4. Antibiotics

• Inhibition of bacterial cell wall synthesis. • Inhibition of bacterial protein synthesis • Inhibition of bacterial DNA synthesis • Inhibition of bacterial RNA synthesis • Inhibition of bacterial folate synthesis

Bacteria have an inner plasma membrane which is surrounded by a peptidoglycan wall Gram-negative species also have an outer lipid bilayer. Beta-lactams such as the penicillins and cephalosporins suppress peptidoglycan synthesis and so destroy the integrity of the whole cell wall Vancomycin and bacitracin also interfere with peptidoglycan wall formation, as do the carbapenems,

30S and 50S comprise the larger 70S ribosome Eukaryotic cells have 80S ribosomes which are unaffected by these antibiotics Tetracyclines also inhibit reactions at the 30S unit. Tobramycin binds to the 30S ribosome but also suppresses initiation of the larger 70S complex. Aminoglycosides block reactions at the 30S and 50S subunits The macrolide erythromycin affects the 50S subunit, as does clarithromycin Protein synthesis is completed by a process of peptide elongation in a reaction catalyzed by peptidyl transferase. Drugs such as clindamycin and lincomycin are specific inhibitors of this enzyme.

A class of enzymes known as the topoisomerases are required for bacterial DNA replication. Drugs such as the fluoroquinolones (ciprofloxacin, levofloxacin) inhibit the activity of topoisomerase II without affecting mammalian enzymes. Metronidazole interferes with DNA synthesis via the direct action of toxic metabolites.

Rifampicin, for example, blocks bacterial, but not mammalian enzymes.

Sulfonamides compete with para-aminobenzoic acid (PABA) to inhibit folate synthesis, while trimethoprim blocks dihydrofolate reductase to achieve the same effect

• Beta-Lactams. Penicillins, Cephalosporins • Sulfonamides • Tetracyclines • Glycopeptides • Carbapenems • (Fluoro)quinolones • Oxazolidinones • Macrolides • Aminoglycosides • Nitroimidazoles

(benzylpenicillin, amoxicillin, flucloxacillin, piperacillin, cefuroxime, cephalexin). beta-lactam ring essential for their mode of action, which is to suppress the synthesis of peptidoglycan, a component of the bacterial cell wall bactericidal. Bacterial resistance is expressed mainly in the production of betalactamase enzymes which rupture the beta-lactam ring; hence the addition of a beta-lactamase inhibitor to co-amoxiclav (amoxicillin/clavulanic acid). They are effective against gram-positive organisms but not against gram-negative bacteria, most of which have an impermeable cell wall.

A sulfonamide was the first commercially available antibiotic (1932). They act by inhibiting bacterial synthesis of folate and are broad-spectrum bacteriostatic agents

oxytetracycline, doxycycline). These inhibit bacterial protein synthesis and are bacteriostatic. They are broad-spectrum antibiotics which are active against both gram-positive and gram-negative species.

vancomycin, teicoplanin). These act by inhibiting cell wall synthesis and are bactericidal at higher blood concentrations. Vancomycin is active against gram-positive organisms, but it is a large molecule that is unable to penetrate the outer lipid bilayer of gram-negatives. Teicoplanin is also mainly active against gram positive species.

(imipenem, meropenem). These are beta-lactams which inhibit bacterial cell wall synthesis but which have a wider spectrum of activity than the penicillins and cephalosporins, being active against gram-positive but particularly against gram-negative organisms. They are also effective against anaerobes.

(ciprofloxacin, levofloxacin). These act by disrupting bacterial DNA replication and transcription. T hey are broad-spectrum agents with particular activity against gram-negative organisms. They are generally less effective against gram-positive species. Fluoroquinolones are bactericidal, but the development of resistance is rapid.

(linezolid). These inhibit bacterial protein synthesis and are effective against gram-positive organisms. They are bacteriostatic and are usually given as a third-line drug of last resort.

(erythromycin, clarithromycin) These inhibit protein synthesis and are bacteriostatic. They are commonly used in patients who are sensitive to penicillins and have a similar, although slightly broader spectrum of antibacterial activity.

(gentamicin, tobramycin, neomycin). These inhibit protein synthesis and are used mainly against gram-negative bacteria. Whether they are bacteriostatic or bactericidal is dose-dependent. Their duration of action is prolonged beyond the time when blood levels have fallen. This is due to irreversible binding to the intracellular bacterial ribosome. They are potentially nephrotoxic and ototoxic and potentiate the effects of neuromuscular blocking drugs.

Nitroimidazoles (metronidazole, tinidazole). Metronidazole is the commonest drug of this class that is in clinical use in the UK. It undergoes reduction to produce toxic metabolites that suppress bacterial DNA synthesis. This reduction takes place only in anaerobic cells, and so the drug has no effect on aerobic organisms. Metronidazole is, however, also active against protozoa such as Giardia lamblia and Entamoeba histolytica

Assuming appropriate asepsis and infection control measures these otherwise include insertion of any metalwork, implant or prosthesis; prolonged surgery; perioperative hypothermia; difficult haemostasis; and the insertion of surgical drains. Patients at greater risk include those at the extremes of age, those who are immunocompromised (for example receiving corticosteroids), those with diabetes mellitus, the obese (BMI >30 kg m–2) and smokers

Narrow spectrum antibiotics should be selected, targeted to the most likely pathogens for the surgical procedure (and taking into account any local patterns of antibiotic resistance that have been identified). Clostridium difficile infection is a higher risk with cephalosporins, fluoroquinolones (ciprofloxacin), carbapenems (imipenem) and clindamycin. The antibiotic should have a half-life long enough to extend the duration of the operation after a single intravenous dose This should be given as close to the time of surgical incision as possible and no more than 1 hour before. Following arthroplasty, antibiotics may be given for up to 24 hours In long procedures such as revision arthroplasty, a second intraoperative dose may also be necessary. If operative blood loss is substantial (>1500 ml), additional doses should also be considered, on the assumption that the effective blood concentration will be lowered as a result

Acquired resistance to antibiotics is usually achieved by inhibition of the usual mode of action. The primary mechanisms include a simple decrease in the permeability of the bacterial cell wall, enzymatic degradation (of which beta-lactamase destruction of the active beta-lactam ring is the most obvious example) and changes in the proteins whose synthesis is the antibiotic target.