Antibiotic Pharmacology and Resistance Mechanisms (incl. Biofilm)

Antibiotic pharmacology is examined as basic science but practised as orthopaedic decision-making. Three clinical problems recur throughout this topic.

Prophylaxis and empirical choice. Both depend on knowing which class hits which target, and which resistance mechanisms are circulating locally (MRSA, ESBL, resistant gram-negatives).

Implant-associated infection. This is a biofilm disease, and the distinction between genetic resistance and phenotypic tolerance is what explains its behaviour and decides its treatment.

Route and duration. Both have been transformed by trial evidence. Early oral switch (OVIVA) and rifampicin-combination therapy for stable-implant staphylococcal infection (Zimmerli) are now defensible standards rather than shortcuts.

Scope. This page covers class mechanisms, bactericidal versus bacteriostatic and concentration- versus time-dependent killing, the four resistance mechanisms, biofilm tolerance, and the toxicities that change surgical practice. Prophylaxis regimens, timing and the penicillin-allergy pathway are developed in Perioperative Antibiotics; treatment regimens, duration and the oral-versus-intravenous evidence in Orthopaedic Antibiotic Therapy; cement and beads in Local Antibiotic Delivery. Periprosthetic Joint Infection and Osteomyelitis cover the diseases this pharmacology serves, and the pharmacology that drives all of them sits here.

Antibiotics work on four main bacterial targets.

Cell-wall synthesis. The beta-lactams (penicillins, cephalosporins, carbapenems) block the penicillin-binding proteins (transpeptidase). The glycopeptides (vancomycin, teicoplanin) bind the D-ala-D-ala terminus and are key for gram-positives and MRSA.

Protein synthesis. The ribosome is the target of the aminoglycosides (gentamicin: 30S, bactericidal, used in cement and beads), the macrolides, clindamycin, linezolid (for MRSA and VRE) and the tetracyclines.

DNA and RNA. Fluoroquinolones inhibit DNA gyrase, rifampicin inhibits RNA polymerase, and metronidazole covers anaerobes. Their bone penetration, oral absorption and, for rifampicin, biofilm penetration are taken up in the sections below.

Folate synthesis. Trimethoprim-sulfamethoxazole inhibits the folate pathway.

Two further agents for resistant gram-positive infection. Daptomycin is a cyclic lipopeptide that inserts into the membrane in a calcium-dependent manner and depolarises it. It is bactericidal against MRSA and VRE, and is classically inactivated by pulmonary surfactant, so it is never used for pneumonia. Fusidic acid blocks elongation factor G.

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Bacteria resist antibiotics by four mechanisms.

• Enzymatic inactivation. Beta-lactamases (penicillinases, extended-spectrum beta-lactamases or ESBL, carbapenemases) and aminoglycoside-modifying enzymes destroy the drug.
• Target modification. MRSA carries an altered penicillin-binding protein, PBP2a, encoded by mecA. VRE builds an altered cell-wall precursor, D-ala-D-lac, via vanA. A mutated DNA gyrase (fluoroquinolone resistance) or ribosome is target modification too.
• Reduced uptake. Gram-negatives lose outer-membrane porins, decreasing permeability.
• Efflux pumps. The drug is actively pumped out of the cell.

How resistance spreads. Resistance genes move between bacteria on plasmids and transposons (horizontal gene transfer). This is what produces MRSA, VRE, ESBL and multidrug-resistant gram-negatives, and it is why resistance is relevant to surgical prophylaxis and to the empirical treatment of infection.

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What a biofilm is. A structured community of bacteria adherent to a surface (an implant, or dead bone such as a sequestrum) within a self-produced extracellular matrix (glycocalyx). It causes antibiotic tolerance, a phenotypic, reversible survival that is distinct from genetic resistance.

How tolerance arises. The biofilm protects its bacteria through:

• Reduced antibiotic penetration into the matrix
• Slow-growing or dormant persister cells and small-colony variants that survive antibiotic exposure
• An altered local microenvironment

Why the laboratory report misleads. Tolerance is quantified by the MBEC (minimum biofilm eradication concentration), which may be hundreds to over a thousand times the MIC of the same organism grown planktonically. A report of "sensitive", derived from a planktonic MIC, says almost nothing about whether the drug will clear a biofilm.

Why implant infection needs surgery. Tolerance is the reason antibiotics alone fail to clear implant-associated infection, and the reason surgical source control (debridement and often implant removal) is essential, combined with antibiotics. Suppressive antibiotics may control, but rarely eradicate, biofilm infection when the implant is retained. Local delivery (gentamicin or vancomycin cement or beads) is used as an adjunct.

Rifampicin. Its penetration of the staphylococcal biofilm and of intracellular bacteria is excellent, which makes it a key agent for staphylococcal implant infection.

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These are the toxicities that change orthopaedic practice and require monitoring. The surgeon-facing high-yield ones are fluoroquinolone tendinopathy and the aminoglycoside and vancomycin toxicity that needs level monitoring.

• Fluoroquinolones. Tendinopathy and tendon rupture, classically the Achilles, highly relevant to the orthopaedic patient; also QT prolongation, dysglycaemia, C. difficile, and a cartilage/arthropathy caution in children (a relative contraindication in the growing patient).
• Aminoglycosides (gentamicin). Dose-related nephrotoxicity and ototoxicity (vestibular and cochlear), hence therapeutic drug monitoring; relevant to systemic use and to high local cement and bead loads.
• Vancomycin. Nephrotoxicity, and the rate-related "red man" infusion reaction, which is not a true allergy; hence level/AUC monitoring.
• Rifampicin. A potent hepatic enzyme inducer (drug interactions: it reduces warfarin, oral contraceptives and many other drugs), hepatotoxicity, and orange discolouration of secretions.
• Linezolid. With prolonged use, myelosuppression (thrombocytopenia), peripheral and optic neuropathy, and serotonin syndrome, as it is a weak MAO inhibitor.
• Clindamycin. The classic association with C. difficile colitis.
• Beta-lactams. Allergy and anaphylaxis, with a low penicillin-cephalosporin cross-reactivity.

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Two ways of classifying a drug. Drugs are classed as bactericidal or bacteriostatic, and as concentration-dependent (aminoglycosides, fluoroquinolones) or time-dependent (beta-lactams, glycopeptides) killers, which determines dosing. The MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) underpin "bactericidal versus bacteriostatic".

Concentration-dependent killing. It is optimised by a high peak relative to the MIC (Cmax/MIC) and by the AUC/MIC ratio. Aminoglycosides are therefore given as a high once-daily dose, which also exploits the post-antibiotic effect, and fluoroquinolones are dosed to AUC/MIC.

Time-dependent killing. It depends on the time the concentration stays above the MIC, so beta-lactams benefit from more frequent dosing or extended or continuous infusions. Vancomycin is dosed to an AUC/MIC target, now roughly 400-600, which has largely replaced trough-only monitoring because it tracks efficacy while limiting nephrotoxicity.

Bone penetration. Fluoroquinolones, clindamycin, rifampicin, linezolid and fusidic acid penetrate bone well, which makes them useful oral options for osteomyelitis, PJI and oral switch. Beta-lactams, and especially glycopeptides (vancomycin), penetrate bone relatively poorly. This informs agent and route choice, and explains the appeal of bone-penetrating oral agents.

Oral bioavailability. This is why an oral switch is possible at all. Fluoroquinolones, linezolid, metronidazole and fusidic acid approach near-complete oral bioavailability, and clindamycin and rifampicin are well absorbed too. For these drugs the oral route achieves serum concentrations close to intravenous, so an oral regimen is a pharmacological equivalent rather than a compromise.

Vancomycin is the exception. It is not absorbed orally at all: oral vancomycin treats C. difficile within the gut lumen and has no systemic activity whatever.

Redosing. Intra-operative redosing is a pharmacokinetic decision driven by half-life. A further dose is due once the operation exceeds roughly two half-lives of the agent, or after major blood loss, because the aim is a tissue concentration above the MIC for the whole time the wound is open. Obesity raises the volume of distribution and is the usual reason a standard dose under-doses.

Synergy. Some combinations kill better than either agent alone, classically a beta-lactam (or vancomycin) plus an aminoglycoside in enterococcal infection, where cell-wall disruption lets the aminoglycoside reach its ribosomal target.

The microbiology report is where pharmacology meets the ward round, and it is routinely over-interpreted.

"Sensitive" is a planktonic statement. Breakpoints (S/I/R) are set against a planktonic MIC and a set of assumptions about achievable serum concentration at a standard dose. They say nothing about whether the drug reaches bone, and nothing about a biofilm on an implant, which is precisely why an organism reported sensitive to vancomycin can persist on a prosthesis. Read the report alongside the site of infection and whether a foreign body is present.

"Intermediate" is usually a dosing statement. It is not a prohibition: it generally means the agent may work at a higher dose or where the drug concentrates.

Sample before antibiotics. Antibiotics given before deep samples are taken substantially reduce culture yield, and are a common reason for a culture-negative bone or joint infection. Unless the patient is septic, hold antibiotics until adequate deep samples, usually multiple, have been obtained.

Selective pressure and collateral damage. Every course selects resistance in the patient's own flora. Clindamycin, fluoroquinolones and broad-spectrum cephalosporins carry the strongest association with C. difficile, and broad gram-negative cover selects ESBL and resistant Pseudomonas. Choosing the narrowest effective agent is a clinical decision, not an administrative one.

Stewardship. In orthopaedic terms it means:

• Prophylaxis is a single perioperative course, not a post-operative drip continued "until the drains are out"
• Empirical therapy is de-escalated once cultures return
• Duration is defined at the outset rather than open-ended
• The oral switch is taken as soon as the agent's bioavailability and bone penetration allow