION
Many bacteria have mutual relationships with humans, with both species benefiting in some way from their coexistence, for example many of the bacteria that live in the human gastrointestinal tract. These bacteria feed on nutrients from ingested food and in return carry out tasks such as producing enzymes involved in the breakdown of complex nutrients.
There are, however, bacteria that cause harm to humans, and these organisms are known as pathogens. Even some normally benign bacteria can cause harm to the human host in certain circumstances, for example when the host resistance is in some way compromised. This phenomenon is known as opportunism and the resulting infection as opportunistic infection.
The resistance of bacteria to antibiotics (p. 293) is increasingly becoming a very significant problem. The cost of resistance is measured not only in terms of failure of therapy but also in the increased costs of more expensive drugs needed to combat the resistant bacteria. In 1994, the World Health Organization Scientific Working Group on the Monitoring and Management of Bacterial Resistance to Antimicrobial Agents (Tenover and Hughes 1995) discouraged the unnecessary use of antibiotic prophylaxis in food animals and stated that ‘antimicrobial agents should not be used as a substitute for adequate hygiene in animal husbandry’.
Many conditions for which antibiotics are prescribed are either of a self-limiting nature or are viral in origin and, as such, do not require antibiotics. The causes of this inappropriate prescribing by clinicians include insufficient training or knowledge, difficulty in selection of the appropriate drug, lack of microbiological information, fear of litigation and patients’ expectations (Binyon and Cooke 2000).
HEALTHCARE-ASSOCIATED INFECTIONS
Approximately 9% of patients in UK hospitals suffer from an infection acquired during their hospital stay (Crowcroft and Catchpole 2002), many of which are due to multiresistant, Gram-positive and Gram-negative pathogens. The incidence of colonisation and infection with these pathogens continues to rise due to failures in hospital hygiene and selective pressures created by overuse of antibiotics.
Infection with these resistant pathogens can adversely affect clinical, microbiological and economic outcomes (Cosgrove and Carmeli 2003), and the costs associated with managing infections are considerable. In the UK, it has been estimated that costs increase threefold when hospital patients present with one or more healthcare-associated infections during an inpatient stay (Plowman 2000).
TREATMENT OF INFECTIONS
The discovery of sulphonamides in the 1930s, followed by penicillin in the 1940s, heralded a new era in the treatment of infections. Since then, a large number of drugs have been produced that either kill or inhibit the growth of bacteria, fungi or viruses. These drugs, in tandem with the patient’s natural immunity, have cured many infectious diseases that previously often proved fatal. It should be noted that when immunity is impaired due to prolonged illness, old age or the use of cytotoxic drugs, infections are more difficult to eradicate. As organisms become resistant to chemotherapy, a continuing search is necessary for new drugs and modifications of those already in use.
CLASSIFICATION OF BACTERIA
Bacteria can be broadly classified according to cell shape (Fig. 15.1), that is:

Fig. 15.1 Bacteria: examples of cell shapes. (A) Cocci (spherical bacteria): 1, staphylococci; 2, streptococci; 3, diplococci. (B) 1–3, Bacilli. (C) 1, 2, Spirochaetes. (D) Actinomyces.
Subdivision of these categories is based on the Gram stain. This staining technique was developed by Christian Gram in 1884. A heat-fixed smear of bacteria undergoes a staining and counterstaining process. Gram-positive cells retain the deep purple conferred on them by the initial staining with crystal violet and iodine, whereas Gram-negative cells, which have been decolorised, exhibit the red colour of the counterstain. As a result, Gram-positive and Gram-negative cells can be readily distinguished under the microscope.
Micro-organisms are also classified as aerobes (those that can live and grow in the presence of oxygen) or as anaerobes (those that can live and grow without oxygen). These three factors:
can be used in the classification of infectious bacteria (Table 15.1).
MICROBIOLOGY
Serious infections can be life-threatening, and decisions require to be made on the most appropriate therapy. For example:
Table 15.2 Causative pathogens in some common bacterial infections
Infection(s) | Bacterium or bacteria responsible |
---|---|
Respiratory infections | |
Exacerbation of chronic bronchitis | Haemophilus influenzae |
Streptococcus pneumoniae | |
Pneumonia | Streptococcus pneumoniae |
Staphylococcus aureus | |
Haemophilus influenzae | |
Urinary tract infections | Escherichia coli |
Proteus spp. | |
Klebsiella spp. | |
Streptococcus faecalis | |
Pseudomonas | |
Venereal disease | |
Gonorrhoea | Neisseria gonorrhoeae |
Non-specific urethritis | Chlamydia |
Skin/soft tissue infections | |
Intravenous catheter site | Staphylococcus aureus |
Staphylococcus epidermidis | |
Surgical wound | Staphylococcus aureus |
Gram-negative rods | |
Furuncle | Staphylococcus aureus |
Endocarditis | |
Acute | Staphylococcus aureus |
Streptococcus pyogenes | |
Gram-negative bacilli | |
Subacute | Streptococcus spp. |
Staphylococcus epidermidis | |
Gram-negative bacilli | |
Septicaemia | Staphylococcus aureus |
Streptococcus pneumoniae | |
Coliforms | |
Enterobacter spp. | |
Meningitis (in adults; many organisms may cause meningitis in neonates) | Streptococcus pneumoniae |
Neisseria meningitides | |
Food poisoning | Salmonellae |
Clostridium perfringens |
Other factors affecting the choice of antibiotic include:
It is advisable to obtain specimens for microbiological investigation before antimicrobial therapy is initiated, so that the antibiotic therapy can be reassessed or started after the organism is identified. Conventional laboratory techniques for identification require at least 18 h of incubation in appropriate media to allow detectable numbers of bacteria to grow. However, more rapid techniques help in diagnosis before culture results are available. The most valuable is a Gram-stained smear of blood or aspirate from the site of infection.
An identification of organisms from culture is followed by sensitivity tests. Filter paper discs impregnated with known concentrations of antibiotic are placed on to an agar culture plate containing the individual strain of organism isolated in the culture process. The degree of sensitivity of the organism to the antibiotic is assessed by the size of inhibition zones around the discs after further incubation. Results are reported back to the prescriber, indicating antibiotics effective in treatment.
ANTIBACTERIAL DRUGS
Antibacterial drugs act by a number of mechanisms (Fig. 15.2). They can be either bactericidal (kill bacteria) or bacteriostatic (arrest the growth of bacteria) (Box 15.1). Bacteriostatic agents, because they do not kill bacteria, rely on the host’s immune and cell defence mechanisms to clear the bacteria. If these defence mechanisms are compromised, a bactericidal drug may be preferable.
MINIMUM INHIBITORY CONCENTRATION OF ANTIBIOTICS
As a guide to the sensitivity of a specific micro-organism to an antibiotic, the minimum inhibitory concentration (MIC) is utilised. This is the lowest concentration of antibiotic that will inhibit the growth of a given strain of micro-organism under controlled conditions. The lower the concentration, the more potent the antibiotic. However, the MIC is determined in laboratory conditions. In vivo, the drug may have to pass from the plasma into infected tissue to destroy bacteria. The penetration of antibiotics into abscess cavities may be poor, and surgical drainage is often necessary. In either case, higher doses would be required to achieve the MIC.
Minimum bactericidal concentration is the lowest concentration of antibiotic that will kill a given strain of bacterium under controlled conditions.
CONTROL OF ANTIBIOTIC USAGE
Because the rates of resistance are proportional to antibiotic use, the unnecessary use of antibiotics contributes to the spread of resistance. Most hospitals have adopted antibiotic policies and guidelines that are aimed at reducing the induction of resistance through controlling the range and use of anti-infective agents. Good antibiotic prescribing requires information about the probable cause and the antibiotic susceptibility of the infective agent. This can be obtained by taking appropriate specimens for culture and prescribing according to the results.
GENERAL PRINCIPLES
The objective of drug therapy in the treatment of infectious disease is to assist the body in overcoming the infecting organism. This is accomplished by the use of an anti-infective agent that is toxic to the causative organism while the normal biochemical functions of the patient are not seriously impaired.
When selecting the anti-infective agent, con-sideration must be given to the dose, route and fre-quency of administration. The dosage regimen for antibiotics excreted primarily by the kidneys will be decided according to the type of infection to be treated and the toxicity of the drug. The dose of antibiotics with a narrow therapeutic spectrum, such as the aminoglycosides, requires to be titrated according to the serum concentration. This is in order to maintain an effective therapeutic level but avoid toxic effects due to too high a level. Where renal dysfunction is present, which results in a longer half-life, dosage schedules should be lowered accordingly to prevent toxicity.
ROUTE OF ADMINISTRATION
If the infection is severe, the general condition of the patient may be poor. Oral absorption may therefore be ineffective due to nausea, vomiting or gastric stasis. In these instances, antibiotics are commonly administered by injection. After the infection is under control, appropriate concentrations will be maintained by the oral route, as this is more cost-effective and easier to administer.
Many antibiotic injections are presented as a sterile powder requiring reconstitution prior to administration. The nurse should refer to the manufacturer’s product insert and to local policies in order to reconstitute the drug with correct diluent and the correct volume. Strict aseptic technique should be followed. It is advisable to discard any remaining solution after the dose has been withdrawn to avoid possible contamination or deterioration of the remaining solution.
ROUTINE PROPHYLAXIS
Routine antibiotic prophylaxis in surgical patients is needed only for those procedures associated with a high risk of postoperative infection (e.g. vaginal or colorectal surgery) or prosthetic insertions. Normally, prophylactic antibiotic treatment should not be extended beyond 48 h following surgery and should be given parenterally. Intravenous administration during induction, or intramuscular administration 30 min before surgery, usually ensures effective blood levels of antibiotic at the time when anticipated bacteraemia is likely to be highest. When gastrointestinal function is unimpaired during the postoperative period, oral administration of antibiotics provides an optimum non-invasive approach.
ALLERGIC RESPONSES
An accurate history of previous allergies is essential before antibiotics are administered. This applies particularly to penicillins with which anaphylactic shock occasionally occurs. Patients with a history of asthma, hay fever and eczema are more likely to experience severe reactions to penicillins. Some 10% of patients allergic to penicillins will also be allergic to cephalosporins. If patients are not allergic to penicillins, they are usually safe drugs.
MONITORING THE PATIENT’S RESPONSE
The patient’s response to antibiotic therapy is monitored with regard to:
Specific toxic effects of antibiotics should be noted, for example hearing or renal impairment in patients receiving aminoglycosides (e.g. gentamicin). Phlebitis can occur on intravenous administration, and the nurse should monitor the patient’s veins carefully for evidence of redness, swelling or pain, and report these to the doctor. When blood samples are taken, the doctor should ensure that times are recorded accurately so that maximum and minimum drug concentrations during the dosing interval can be accurately estimated.
SUPERINFECTION
Superinfection may occur as a result of the following.
BACTERIAL RESISTANCE TO ANTIBIOTICS
The resistance of bacteria to antibiotics is a problem that has continued to grow in parallel with the development of new antibiotics. Bacterial resistance reflects antibiotic use and is more of a problem when controls on antibiotic use are lax. The sensible use of antibiotics reduces this. There are several mechanisms by which resistance may emerge.
SELECTION
An antibiotic will eliminate the sensitive organisms within a bacterial population, and the resistant forms will proliferate.
MUTATION
Resistance to an antibiotic may develop as a result of a genetic change that converts a previously susceptible bacterium to a resistant one. This genetic change may be as a result of spontaneous randomly occurring gene mutation during the process of cell division. These mutants will then proliferate.
TRANSFERRED RESISTANCE
Resistance may be acquired by the exchange of genetic material between bacteria, which confers antibiotic resistance from one organism to another. Exchange of genetic material occurs primarily by the exchange of fragments of DNA known as plasmids. If these plasmids contain resistant genes, the genes are passed between bacteria conferring a survival advantage and promoting proliferation of resistant bacteria. This ability to share resistant genes has led to the rapid proliferation of bacterial resistance.
Transfer of plasmids is not confined to the same species, and they can be passed from, for example, Escherichia coli to Salmonella. Either way, new DNA enters the bacterium and codes for a mechanism that confers resistance. The real dilemma facing clinicians lies in the fact that many bacterial strains are resistant to multiple antibiotics, a phenomenon known as multiple resistance.
There are several mechanisms of antibiotic resistance.
The general spread of antibiotic resistance is most likely to occur in an environment in which there is a significant use of antibiotics and the opportunity to move from one host to another exists. In an environment where little use is made of antibiotics, there will be no selective advantage for the resistant bacteria. When antibiotics are used in low dose, there will be greater opportunity for resistance to develop and spread because strains will survive at low dose that would have been eliminated at a higher dose. An example of this is the huge increase in the level of resistance in Salmonella due to the use of low-dose antibiotics as growth enhancers in farm animals.
METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS
Approximately 30% of the population carry the organism Staphylococcus aureus. This is a bacterium that is normally found in the nose and on skin. Although most healthy people are unaffected by it, it does have the potential to cause infection in those who have severely weakened immune systems (e.g. some ill patients in hospital).
Methicillin-resistant Staphylococcus aureus (MRSA) is a form of Staphylococcus aureus. It is transmitted in the same way and causes the same range of infections as other strains of Staphylococcus aureus. However, it has developed resistance to the more commonly used antibiotics. This makes infections caused by MRSA more difficult and costly to treat, and every effort should be made to prevent its spread.
The majority of individuals are colonised when the organism lives harmlessly on the body with no ill effects, as opposed to infected, which is when the organism penetrates tissue and causes disease.
In order to control and minimise the spread of MRSA, there must be compliance with the following:
TREATMENT OF MRSA INFECTION
Patients who demonstrate clinical signs of infection will require treatment with the appropriate antibiotics. The agent used will depend on the site of infection (Table 15.3). Some of these organisms are sensitive only to vancomycin or teicoplanin. Strains may be susceptible to rifampicin, sodium fusidate, tetra-cyclines, aminoglycosides and macrolides. Treatment is guided by the sensitivity of the infecting strain. Swabs are taken from the nose and throat to establish a diagnosis (Figs 15.3 and 15.4).
Site | Treatment |
---|---|
Nasal carriage only | Nasal decolonisation only |
Throat carriage | Nasal and throat decolonisation |
Axilla or groin carriage | Nasal and body decolonisation |
Nasal decolonisation
Nasal carriage treatment is to apply, with a cotton bud, mupirocin 2% nasal ointment three times daily to the inner surface of each nostril for 5 days. When mupirocin resistance is encountered, second-line treatment is with neomycin and chlorhexidine cream (Naseptin) provided that the organism is neomycin-susceptible.
Throat decolonisation
Oral hygiene is very important, as teeth and dentures may harbour MRSA. First-line treatment is oral trimethoprim (200 mg twice daily) and sodium fusidate tablets (500 mg three times daily) for 5 days. In the event of resistance or patient intolerance, an alternative is a combination of oral rifampicin (600 mg once daily) and trimethoprim 200 mg twice daily for 5 days. Rifampicin or sodium fusidate should not be used alone, because resistance may develop rapidly.
Skin decolonisation
Treatment consists of a direct application of 4% chlorhexidine to all skin using a damp disposable cloth daily for 5 days, using the chlorhexidine as a soap substitute and then rinsing it off. The hair should be washed twice during the 5-day period with 4% chlorhexidine. Alternatively, 2% triclosan or 7.5% povidone–iodine could be used. Hair conditioners and body lotions can be used after treatment if required.
Linezolid and quinupristin with dalfopristin
Linezolid and the combination of quinupristin and dalfopristin are active against MRSA, but these antibacterial drugs should be reserved for organisms resistant to other antibacterials or for patients who cannot tolerate other antibacterial drugs. Linezolid is available both orally (600 mg every 12 h) and by intravenous infusion. Thrombocytopenia, anaemia, leucopenia and pancytopenia have been reported, and weekly monitoring of full blood counts is recommended. Quinupristin with dalfopristin is available as an intravenous infusion. A novel broad-spectrum glycycline antibiotic (tigecycline) is active against Gram-positive, Gram-negative and anaerobic organisms including multidrug-resistant strains (see p. 301).
THE PENICILLINS
The penicillins are bactericidal and interfere with cell wall synthesis in growing and dividing bacteria. Lysis and cell death result from weakening of the cell wall. Penicillins are excreted in the urine in therapeutic concentrations.
The most significant and adverse effect of the penicillins is hypersensitivity, which manifests as rashes and, on occasion, anaphylaxis. Allergy to one penicillin indicates allergy to them all, because the hypersensitivity is related to the basic penicillin structure.
Excessively high serum levels due to either very high doses or to renal failure in patients given normal doses may give rise to encephalopathy, a rare but serious toxic effect due to cerebral irritation. The penicillins should not be given by intrathecal injection, as this can cause encephalopathy, which may be fatal. A second problem is accumulation of electrolyte, because most injectable penicillins contain either sodium or potassium.
Diarrhoea often occurs during oral penicillin therapy.
BENZYLPENICILLIN AND PHENOXYMETHYLPENICILLIN
Benzylpenicillin (penicillin G) is readily inactivated by gastric acid juice and is given by injection. It diffuses into most of the body tissues but does not pass the blood–brain barrier unless the meninges are inflamed; neither does it penetrate well into the pleural cavity nor into the synovial or ocular fluids. It is inactivated by bacterial beta-lactamases. Beta-Lactamases are enzymes that inactivate penicillin by attacking part of the penicillin molecule known as the beta-lactam ring. This structure is an essential part of penicillins and cephalosporins. Notable producers of beta-lactamases are staphylococci.
Benzylpenicillin is effective in a wide range of infections, including those shown in Table 15.4.
Table 15.4 Infections for which benzylpenicillin is effective
Organism | Disease |
---|---|
Beta-haemolytic streptococci | Septicaemia, tonsillitis |
Viridans streptococci | Subacute bacterial endocarditis |
Streptococcus pneumoniae | Pneumonia |
Neisseria meningitidis | Meningococcal meningitis |
Clostridium tetani | Tetanus |
Clostridium perfringens | Gas gangrene |
Treponema pallidum | Syphilis |
Neisseria gonorrhoeae | Gonorrhoea |
Borrelia burgdorferi | Lyme disease |
Phenoxymethylpenicillin (penicillin V) has a similar but less active antibacterial spectrum. It is indicated principally for respiratory infections in children, streptococcal tonsillitis and continued treatment following benzylpenicillin injection. It is used as a prophylactic against reinfection after recovery from rheumatic fever. Phenoxymethylpenicillin is not destroyed in the stomach and is quickly but unpredictably absorbed from the small intestine. Absorption is superior when administered on an empty stomach. Phenoxymethylpenicillin is not suitable for the treatment of severe conditions in which high blood levels of penicillin are necessary.
The dose range and side effects of benzylpenicillin and phenoxymethylpenicillin are shown in Table 15.5.
PENICILLINASE-RESISTANT PENICILLINS
Some organisms are resistant to penicillin because of their ability to produce the enzyme penicillinase, which destroys penicillin. Flucloxacillin is available for treatment of staphylococcal infections when resistant organisms are particularly common (see Table 15.6). Flucloxacillin is available in oral as well as injectable form and is well absorbed.
Table 15.6 Penicillinase-resistant penicillin
Drug | Adult dose range | Notes |
---|---|---|
Flucloxacillin | Oral: 250 mg 6-hourly at least 30 min before food. | Side-effects as for benzylpenicillin; doses can be doubled in severe infections |
IM: 250 mg 6-hourly. | ||
Slow IV injection or infusion: 0.25–1 g every 6 h. |
BROAD-SPECTRUM PENICILLINS
This group includes ampicillin and amoxicillin. The main difference between ampicillin and amoxicillin is in absorption from the gut. Less than half the dose of ampicillin is absorbed from the gut, and this is decreased by the presence of food. About 40% passes into the large bowel and diarrhoea, a common side-effect, is thought to be caused by a disturbance of the large bowel flora. Amoxicillin is better absorbed, producing higher plasma and tissue concentrations, absorption not being affected by the presence of food in the stomach. Both of these drugs are inactivated by b-lactamases, including those produced by almost all staphylococci, 50% of Escherichia coli strains and 15% of Haemophilus influenzae strains. They should not be used for hospital patients without checking sensitivity.
Co-amoxiclav is a combination of amoxicillin and beta-lactamase inhibitor, clavulanic acid. The clavulanate molecules penetrate the bacterial cell and combine with the beta-lactamase molecules. This inactivates the beta-lactamases, leaving the amoxicillin free to exert a full bactericidal effect. This makes the combination active against beta-lactamase-producing bacteria that are resistant to amoxicillin: Staphylococcus aureus, Escherichia coli and Haemophilus influenzae, as well as many Bacteroides and Klebsiella species. The broad-spectrum penicillins are summarised in Table 15.7.

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