Pharmacology: Antimicrobials

Antimicrobials are anti-infective drugs used to prevent or treat infections caused by bacteria, viruses, fungi, and parasites. Their clinical value depends on three practical questions: what organism is present, what drug concentrations can be achieved at the site of infection, and what resistance mechanisms might render therapy ineffective. Understanding antimicrobial pharmacology means linking mechanism of action to antimicrobial spectrum, predictable resistance patterns, and the clinical context in which a drug is used.

Core principles of antimicrobial pharmacology

Selective toxicity and therapeutic window

Most antimicrobials exploit differences between microbial and human cells. Bacteria have cell walls and 70S ribosomes; fungi use ergosterol instead of cholesterol; viruses depend on host machinery but have unique enzymes at key replication steps. Selective toxicity is never perfect, so dosing must balance efficacy against adverse effects.

Spectrum of activity and empiric therapy

Spectrum refers to the range of organisms inhibited or killed by a drug. Broad-spectrum agents cover multiple pathogen classes, while narrow-spectrum agents target specific groups. Empiric therapy often starts broad when the pathogen is unknown and the infection is serious, then narrows (“de-escalates”) once cultures, susceptibilities, and clinical response clarify the cause.

Bactericidal vs bacteriostatic (and why it matters)

Bactericidal drugs kill bacteria; bacteriostatic drugs inhibit growth and rely more heavily on host immunity for clearance. This distinction can matter in endocarditis, meningitis, and severe immunosuppression, where rapid organism eradication is critical. In practice, drug choice is still driven by site penetration, organism, and resistance.

Pharmacodynamics: time vs concentration dependence

Some antimicrobials work best when drug levels remain above the minimum inhibitory concentration (time-dependent), while others correlate with peak concentration or overall exposure (concentration-dependent or AUC-driven). These concepts shape dosing strategies and can influence outcomes, especially in severe infections.

Antibiotics by mechanism of action

Cell wall synthesis inhibitors

Beta-lactams inhibit bacterial cell wall cross-linking by binding penicillin-binding proteins. They include penicillins, cephalosporins, carbapenems, and monobactams. Their spectrum varies by subclass, but a recurring clinical theme is resistance through:

• Beta-lactamases that hydrolyze the drug
• Altered target sites (modified penicillin-binding proteins)
• Reduced permeability (porin changes in Gram-negative bacteria)
• Efflux pumps that decrease intracellular drug levels

Beta-lactamase inhibitors (paired with certain penicillins) broaden activity against beta-lactamase producing organisms, but they do not overcome every enzyme class. Interpreting susceptibility reports and local antibiograms is essential.

Glycopeptides (such as agents targeting peptidoglycan assembly) are key options for Gram-positive infections, especially when resistance to beta-lactams is suspected. Resistance can emerge via altered cell wall precursors that reduce binding.

Clinical insight: cell wall agents are often preferred when feasible because of robust bactericidal activity and long clinical experience. However, penetration to certain sites (for example, cerebrospinal fluid) and resistance patterns must guide selection.

Protein synthesis inhibitors (bacterial ribosomes)

Bacterial ribosomes (30S and 50S subunits) are common targets.

• 30S inhibitors include aminoglycosides and tetracyclines.
• Aminoglycosides are typically bactericidal and particularly useful against many aerobic Gram-negative organisms. Resistance commonly involves drug-modifying enzymes or altered transport into the cell.
• Tetracyclines are generally bacteriostatic and have broad activity, including atypical organisms. Resistance often occurs via efflux pumps or ribosomal protection proteins.

• 50S inhibitors include macrolides, lincosamides, chloramphenicol, oxazolidinones, and streptogramins.
• Macrolides are widely used for respiratory pathogens and atypicals; resistance may occur through target-site methylation or efflux.
• Certain agents in this group are reserved for resistant Gram-positive infections because of reliable activity against organisms with limited options.

Clinical insight: protein synthesis inhibitors often fill specific niches such as atypical pneumonia, skin and soft tissue infections, or resistant Gram-positive disease. They also vary in drug interaction profiles and tissue penetration.

Nucleic acid synthesis and function inhibitors

• Fluoroquinolones inhibit DNA gyrase and topoisomerase IV. They offer broad coverage but resistance can develop through target mutations and efflux. Because resistance can arise rapidly and adverse effects can be clinically significant, careful indication selection matters.
• Rifamycins inhibit RNA polymerase and are notable for rapid resistance when used as monotherapy in certain infections, so they are often used in combination regimens.
• Nitroimidazoles are activated under anaerobic conditions and are valuable for anaerobic bacterial infections and certain protozoal infections.

Antimetabolites (folate pathway inhibitors)

Drugs that block folate synthesis interfere with nucleotide formation. Combination therapy targeting sequential steps can be synergistic and reduce resistance emergence. Resistance may occur via altered enzymes or increased production of pathway substrates.

Antivirals: targeting the viral life cycle

Viruses lack many independent metabolic pathways, so antiviral drugs focus on virus-specific enzymes and life cycle stages such as entry, uncoating, genome replication, integration, and proteolytic processing.

• Polymerase and reverse transcriptase inhibitors interfere with viral genome replication. They are central to therapy for several chronic viral infections and must be selected with attention to resistance mutations.
• Protease inhibitors block viral polyprotein processing, preventing maturation of infectious particles.
• Integrase inhibitors prevent incorporation of viral genetic material into the host genome for viruses that require integration.
• Entry and fusion inhibitors reduce infection of new cells, often used when resistance or intolerance limits other options.

Clinical insight: antiviral resistance is strongly influenced by adherence and drug levels. Combination therapy is used in several viral diseases to suppress replication and minimize resistance selection.

Antifungals: ergosterol, cell walls, and unique targets

Fungal cells resemble human cells more than bacteria do, so antifungal toxicity and drug interactions can be more challenging.

• Azoles inhibit ergosterol synthesis, disrupting membrane function. Resistance can develop through target enzyme alterations, efflux pumps, or pathway bypass mechanisms.
• Polyenes bind ergosterol directly, creating membrane pores. They can be effective but are associated with notable toxicity risks.
• Echinocandins inhibit synthesis of key fungal cell wall components, offering a favorable selectivity profile for many invasive infections.
• Antimetabolite antifungals interfere with nucleic acid synthesis and are commonly used in combination to reduce resistance and improve efficacy.

Clinical insight: antifungal selection depends heavily on the suspected species, the site of infection (bloodstream, lung, central nervous system), and host factors such as immune status.

Antiparasitics: diverse organisms, tailored therapies

Parasites include protozoa and helminths with complex life cycles, so therapy often targets unique metabolic pathways or neuromuscular function.

• Antiprotozoals may interfere with DNA synthesis, redox balance, or energy metabolism. Some agents overlap with antibacterial drugs in mechanism, reflecting shared metabolic vulnerabilities.
• Antihelminthics frequently act by disrupting microtubules, altering neuromuscular transmission, or affecting parasite energy production, leading to immobilization or death.

Clinical insight: parasitic infections often require attention to exposure history, geography, and life cycle stages. In some cases, treatment decisions differ for intestinal infection versus invasive disease.

Resistance: how it emerges and how to slow it

Antimicrobial resistance arises through mutation and gene acquisition, then spreads under selective pressure. Key mechanisms include:

• Enzymatic drug inactivation
• Target modification
• Decreased permeability or increased efflux
• Metabolic pathway bypass

Practical strategies to limit resistance include using the narrowest effective agent, dosing appropriately to achieve therapeutic exposure, shortening duration when evidence supports it, and avoiding unnecessary antimicrobial use. Infection prevention and antimicrobial stewardship are as important as new drug development.

Putting it together: choosing the right antimicrobial

Effective antimicrobial therapy combines pharmacology with clinical reasoning:

1. Identify the likely pathogens based on syndrome, site, and risk factors.
2. Choose an agent with appropriate spectrum and penetration.
3. Anticipate resistance using local patterns and patient history (recent antibiotics, healthcare exposure).
4. Reassess when microbiology results return, narrowing therapy when possible.
5. Monitor response and toxicity, adjusting dose for organ function and drug interactions.

Antimicrobials remain among the most impactful therapies in medicine, but their power is fragile. Mastery of mechanisms, spectrum, and resistance patterns supports better outcomes today and preserves effectiveness for future patients.