Infections

INFECTIOUS diseases comprise a wide spectrum of illnesses caused by pathogenic microorganisms. Some common pathogens and their likely sites of infection in the body are listed in Table 43-1. These pathogens can cause pneumonia, urinary tract infections, upper respiratory tract infections, gastroenteritis, venereal disease, vaginitis, tuberculosis and candidiasis, to name but a few.

Table 43-1 Primary organisms and common sites of infection

Infection, the invasion and multiplication of pathogenic microorganisms in body tissues, causing disease by local cellular injury, secretion of a toxin or by antigen–antibody reaction in the host, is classified primarily as local or systemic. A localised infection involving the skin or internal organs may progress to a systemic infection. A systemic infection involves the whole body rather than a localised area of the body. Several terms describe the degree of local or systemic infection.

Colonisation is the localised presence of microorganisms in body tissues or organs; these microorganisms can be pathogenic or part of the normal flora. Colonisation alone is not necessarily an infection: it signifies the potential for infection, depending on the multiplication of the microorganisms or an alteration in the individual’s host defence mechanisms. When flora at their normal colonisation site are altered (e.g. by the administration of an antibiotic that affects pathogens and some but not all of the normal microorganisms), the unaffected microorganisms within that environment may grow in an uninhibited manner, causing a secondary infection.

Inflammation is a protective mechanism of body tissues in response to invasion or toxins produced by colonising microorganisms (see Chapter 47). This reaction consists of cytological and histological tissue responses for the localisation of phagocytic activity and destruction or removal of injurious material, leading to repair and healing.

Bacteraemia is the presence of viable bacteria in the circulatory system. Septicaemia refers to a systemic infection caused by microorganism multiplication in the circulation. Although bacteraemia can lead to septicaemia in an immunocompromised host, it is (depending on the pathogen) usually a short-lived, self-limited process. In an immunocompromised host, bacteraemia can rapidly produce an overwhelming systemic disease. Sepsis is a syndrome with multiple organ involvement that is a result of microorganisms or their toxins circulating in the blood.

For non-pathogenic organisms colonising humans or causing transient bacteraemia without tissue invasion, antibiotic therapy is rarely required in immunocompetent people, whereas prophylactic antibiotic therapy might be required in immunocompromised individuals. In most cases of localised inflammation, such as wound infections, pneumonia or urinary tract infections, antimicrobial drugs reduce the number of viable pathogens. This permits the immune system to eliminate microorganisms. Antimicrobial drugs are also an essential part of the treatment of septicaemia and sepsis.

Microorganisms are divided into several groups: bacteria, mycoplasma, spirochaetes, fungi and viruses. Bacteria are classified according to their shape, such as bacilli, spirilla and cocci, and their capacity to be stained. Specific identification of bacteria requires a Gram stain and culture with chemical testing. A Gram stain is a sequential procedure involving crystal violet and iodine solutions followed by alcohol that allows the rapid classification of organisms into groups such as Gram-positive or Gramnegative bacilli (rods) or cocci. The culture procedures identify specific organisms, but they require 24–48 hours for completion.

Often, antibiotic selection is empirical and is based on the prescriber’s clinical impression. Once culture and sensitivity results are available, the antibiotic might be changed. This is referred to as directed therapy.

Antibiotic pharmacodynamics

The goal of antimicrobial therapy is to destroy or suppress the growth of infecting microorganisms so that normal host defences and other supporting mechanisms can control the infection, resulting in a cure. With regard to antibiotics, pharmacodynamics relates the concentration of the antibiotic to its antimicrobial efficacy. This relationship is influenced by the drug’s pharmacokinetic profile; the latter includes absorption, distribution, metabolism and excretion. Ultimately the success of antimicrobial therapy depends on:

In pharmacokinetic terms this translates to:

The varying relationships between T, C_max, MIC and AUC_0-24 have been shown to correlate with antimicrobial efficacy, bacterial eradication and a reduction in the development of resistance. In simple terms antimicrobial drugs can display concentration-dependent kill characteristics and/or time-dependent effects. For example, depending on the bacteria a high ciprofloxacin C_max:MIC ratio (∼10) assists bacterial killing while a high AUC_0–24/ MIC (>125) predicts better clinical outcomes for infections caused by Gram-negative organisms. Similarly, aminoglycosides exhibit concentration-dependent kill characteristics and suboptimal dosing may lead to adaptive resistance because of reduced drug uptake by the bacteria. In contrast the β-lactam antibiotics exhibit time-dependent killing; that is, their efficacy is related to the time that the concentration of the β-lactam exceeds the MIC of the bacteria, that is, T > MIC. Current data suggest that for penicillin the plasma drug concentration should be above the MIC for ∼50% of the dosing interval, 60%–70% for cephalosporins and 40% for carbapenems (Drusano 2004). It is apparent that achieving the pharmacodynamic target for antibiotic exposure is essential for both clinical efficacy and for reducing the emergence of resistant microbial strains.

Mechanism of action

To exert its effects, an antimicrobial agent must first gain access to the target site. Specific antibiotics or antimicrobial agents in certain circumstances (e.g. changes in permeability of the blood–brain barrier with meningitis) are capable of penetrating the site of infection and exerting a pharmacological effect on the bacteria. Sometimes, as in the case of infections of the skin and eyes, local application to the infected area is necessary. Once the drug has reached its site of action, it can exert either bactericidal or bacteriostatic effects, depending on its mechanism of action.

Bacteriostatic agents inhibit bacterial growth, allowing intact and active host defence systems time to remove the invading microorganisms. Bactericidal agents, on the other hand, cause bacterial cell death and lysis and eradicate the infection, which is important especially in situations of impaired host defences. Antimicrobial agents can be divided into bacteriostatic and bactericidal categories; the sulfonamides are an example of the former and the penicillins of the latter. Such categorisation is not always valid or reliable because the same antimicrobial agent might have either effect depending on the dose administered and the concentration achieved at its site of action. Tetracycline, for example, is generally bacteriostatic but may be bactericidal in high concentrations. Chloramphenicol, which is often listed as a bacteriostatic drug, has bactericidal effects against Streptococcus pneumoniae and Haemophilus influenzae in the cerebrospinal fluid.

Antimicrobial agents exert their bacteriostatic or bactericidal effects in one of four major ways (see Chapter 44):

Mechanisms of antimicrobial drug resistance

Resistance can occur in one of several ways (Figure 43-1), for example:

Figure 43-1 Seven mechanisms of antibiotic resistance.

Combating antimicrobial drug resistance

Many resistant strains of bacteria exist in Australasia, and there are on-going problems with methicillin-resistant Staphylococcus aureus in outpatients and inpatients in Australia. In 1994, the first case of vancomycin-resistant Enterococcus faecium was reported in Melbourne. The appearance and spread of antimicrobial resistance is, however, not limited to bacteria. Resistance has now been reported among fungi, e.g. Candida albicans, and helminths (Geerts & Gryseels 2000). Of increasing importance worldwide is the emergence and spread of multi-drugresistant HIV-1 (Omrani & Pillay 2000) and Mycobacterium tuberculosis (Schluger 2000). The latter is of particular concern with evidence of multi-drug-resistant tuberculosis in provinces in China and countries of the former Soviet Union (Wright et al 2009).

The adverse consequences of increasing antimicrobial drug resistance will inevitably be increases in rates of hospitalisation, duration of hospital stay and rates of mortality. To assist in combating these problems cooperative relationships have developed between health professionals. Variously called antibiotic management programs, anti biotic vigilance programs and antibiotic management strategies, they are more frequently referred to as antimicrobial stewardship programs. These programs focus on:

Such programs require long-term commitment and a willingness to invest resources and a process of evaluation to determine their benefit.

Other strategies to combat antimicrobial drug resistance include:

Superinfection

Superinfection is an infection that occurs during antimicrobial therapy delivered for therapeutic or prophylactic reasons. Most antibiotics reduce or eradicate the normal microbial flora of the body, which are then replaced by resistant exogenous or endogenous bacteria. If the number of these replacement organisms is large and the host conditions favourable, clinical superinfection can occur.

Around 2% of people treated with antibiotics contract superinfections. The risk is greater when large doses of antibiotics are given, when more than one antibiotic is administered concurrently and when broad-spectrum drugs are used. Some specific antimicrobials are more commonly associated with superinfection than others. For example, Pseudomonas organisms frequently colonise and infect individuals taking cephalosporins. In a similar manner, people taking tetracyclines may become infected with Candida albicans. Generally, superinfections are caused by microorganisms that are resistant to the drug the individual is receiving. In the past, penicillinase-producing staphylococci were the most common cause of superinfection. Staphylococcus aureus and Staphylococcus epidermidis super infections, especially with methicillin-resistant strains, are again on the rise. Gram-negative enteric bacilli and fungi are the most common offenders. The proper management of superinfections includes discontinuing the drug being given or replacing it with another drug to which the organism is sensitive, culturing the suspected infected area and administering an antimicrobial agent effective against the new offending organism.

Dosage and duration of therapy

Administering antimicrobial drugs for therapeutic purposes in adequate dosage and for long enough periods is an important principle of infectious disease therapy. Fortunately, plasma concentrations of some of the more potent antibiotics (e.g. aminoglycosides) can be monitored to prevent or minimise the risk of toxicity. Failure of antimicrobial therapy is frequently the result of drug doses being too small or being given for too short a period. Follow-up cultures should be obtained to assess the effectiveness of therapy.

Inadequate drug therapy may lead to remissions and exacerbations of the infectious process and can contribute to the development of resistance. When antibiotics are used prophylactically, they are usually given for short periods to enhance host defence mechanisms. For example, with perioperative antibiotics, a loading dose is given immediately before surgery and continued for 48 hours after surgery.

Many antimicrobial agents are currently in use, and health-care professionals should be familiar with the general characteristics of each drug group or category and with one or two prototype drugs in each group. Because the dosage for any given antibiotic varies with the type of infection, the site of infection and the age and health status of the individual, only general dosages or dose ranges are given in this text. The manufacturer’s package insert or a hospital formulary or pharmacy should be consulted for specific dosages.

Paediatric implications

In assessing the appropriateness of antibiotic therapy in children, the following criteria are generally accepted:

Role of host defence mechanisms

No antimicrobial agent will cure an infectious process if host defence mechanisms are inadequate. Such drugs act only on the causative organisms of infectious disease and have no effect on the defence mechanisms of the body, which need to be assessed and supported. Many infections do not require drug therapy and are adequately combated by the individual’s defence mechanisms, including antibody production, phagocytosis, interferon produc tion, fibrosis or gastrointestinal rejection (vomiting and diarrhoea). Host defence mechanisms may, however, be diminished, for example in people with diabetes mellitus or neoplastic disease and in immunocompromised individuals (e.g. those with HIV).

The status of the host’s defence mechanisms will also influence the choice of therapy, route of administration and dosage. If an infection is fulminating, for example, parenteral (preferably intravenous) administration of a bactericidal drug will be selected rather than oral administration of a bacteriostatic drug. Large loading doses of antimicrobial agents are often administered at the beginning of treatment of severe infections to achieve maximum blood concentrations rapidly. Factors influencing drug dosage are, however, often related to the status of a patient’s renal function. Because many antimicrobial agents are excreted by the kidneys, a major management problem exists with individuals who have compromised renal function. Drug dosages are then generally reduced in parallel with the person’s creatinine clearance. Haemodialysis can further alter the therapeutic regimen. In some disease states (such as burns), antibiotic dosage may need to be increased to achieve therapeutic levels. In short, the administration of an antimicrobial agent specifically toxic to the isolated microorganism is not the only important measure in antimicrobial therapy. An additional and very important determinant of the effectiveness of an antimicrobial agent is the functional state of the host’s defence mechanisms.