7: Antimicrobial chemotherapy

Chapter 7 Antimicrobial chemotherapy

Antimicrobial compounds include antibacterial, antiviral, antifungal and antiprotozoal agents. All of these, apart from the last group, are prescribed in dentistry.

All antimicrobials demonstrate selective toxicity; i.e. the drug can be administered to humans with reasonable safety while having a marked lethal or toxic effect on specific microbes. The corollary of this is that all antimicrobials have adverse effects on humans and should therefore be used rationally and only when required.

Antimicrobial therapy aims to treat infection with a drug to which the causative organism is sensitive. Antimicrobials can be administered on a ‘best-guess’ basis, with a sound knowledge of the:

• infectious disease

• most probable pathogen

• usual antibiotic sensitivity pattern of the pathogen.

This is called empirical antibiotic therapy and contrasts with rational antibiotic therapy in which antibiotics are administered after the sensitivity of the pathogen has been established by culture and in vitro testing in the laboratory. In general, empirical therapy is undertaken in the majority of situations encountered in dentistry.

Bacteriostatic and bactericidal antimicrobial agents

Antimicrobial agents are classically divisible into two major groups: bactericidal agents, which kill bacteria; and bacteriostatic agents, which inhibit multiplication without actually killing the pathogen. However, the distinction is rather hazy and is dependent on factors such as the concentration of the drug (e.g. erythromycin is bacteriostatic at low concentrations and bactericidal at high concentrations), the pathogen in question and the severity of infection. Further, host defence mechanisms play a major role in the eradication of pathogens from the body, and it is not essential to use bactericidal drugs to treat most infections. A bacteriostatic drug that arrests the multiplication of pathogens and so tips the balance in favour of the host defence mechanisms is satisfactory in many situations.

Principles of antimicrobial therapy

Antimicrobial agents should be prescribed on a rational clinical and microbiological basis. In general, therapy should be considered for patients when one or more of the following conditions are present:

• fever and an acute infection

• spreading infection without localization

• chronic infection despite drainage or debridement

• infection in medically compromised patients

• cases of osteomyelitis, bacterial sialadenitis and some periodontal diseases, such as acute ulcerative gingivitis and localized aggressive periodontitis (previously localized juvenile periodontitis).

(Note: this is not an exhaustive list.)

Choice of drug

The choice of drug is strictly dependent upon the nature of the infecting organisms and their sensitivity patterns. However, in a clinical emergency such as septicaemia or Ludwig’s angina, antimicrobial agents must be prescribed empirically until laboratory tests are completed. In general, another antimicrobial drug should be prescribed if the patient has had penicillin within the previous month because of the possible presence of penicillin-resistant bacterial populations previously exposed to the drug.

Spectrum of activity of antimicrobial agents

Antimicrobial agents can be categorized as broad-spectrum and narrow-spectrum antibiotics, depending on their activity against a range of Gram-positive and Gram-negative bacteria. For example, penicillin is a narrow-spectrum antibiotic with activity mainly against the Gram-positive bacteria, as is metronidazole, which acts almost entirely against strict anaerobes and some protozoa.

Broad-spectrum antimicrobials (e.g. tetracyclines, ampicillins) are active against many Gram-positive and Gram-negative bacteria, and they are often used for empirical or ‘blind’ treatment of infections when the likely causative pathogen is unknown. This unfortunately leads to ‘abuse’ of broad-spectrum agents, with the consequent emergence of resistance in organisms that were originally sensitive to the drug. The spectrum of activity of some broad-spectrum and narrow-spectrum antimicrobial agents is shown in Table 7.2.

Table 7.2 Spectrum of activity of some commonly used antimicrobial agents

Drug	Spectrum
Phenoxymethylpenicillin (penicillin V)	1. Aerobic Gram-positives (e.g. streptococci, pneumococci, β-lactamase-negative)
	2. Anaerobic Gram-positives (e.g. anaerobic streptococci)
	3. Anaerobic Gram-negatives (e.g. most Bacteroides, fusobacteria, Veillonella)
Penicillinase-resistant penicillins (e.g. flucloxacillin)	All the above, including β-lactamase-producing staphylococci
Ampicillin	As for penicillin, also includes Haemophilus spp.
Cephalosporins	As for penicillin, also includes some coliforms
Erythromycin	Gram-positives mainly but some anaerobes not susceptible at levels obtained by oral administration
Tetracycline	Broad-spectrum. Many Gram-positives and -negatives
Metronidazole	All strict anaerobes are sensitive, including some protozoa. Of questionable value for facultative anaerobes

Combination therapy

Whenever possible, a single antimicrobial agent should be used to reduce the:

• incidence of possible side effects

• emergence of resistant bacteria

• drug costs.

However, there are certain clinical situations where a combination of drugs is valuable: for example, to achieve a high bactericidal level when treating patients with infective endocarditis; the use of gentamicin and metronidazole in the empirical treatment of a patient with serious abdominal sepsis; and combination therapy in the management of tuberculosis. In dentistry, combination therapy should be avoided as far as possible.

Antimicrobial prophylaxis

Antimicrobial prophylaxis is the use of a drug to prevent colonization or multiplication of microorganisms in a susceptible host. The value of prophylaxis depends upon a balance between:

• the benefit of reducing the infection risk and consequent secondary morbidity

• the possible toxic effects to the host, including alterations of the host commensal flora

• the cost-effectiveness.

When used appropriately, prophylaxis can reduce morbidity and the cost of medical care. Irrational prophylaxis leads to a false sense of security, increased treatment cost and the possible emergence of resistant flora.

Aims

The aims of antimicrobial prophylaxis are:

• eradication of the colonization of the host by virulent agents, e.g. chemoprophylaxis (with rifampicin) given to close contacts of patients with meningococcal meningitis (see Chapter 25)

• prevention of implantation and/or implanted organisms reaching a critical mass sufficient to produce infection, e.g. antimicrobial prophylaxis in infective endocarditis patients before surgical procedures

• prevention of the emergence of latent infection, e.g. antifungal agents given either intermittently or continuously to prevent candidal infection in human immunodeficiency virus (HIV)-infected patients.

In dentistry, antibiotics are used as prophylactic agents before dental or surgical treatment of patients who:

• are at risk of infective endocarditis (see Chapter 24)

• have facial fractures or compound skull fractures, and cerebral rhinorrhoea

• are immunocompromised

• have recently received radiotherapy to the jaws (as they succumb to infection as a result of severe ischaemia of the bone caused by radiotherapy)

• have prosthetic hip replacements, ventriculoatrial shunts, insertion of implants or bone grafting.

However, the advantages and disadvantages of prophylactic antimicrobial therapy in the latter three groups should be carefully weighed as some consider this superfluous.

Prescribing an antimicrobial agent

The following should be considered before any antimicrobial agent is prescribed.

Is there an infective aetiology?

When there is no good clinical evidence of infection, antimicrobial therapy is unnecessary, except in prophylaxis (discussed above).

Have relevant specimens been taken before treatment?

Appropriate specimens should be collected before drug therapy is begun as the population of pathogens may be reduced, and therefore less easily isolated, if specimens are collected after antimicrobial agents have been taken. Further, the earlier the specimens are taken, the more likely it is that the results will be useful for patient management.

When should the treatment be started?

In patients with life-threatening infections, e.g. Ludwig’s angina, intravenous therapy should generally be instituted immediately after specimen collection. Antimicrobial therapy may be withheld in chronic infections until laboratory results are available (e.g. actinomycosis).

Which antimicrobial agent?

Consider the pharmacodynamic effects, including toxicity, when choosing a drug from a number of similar antimicrobial agents that are available to treat many infections (see below). An adequate medical history, especially in relation to past allergies and toxic effects, should be taken before deciding on therapy.

Pharmacodynamics of antimicrobials

Dosage

Antimicrobial agents should be given in therapeutic doses sufficient to produce a tissue concentration greater than that required to kill or inhibit the growth of the causative microorganism(s).

Duration of treatment

Ideally, treatment should continue for long enough to eliminate all or nearly all of the pathogens, as the remainder will, in most instances, be destroyed by the host defences. Conventionally, this cannot be precisely timed, and standard regimens last for some 3–5 days, depending on the drug. However, a short-course, high-dose therapy of certain antibiotics such as amoxicillin is as effective as a conventional 5-day course. The other advantages of short courses of antimicrobial agents are good patient compliance and minimal disturbance to commensal flora, leading to an associated reduction in side effects such as diarrhoea.

Route of administration

In seriously ill patients, drugs should be given by the parenteral route to overcome problems of absorption from the intestinal tract. All antimicrobial agents given by mouth must be acid-stable.

Distribution

The drug must reach adequate concentrations at the infective focus. Some antibiotics, such as clindamycin, that penetrate well into bone are preferred in chronic bone infections; in meningitis, a drug that penetrates the cerebrospinal fluid should be given.

Excretion

The pathway of excretion of an antimicrobial agent should be noted. For example, drugs metabolized in the liver, such as erythromycin estolate, should not be given to patients with a history of liver disease because they may cause hepatotoxicity, leading to jaundice.

Toxicity

Most antimicrobials have side effects and the clinician should be aware of these (for examples, see the following section on antibacterial agents).

Drug interactions

Drug interactions are becoming increasingly common owing to the extensive use of a variety of drugs. For instance, antibiotics such as penicillin and erythromycin can significantly reduce the efficacy of some oral contraceptives, and antacids can interfere with the action of tetracyclines. All clinicians should therefore be aware of the drug interactions of any antimicrobial they prescribe. The major drug interactions of antimicrobials commonly used in dentistry are given in Table 7.3.

Table 7.3 Some drug interactions of antimicrobials commonly used in dentistry

Drug affected	Drug interacting	Effect
Penicillins	Probenecid, neomycin	May potentiate the effect of penicillin. Reduced absorption
Erythromycin	Theophylline	Increase theophylline levels, leading to potential toxicity
Cephalosporins	Gentamicin	Additive effect leading to nephrotoxicity
	Furosemide (Lasix)	Possible increase in nephrotoxicity
Tetracycline	Antacids, dairy products, oral iron, zinc sulphate	Reduced absorption
Metronidazole	Alcohol	‘Antabuse’ effect
	Disulfiram, phenobarbital, phenytoin	Reduced effect

Failure of antimicrobial therapy

Consideration should be given to the following potential problems if an infection does not respond to drugs within 48 h:

• inadequate drainage of pus or debridement

• inappropriateness of the antimicrobial agent, including bacterial resistance to the drug, dosage and drug interactions

• presence of local factors such as foreign bodies, which may act as reservoirs of reinfection

• impaired host response, e.g. in patients who are immunocompromised by drugs or HIV infection

• poor patient compliance

• possibility of an unusual infection or that the disease has no infective aetiology

• poor blood supply to tissues.

Antibiotic resistance in bacteria

Emergence of drug resistance in bacteria is a major problem in antibiotic therapy and depends on the organism and the antibiotic concerned. Whereas some bacteria rapidly acquire resistance (e.g. Staphylococcus aureus), others rarely do so (e.g. Streptococcus pyogenes). Resistance to some antibiotics is virtually unknown (e.g. metronidazole), but strains resistant to others (e.g. penicillin) readily emerge.

Antibiotic resistance develops when progeny of resistant bacteria emerge. As they will be at a selective advantage over their sensitive counterparts, and as long as the original antibiotic is prescribed, the resistant strains can multiply uninhibitedly (e.g. hospital staphylococci with almost universal resistance to penicillin). Such antibiotic resistance can be divided into:

• primary (intrinsic) resistance: where the organism is naturally resistant to the drug; i.e. its resistance is unrelated to contact with the drug (e.g. resistance of coliforms to penicillin)

• acquired resistance: due to either mutation within the same species (chromosomal resistance) or gene transfer between different species via plasmids (extrachromosomal resistance) (see Fig. 3.6)

• cross-resistance: when resistance to one drug confers resistance to another chemically related drug (e.g. bacteria resistant to one type of tetracycline may be resistant to all other types of tetracycline).

Mechanisms of antibiotic resistance (Table 7.4)

Inactivation of the drug

This is very common, e.g. production of β-lactamase by staphylococci. The enzyme, which is plasmid coded, destroys the β-lactam ring responsible for the antibacterial activity of penicillins.

Table 7.4 Plasmid-mediated antibiotic resistance

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Jan 4, 2015 | Posted by mrzezo in General Dentistry | Comments Off

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