Antibiotics

Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi or viruses. Antibiotics are antimicrobials that are effective against bacteria only. Antibiotics either destroy bacterial structure by targeting bacterial cell walls, cell membranes, etc. Or they inhibit bacterial growth and metabolism by targeting bacterial enzymes. Antibiotics can be classified according to the mechanism of action, as discussed below.

Cell wall active agents: This group includes different types of antibiotics that target the cell wall of bacteria and eventually disrupt the cell wall, hence killing the bacteria. They include beta lactam antibiotics, glycopeptides, and bacitracin.

Beta lactam antibiotics bind to the penicillin binding proteins or PBPs, which are building blocks of the peptidoglycan layer in the bacterial cell wall and break it. They all have a beta-lactam ring in their structures. They include penicillins, cephalosporins, carbapenems and monobactams.

Penicillins are the most commonly used group of antibiotics. They vary in what type of bacteria are killed and resistance to inactivating enzymes like penicillinase and beta lactamase. Commonly used penicillins are ampicillin (Principen), amoxicillin (Amoxil), penicillin V (Penicillin VK, Veetids), and penicillin G benzathine (Bicillin L-A). Certain penicillins are combined with beta lactamase inhibitors like clavulanate, sulbactam, and tazobactam to make them resistant to the action of beta lactamase enzyme, e.g., amoxicillin with clavulanate (Augmentin), ampicillin with sulbactam (Unasyn) and piperacillin with tazobactam (Zosyn).

Cephalosporins have a broader spectrum of activity compared to penicillins. Depending on modifications over time, cephalosporins have been divided into five generations, with the fifth generation being the newest one. First generation are mostly effective against gram-positive bacteria and include cephalexin (Keflex), cefadroxil (Duricef), and cefazolin (Ancef). Second-generation bacteria are active against some gram-negative bacteria as well. They include cefaclor, cefoxitin, cefprozil, and cefuroxime (Zinacef). Third generation are broader spectrum than the second and first generation and includes cefotaxime (Claforan), ceftriaxone (Rocephin), cefixime (Suprax), cefpodoxime and ceftazidime (Fortaz, Tazicef). Third generation are active against some drug resistant gram-negative and gram-positive bacteria. Cefepime (Maxipime) is the only available option. Fifth generation includes ceftaroline (Teflaro).

Carbapenems are broad spectrum bactericidal antibiotics effective against both gram positive and gram negative bacteria as well as anaerobes. Examples include meropenem (Merrem), imipenem-cilastatin (Primaxin), doripenem (Doribax) and ertapenem (Invanz).

Monobactams are effective against aerobic gram negative bacteria only. Aztreonam (Azactam, Cayston) is most commonly used.

Glycopeptides inhibit cell wall synthesis by binding to D-alanyl D-alanine, a component of the peptide chain. They include vancomycin (Vancocin, Firvanq).

Bacitracin is a polypeptide antibiotic that inhibits cell wall synthesis by binding to and blocking a carrier molecule involved in the transport of polysaccharides, peptidoglycans, and lipopolysaccharides to the growing bacterial cell wall. It is sold individually as Baci-IM and in combination with other antibiotics, polymyxin and neomycin, as Neosporin.

Cell membrane active agents: Colistin and polymyxin B disrupt the bacterial cell membrane. They are cationic polypeptides that bind to anionic lipopolysaccharide in the outer membrane of gram negative bacteria, leading to displacement of Ca++ and Mg++ ions.

Antibiotics inhibiting bacterial protein synthesis: Some antibiotics inhibit protein synthesis in ribosomes in the bacterial cell. Bacterial ribosomes have two subunits - 50S and 30S. Some antibiotics act on the 30S subunit. They include aminoglycosides, tigecycline, and tetracyclines. Antibiotics acting on 50S subunit include chloramphenicol, linezolid, clindamycin, and macrolides.

Common aminoglycosides include gentamicin (Garamycin), streptomycin, amikacin (Amikin), tobramycin (Tobi, Kitabis Pak, Bethkis), and paromomycin (Humatin). Tetracyclines include tetracycline (Ala-tet), doxycycline (Adoxa, Doryx), minocycline (Dynacin, Minocin, Solodyn), and demeclocycline. Tigecycline is available as Tygacil.

Macrolides are wide spectrum bacteriostatic drugs that include azithromycin (Zithromax), erythromycin (EES Granules, Ery-tab,Erythrocin, Eryped), fidaxomicin (Dificid) and clarithromycin (Biaxin XL). Linezolid is sold as Zyvox. Clindamycin is sold as Cleocin, ClindaMax and Clindesse.

Inhibitors of DNA synthesis: They inhibit DNA synthesis or replication and include quinolones, sulfonamides, and trimethoprim. Fluoroquionolones inhibit the enzyme DNA gyras,e also known as topoisomerase IV. Sulfonamides and trimethoprim inhibit different steps in the folate synthesis. Sulfonamides are competitive inhibitors of dihydropteroate synthase, while trimethoprim inhibits dihydrofolate reductase.

Quinolones include ciprofloxacin (Cipro), levofloxacin (Levaquin), gemifloxacin (Factive), moxifloxacin (Avelox) and ofloxacin (Floxin). The sulfonamide sulfamethoxazole is sold in combination with trimethoprim as Bactrim and Bactrim DS. Trimethoprim (Primsol) is also used alone in certain infections.

Metronidazole: Metronidazole forms free radicals within the bacterial cell that damage bacterial DNA. It is useful against anaerobic bacteria. It is sold as Flagyl, Flagyl ER and Likmez.

Nitrofurantoin: Nitrofurantoin is sold under the brand names Macrobid, Macrodantin and Furadantin. Nitrofurantoin affects bacterial metabolism through intermediary metabolites and is effective against both gram-positive and gram-negative bacteria, in the treatment of lower urinary tract infections (UTIs). Adverse effects include nausea, heartburn, gas, headache, hair loss, and rarely liver and lung dysfunction and peripheral neuropathy. Nitrofurantoin may cause false test results in urine glucose tests and change urine color to dark yellow or brown. It is contraindicated in patients with a history of cholestatic jaundice and G6PD deficiency.

Adverse effects of antibiotics: Nausea, gastrointestinal upset, and diarrhea are common adverse effects of antibiotics. Some unique adverse effects are discussed below.

Aminoglycosides: Nephrotoxicity, muscle weakness and paralysis, hearing loss.

**Fluoroquinolones: **Tendinitis, bone and cartilage anomalies like Achilles tendon rupture, prolongation of QTc, pseudomembranous colitis, photosensitivity.

Chloramphenicol: Aplastic anemia, “gray baby” syndrome due to severe inhibition of red blood cell production in the bone marrow.

Macrolides: Hypersensitivity reactions, erythromycin and clarithromycin have highest risk of QTc prolongation, cholestatic jaundice, tinnitus and deafness; clarithromycin and erythromycin are potent inhibitors of liver enzymes cyt P450.

Colistin and Polymyxin B: Nephrotoxicity

Tetracyclines: Yellowing of teeth, dizziness, vertigo, pseudomembranous colitis, photosensitivity, fatty liver, risk of esophageal ulcerations

Trimethoprim plus sulfamethoxazole: Stevens-Johnson syndrome, crystalluria, kernicterus (severe jaundice in neonates), renal failure, sulfa allergies.

Metronidazole: Neuropathy, headache, seizures, alcohol withdrawal syndrome with severe nausea, vomiting, dizziness, sweating, etc when taken with alcohol.

Clindamycin: Pseudomembranous colitis, esophageal ulcers

Imipenem: Seizures

Cephalosporins: Pseudomembranous colitis, hypersensitivity reactions, leukopenia, thrombocytopenia, Coombs positive hemolytic anemia

Penicillins: Hypersensitivity reactions, rashes, anaphylaxis, urticaria, angioedema, serum sickness, exfoliative dermatitis, seizures, nephritis, pseudomembranous colitis, Coombs positive hemolytic anemia, leukopenia, thrombocytopenia. Patients who are allergic to penicillin may show 2-10% cross reactivity to cephalosporins.

Vancomycin: Hypersensitivity reactions like rash, fever, neutropenia, phlebitis, and “red man” syndrome due to histamine release on rapid intravenous infusion.

Bacteria employ various mechanisms to acquire resistance to antibiotics. Not only do they themselves become resistant but they can transfer this characteristic to other species of bacteria via plasmids and transposons. Resistance mechanisms include decreased uptake of antibiotic by reducing number or porins in the bacterial cell membrane or pumping out by using efflux pumps, modifying target site to prevent binding of the antibiotic and enzymatic inactivation of antibiotic.

Methicillin resistant Staphylococcus aureus or MRSA: They are highly resistant Staphylococci that are resistant to penicillins, cephalosporins and carbapenems. They can cause skin and systemic infections and sepsis. MRSA is treated with vancomycin, linezolid, trimethoprim-sulfamethoxazole, clindamycin, daptomycin and doxycycline.