MediLearnBD: Antimicrobial Agents A to Z full details covered

Antimicrobial Agents A to Z full details covered

Antimicrobials — Definition, Classification & Mechanisms

Definition

Antimicrobials are agents that kill or inhibit the growth of microorganisms such as bacteria, viruses, fungi, and parasites. They may be natural, semi-synthetic, or synthetic.

Types of Antimicrobials

Antibacterial agents — active against bacteria
Antiviral agents — active against viruses
Antifungal agents — active against fungi
Antiparasitic agents — active against protozoa & helminths

Overview / Classification

Based on target: antibacterial, antiviral, antifungal, antiparasitic
Based on mechanism: inhibit cell wall synthesis, protein synthesis, nucleic acids, metabolic pathways, or membranes
Based on spectrum: broad-spectrum vs narrow-spectrum

Combination therapy:

It is sometimes appropriate to combine antimicrobial agents:
1. when there is a need to increase clinical effectiveness (e.g. biofilm infections)
2. when no single agent’s spectrum covers all potential pathogens (e.g. polymicrobial infection)
3. when there is a need to reduce development of antimicrobial resist- ance in the target pathogen, as the organism would need to develop resistance to multiple agents simultaneously (e.g. antituberculous chemotherapy and antiretroviral therapy (ART) for HIV.

-Antimicrobial resistance

Microorganisms have evolved in the presence of naturally occur- ring antibiotics and have therefore developed resistance mechanisms to all classes of antimicrobial agent (antibiotics and their derivatives) . Intrinsic resistance is an innate property of a microorganism, whereas acquired resistance arises by spontaneous mutation or hori- zontal transfer of genetic material from another organism, usually via a plasmid. Plasmids can be easily transferred between bacteria (especially Enterobacterales) and often encode resistance to multiple antibiotics. Penicillin-binding proteins (PBP) are enzymes involved in bacterial cell wall synthesis. The mecA gene encodes a PBP, which has a low affinity for penicillins and therefore confers resistance to β-lactam antibiotics in staphylococci. Extended-spectrum β-lactamases (ESBLs) are bacte- rial-produced enzymes that break down β-lactam antibiotics, and are frequently encoded on plasmids in Enterobacterales. Plasmid-encoded carbapenemases have been detected in strains of Klebsiella pneumo- niae (e.g. New Delhi metallo-β-lactamase 1, NDM-1). Strains of MRSA have been described that also have reduced susceptibility to glycopep- tides through the development of a relatively impermeable cell wall.
Factors promoting antimicrobial resistance include the inappropriate use of antibiotics (e.g. to treat viral infections), inadequate dosage or unnecessarily prolonged treatment, and use of antimicrobials as growth promoters in agriculture. However, any antimicrobial use exerts a selec- tion pressure that favours the development of resistance. Combination antimicrobial therapy may reduce the emergence of resistance in the target pathogen but not in the normal ora that it also affects. Despite use of combination therapy for M. tuberculosis, multi-resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB) have been reported worldwide and are increasing in incidence (see p. 524). The term ‘post-antibiotic era’ was coined to describe a future in which widespread antimicrobial resistance will render antimicrobials useless. At present there is a gradual but inexorable progression of resistance globally, necessitating the use of more expensive antimicrobials or older antimicrobials with significant toxicity.

Duration of Antimicrobial Therapy for Some Common Infections

Infection	Duration of Therapy
Viral infections
Herpes simplex encephalitis	2–3 weeks
Bacterial infections
Gonorrhoea	Single dose
Infective endocarditis (streptococcal, native valve)	4 weeks ± gentamicin for first 2 weeks
Infective endocarditis (prosthetic valve)	6 weeks
Osteomyelitis	6 weeks
Pneumonia (community-acquired, severe)	7–10 days (no organism identified), 14–21 days (Staphylococcus aureus or Legionella spp.)
Septic arthritis	2–4 weeks
Urinary tract infection (male)	1–2 weeks depending on severity
Urinary tract infection, upper tract, uncomplicated (female)	7 days
Urinary tract infection, lower (female)	3 days
Mycobacterial infections
Tuberculosis (meningeal)	12 months
Tuberculosis (pulmonary)	6 months
Fungal infections
Invasive pulmonary aspergillosis	Until clinical/radiological resolution and reversal of predisposition
Candidaemia (acute disseminated)	2 weeks after last positive blood culture and resolution of signs and symptoms

Antimicrobial prophylaxis:

Antimicrobial prophylaxis is the use of antimicrobial agents to prevent infection. Primary prophylaxis is used to reduce the risk of infection following certain medical procedures (e.g. colonic resection or prosthetic hip insertion), following exposure to a specific pathogen (e.g. Bordetella pertussis) or in specific situations such as post-splenectomy . Antimicrobial prophylaxis should be chosen to have minimal adverse effects and based on robust evidence. In the case of exposure, it may be combined with passive immunisation . Secondary prophylaxis is used in patients who have been treated successfully for an infection but remain predisposed to it. It is used in haemato-oncology patients in the context of fungal infection and in HIV-positive individuals with an opportunistic infection until a defined level of immune reconstitution is achieved.

Recommendations for Antimicrobial Prophylaxis in Adults

Infection Risk	Recommended Antimicrobial
Bacterial
Diphtheria (prevention of secondary cases)	Erythromycin
Gas gangrene (after high amputation or major trauma)	Penicillin or metronidazole
Lower gastrointestinal tract surgery	Cefuroxime + metronidazole, gentamicin + metronidazole, or co-amoxiclav (single dose only)
Meningococcal disease (prevention of secondary cases)	Rifampicin or ciprofloxacin
Rheumatic fever (prevention of recurrence)	Phenoxymethylpenicillin or sulfadiazine
Tuberculosis (prevention of secondary cases)	Isoniazid ± rifampicin
Whooping cough (prevention of secondary cases)	Erythromycin
Viral
HIV, occupational exposure (sharps injury)	Combination tenofovir/emtricitabine and raltegravir. Modified if index case’s virus known to be resistant
Influenza A (prevention of secondary cases in adults with chronic respiratory, cardiovascular or renal disease, immunosuppression or diabetes mellitus)	Oseltamivir
Fungal
Aspergillosis (in high-risk haematology patients)	Posaconazole (voriconazole or itraconazole alternatives if intolerant)
Pneumocystis pneumonia (prevention in HIV and other immunosuppressed states)	Co-trimoxazole, pentamidine or dapsone
Protozoal
Malaria (prevention of travel-associated disease)	Specific antimalarials depend on travel itinerary. Specialist guidance should be consulted

Antimicrobial Agents in Pregnancy:

Contraindicated

Chloramphenicol: neonatal ‘grey baby’ syndrome – collapse, hypotension and cyanosis.
Fluconazole: teratogenic in high doses.
Quinolones: arthropathy in animal studies.
Sulphonamides: neonatal haemolysis and methaemoglobinaemia.
Tetracyclines, glycylcyclines: skeletal abnormalities in animals in first trimester; fetal dental discoloration and maternal hepatotoxicity with large parenteral doses in second or third trimesters.
Trimethoprim: teratogenic in first trimester.
Macrolides: major malformations in first trimester and genital malformations any trimester.

Relatively Contraindicated

Aminoglycosides: potential damage to fetal auditory and vestibular nerves in second and third trimesters.
Metronidazole: avoidance of high dosages is recommended.

Not Known to Be Harmful; Use Only When Necessary

Aciclovir
Penicillins and cephalosporins
Clindamycin
Glycopeptides
Linezolid
Meropenem

Problems with Antimicrobial Therapy in Old Age:

Clostridioides difficile infection: all antibiotics predispose to some extent, but second- and third-generation cephalosporins, co-amoxiclav, and clindamycin especially so.
Hypersensitivity reactions: rise in incidence due to increased previous exposure.
Renal impairment: may be significant in old age, despite creatinine levels being within the reference range.
Nephrotoxicity: more likely, e.g., aminoglycosides.
Accumulation of β-lactam antibiotics: may result in myoclonus, seizures or coma.
Reduced gastric acid production: gastric pH is higher, which causes increased penicillin absorption.
Reduced hepatic metabolism: results in a higher risk of isoniazid-related hepatotoxicity.
Quinolones: associated with delirium and may increase the risk of seizures.

Targets & Mechanisms of Action

1. Antibacterial Agents

Agent/Class	Mechanism of Action
Aminoglycosides, Chloramphenicol, Macrolides, Lincosamides, Oxazolidinones	Inhibit bacterial protein synthesis by binding to subunits of bacterial ribosomes.
Tetracyclines	Inhibit protein synthesis by preventing transfer RNA (tRNA) binding to the ribosome.
β-lactams	Inhibit cell wall peptidoglycan synthesis by competitive inhibition of transpeptidases (penicillin-binding proteins).
Cyclic lipopeptide (Daptomycin)	Inserts lipophilic tail into plasma membrane, causing depolarisation and cell death.
Fluoroquinolones	Inhibit DNA replication by binding to DNA topoisomerases (DNA gyrase and topoisomerase IV).
Glycopeptides	Inhibit cell wall synthesis by binding D-alanine residues of peptidoglycan precursors.
Nitroimidazoles	Reduced form of the drug causes strand breaks in DNA.
Rifamycins	Inhibit RNA synthesis by inhibiting DNA-dependent RNA polymerase.
Sulphonamides & Trimethoprim	Inhibit folate synthesis: sulphonamides inhibit dihydropteroate synthase, trimethoprim inhibits dihydrofolate reductase.

2. Antiviral Agents

Agent/Class	Mechanism of Action
Nucleoside & Nucleotide Analogues (e.g., Acyclovir, Zidovudine)	Inhibit viral DNA/RNA polymerases by chain termination.
Protease Inhibitors (e.g., Ritonavir)	Inhibit viral proteases, preventing processing of viral polyproteins.
Integrase Inhibitors (e.g., Raltegravir)	Block integration of viral DNA into host genome.
Neuraminidase Inhibitors (e.g., Oseltamivir)	Prevent release of new viral particles from infected cells.
Entry/Fusion Inhibitors	Block viral entry into host cells by preventing attachment or fusion.

3. Antifungal Agents

Agent/Class	Mechanism of Action
Polyenes (e.g., Amphotericin B)	Bind to ergosterol in fungal membranes, forming pores and causing leakage.
Azoles (e.g., Fluconazole)	Inhibit ergosterol synthesis by blocking fungal cytochrome P450 enzymes.
Echinocandins (e.g., Caspofungin)	Inhibit β-glucan synthesis, disrupting fungal cell wall.
Allylamines (e.g., Terbinafine)	Inhibit squalene epoxidase, blocking ergosterol synthesis.

4. Antiparasitic Agents

Agent/Class	Mechanism of Action
Antimalarials (e.g., Chloroquine, Artemisinin)	Interfere with heme detoxification or generate free radicals toxic to Plasmodium.
Anti-protozoals (e.g., Metronidazole)	Reduced drug form damages DNA in anaerobic protozoa.
Anti-helminthics (e.g., Albendazole, Ivermectin)	Disrupt microtubules (benzimidazoles) or cause paralysis of helminths (ivermectin).

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