Antibacterial Drugs (Part 2)

Prokaryotic Structure

70S size, located free in the cytoplasm

Eukaryotic Structure

80S size, located attached to endoplasmic reticulum and free in cytoplasm 

Tetracyclines Examples

Tetracycline, doxycycline, minocycline

Tetracyclines

Broad-spectrum antibacterials derived from streptomyces and with bacteriostatic activity

Tetracycline MOA

Binds to 30S ribosomal subunit and prevents attachment of aminoacyl-tRNA to the ribosome, inhibiting bacterial protein synthesis

Therapeutic Uses of Tetracyclines

Respiratory, UTIs, skin infections (acne), STIs, rickettsial infections, lyme disease

Tetracyclines Adverse Reactions

GI upset, photosensitivity, discoloration of teeth, hepatoxicity, intracranial hypertension, blood disorders

Contraindications of Tetracyclines

Pregnancy, breastfeeding, children under 8 years of age

Macrolides Examples

“-romycin”

Macrolides

Broad-spectrum antibacterials derived from Streptomyces, bacteriostatic effect with time-dependent effect

Macrolides MOA

Binds to the 50S ribosomal subunit and blocks translocation of peptides, inhibiting bacterial protein synthesis

Therapeutic Uses of Macrolides

Gram+ and atypical bacterial infections, RITs, STIs, whooping cough

Macrolides Adverse Reactions

GI upset, taste disturbances with clarithromycin, hepatotoxicity, QT prolongation, cardiac arrhythmias, cholestatic jaundice

What does macrolides inhibit?

CYP3A4 enzyme increasing levels of drug metabolized by CYP3A4 (statins, warfarin, theophylline)

Macrolides Contraindications

History of cholestatic jaundice or hepatic dysfunction with prior use, known hypersensitivity

Precautions with Macrolides

Hepatic impairment, monitor for signs of QT prolongation, especially in patients with cardiac conditions

Immunomodulatory + Anti-Inflammatory Effects of Macrolides

Inhibit cytokine production, reduce neutrophil activity, decrease bacterial virulence, suppress inflammatory cytokines

Macrolides Absorption

Food decrease absorption of erythromycin (azithromycin + clarithromycin are less affected)

Macrolides Metabolism

Primarily metabolized by liver, especially by CYP3A4

Macrolides Distribution

Wide distribution with excellent tissue and fluid penetration

Macrolides Excretion

Via bile in feces (except for azithromycin)

Lincosamides

Bacteriostatic drugs with time-dependent antibacterial effect, safe in pregnancy

Lincosamides MOA

Inhibits protein synthesis by binding to the 50S ribosomal subunit

Therapeutic Uses of Lincosamides

Reserved for serious infections, effective against anaerobic bacteria (except C. diff), osteomyelitis

Lincosamides Absorption

High oral bioavailability

Lincosamides Metabolism

Primarily hepatic

Lincosamides Excretion

Both renal and fecal excretion

Lincosamides Distribution

Good penetration into most body fluids and tissues, including bone

Lincosamides Adverse Reactions

N/D, rash, C. diff diarrhea, hepatotoxicity

Contraindications of Lincosamides

History of GI disease (particularly colitis), allergy to lincosamides

Aminoglycosides Examples

Gentamycin, tobramycin, amikacin, neomycin

Aminoglycosides

Bactericidal drugs, mainly effective against aerobic gram-

Aminoglycosides MOA

Inhibits the 30S ribosomal subunit, causing misreading of mRNA

Aminoglycosides Therapeutic Uses

Sepsis, respiratory tract infections, complicated UTIs caused by aerobic gram- bacteria

Aminoglycosides Absorption

Poor oral absorption, typically administered via IV

Aminoglycosides Metabolism

Minimal metabolism, activity dependent on renal function for excretion

Aminoglycosides Distribution

Rapid distribution into extracellular fluids (water soluble), poor penetration into CNS

Aminoglycosides Excretion

Almost entirely excreted unchanged by the kidneys, useful in complicated urinary infections

Aminoglycosides Adverse Reactions

Neuromuscular blockade, nephrotoxicity, ototoxicity

Contraindications of Aminoglycosides

Pre-existing renal or auditory impairment

What type of drugs are Aminoglycosides?

Concentration-dependent drugs

Sulfonamides Examples

“Sulfa-”

Folate + Sulfonamides

Essential for the synthesis of nucleotides (building blocks of DNA/RNA), converted into DHF then THF

Tetrahydrofolate (THF)

Coenzyme that facilitates the nucleotide synthesis

What does the inhibition of folate synthesis result in?

Interruption of cell division and proliferation

Sulfonamides MOA

Competes with para-aminobenzoic acid (PABA), inhibiting dihydropteroate synthase and the folate synthesis, indirectly affects the bacterial synthesis of nucleotide + DNA/RNA

What type of drugs are Sulfonamides?

Antimetabolite drugs with bacteriostatic effects

Sulfonamides Therapeutic Uses

Effective against a broad spectrum of gram+/gram- bacteria, UTIs, respiratory infections

Sulfonamides Absorption

High oral bioavailability

Sulfonamides Distribution

Well distributed in the body, including fluids and tissues

Sulfonamides Metabolism

Metabolized in the liver

Sulfonamides Excretion

Primarily excreted through the kidneys

Sulfonamides Adverse Reactions

Stevens-Johnson syndrome, hemolytic anemia, photosensitivity, agranulocytosis, skin rash, fever

Sulfonamides Contraindications

Pregnant, renal or hepatic failure, allergy to sulfonamides

Trimethoprim MOA

Inhibits bacterial dihydrofolate reductase, blocking the production of tetrahydrofolate needed for nucleic acid synthesis

What type of drug is Trimethoprim?

Antimetabolite drug with bacteriostatic effects

What happens hen Trimethoprim and Sulfonamides are combined?

Enhances antibacterial efficacy resulting in bactericidal effect

Trimethoprim Therapeutic Uses

Pneumocystis pneumonia, UTIs, RTIs

Adverse Effects of Trimethoprim

N/V, rash, hyperkalemia, anemia, leukopenia, thrombocytopenia

What type of drugs are Fluroquinolones?

Bactericidal drugs, concentration-dependent drugs

Fluroquinolones MOA

Inhibit bacterial DNA gyrase and topoisomerase IV (which are crucial for DNA replication and cell division)

Fluroquinolones Examples

“-Floxacin”

Fluroquinolones Therapeutic Uses

RTIs (tuberculosis), UTIs, genital infections, bone + joint infections

Fluoroquinolones Absorption

Good oral absorption, affected by food, antacids, iron supplements

Fluoroquinolones Distribution

Wide distribution into body tissues and fluids

Fluoroquinolones Metabolism

Liver metabolism varies by drugs, ciprofloxacin has minimal metabolism

Fluoroquinolones Excretion

Primarily renal excretion for ciprofloxacin and levofloxacin, moxifloxacin mainly excreted in bile

Fluoroquinolones Adverse Reactions

Tendonitis + tendon rupture, QT prolongation, GI discomfort 

Fluoroquinolones Contraindications

Tendon disorders, myasthenia gravis, pregnancy, pediatric use, QT prolongation 

Fluoroquinolones Mechanism of Resistance

Efflux pumps, target site mutations, reduced porin expression

What type of drug is Metronidazole?

Bactericidal drug with narrow spectrum

Metronidazole MOA

Activated in anerobic conditions, damaging DNA in bacteria and protozoa (nitro group is reduced in anaerobic conditions becoming highly reactive)

Metronidazole Therapeutic Uses

C. diff, H. pylori, protozoa infections, and other anaerobic bacteria

Metronidazole Absorption

Well absorbed orally with over 80% bioavailability

Metronidazole Distribution

Wide distribution, including reading the CNS and crossing placental barrier

Metronidazole Metabolism

Hepatically metabolized

Metronidazole Excretion

Primarily via kidneys, some metabolites are excreted in the urine

Metronidazole Adverse Reactions

Neurotoxic effects (neuropathy), potential carcinogenic effects with long-term use, metallic taste in mouth

Daptomycin

Cyclic lipopeptide with bactericidal effect against all gram+ bacteria (including MRSA)

Daptomycin MOA

Binds to bacterial cell membrane (Ca2+ dependent), forms pores, causing membrane depolarization (K+ leaks out) l/t rapid bacterial cell death

Daptomycin Therapeutic Uses

Effective against MRSA and other resistant strains of gram+ bacteria

Daptomycin Absorption

Administered IV, not suitable for oral administration

Daptomycin Metabolism

Minimal metabolism, mostly excreted unchanged

Daptomycin Excretion

Primarily renal excretion

Daptomycin Distribution

Rapid distribution into tissues + fluids, including lungs and infected tissues

Daptomycin Adverse Reactions

Myopathy, eosinophilic pneumonia, GI symptoms, muscle pain/weakness

Contraindications of Daptomycin

Muscle toxicity with statins, renal impairment, hypersensitivity, ineffective with pulmonary infections

Drug Resistance

Resistance of bacterial to antibacterial drugs that were once effective

Factors Contributing to Drug Resistance

Overuse, misuse, hospital use, global travel and trade, lack of new antibacterials, poor hygiene and sanitation

Mechanisms of Drug Resistance

Active efflux pumps, target protection, antibacterial-modifying enzymes, target bypass, decreased influx, target site modification

Intrinsic Bacterial Resistance

Naturally occurring resistance in certain bacterial species

Acquired Bacterial Resistance

Resistance that develops through mutation or acquiring resistance genes

Cross Bacterial Resistance

Resistance to multiple antibacterials within the same class

Multi Drug Bacterial Resistance

Bacteria resistant to multiple classes of antibacterials

Pan Bacterial Resistance

Bacteria resistant to all available antibacterials

Antibacterial De-Escalation

Switching from broad-spectrum antibacterials to narrower-spectrum antibacterials based on culture results and patient clinical status

Importance of Antibacterial De-Escalation

Prevents adverse reactions and reduces antibacterials resistance