Antibacterial Agents

• Chapter 41 focuses on antibacterial agents

Learning Outcomes

• Use of the gram stain is explained in bacterial identification and understanding culture and sensitivity testing.
• Important terms and their meanings are identified as antibacterial spectrum, bacterial resistance, chemoprophylaxis, and chemotherapy.
• Mechanisms of action, main uses, and most serious adverse effects of specific drugs are explained including: Penicillins, Cephalosporins, Aminoglycosides, Tetracyclines, Sulfonamides, Macrolides, Fluoroquinolones, Miscellaneous antimicrobial drugs, and Antitubercular drugs.
• Preferred therapies for common bacterial infections are explained.

Bacterial Morphology

• Gram stain contains dyes such as crystal violet (purple) and safranin (red).
• Gram-positive bacteria retain a purple color after staining.
• Gram-negative bacteria retain a red color after staining.
• Antibiotic susceptibility testing involves finding the antibiotic to which the bacteria are most susceptible.
• Disk tests and serial dilutions are methods used to determine antibiotic susceptibility.
• Cocci are spherical bacteria, which can occur in pairs (Diplococci), chains (Streptococci), or clusters (Staphylococci).
• Bacilli are rod-shaped bacteria with a straight shape.
• Spirillum are spiral-shaped bacteria that can be twisted.

Chemotherapy

• Involves the usage of drugs to kill or inhibit growth of cancerous cells or infectious organisms.
• Bactericidal drugs kill bacteria.
• Bacteriostatic drugs inhibit the reproduction of bacteria.
• Sources of antibacterial drugs include soil microorganisms and chemical synthesis.
• Antibiotics are chemical substances obtained from microorganisms.
• Antimicrobials are chemical substances obtained by synthesis.
• The antibacterial spectrum refers to the range of bacteria susceptible to an antibiotic.
• Broad-spectrum antibiotics are effective against a wide range of bacteria.
• Drug resistance is the ability of bacteria to resist the effects of an antibiotic.
• Beta-lactamase enzymes are secreted by bacteria and break down certain antibiotics.
• Chemoprophylaxis involves the use of antibiotics before a bacterial infection has occurred to prevent infection.

Penicillin

• Is obtained from mold, with a bactericidal mechanism disrupts cell-wall synthesis.
• The antibacterial spectrum of penicillins is divided into generations, including first, second, third, and fourth-generation drugs.
• First-generation penicillins include Penicillin G and Penicillin V, are narrow spectrum and effective against gram-positive bacteria like streptococci.
• Second-generation penicillins include ampicillin and amoxicillin, have a broad spectrum, and are effective against the same bacteria as first generation.
• Second-generation penicillins are also effective against some gram-negative bacteria, including E. coli and H. influenzae.
• Third-generation penicillins like carbenicillin and ticarcillin have a broader spectrum than second-generation drugs.
• Third-generation penicillins are useful in the treatment against gram-negative P. aeruginosa and P. vulgaris.
• Fourth generation antibiotics include mezlocillin and piperacillin, have the broadest spectrum and can reduce the amount of sodium ingested.
• Fourth generation are not resistant to penicillinase-producing organisms.
• Beta-Lactamase Inhibitors:
  • Penicillinase is an enzyme that prevents penicillin from working.
  • Inhibitors are administered with penicillin antibiotics to block enzyme activity.
  • Inhibitors allow penicillin to continue to work effectively.
  • Augmentin (clavulanic acid), is an example of an inhibitor.
• Common adverse effects include nausea, diarrhea, and, in high doses, convulsions.
• Allergic reactions to penicillin can manifest as rash, fever, and anaphylaxis.
• Carbapenems and monobactams are antibiotics structurally similar to penicillin.
• Carbapenems have a broad spectrum and increased resistance to beta-lactamases.
• Monobactams are highly resistant to penicillinase and are effective against gram-negative bacteria.

Cephalosporins

• Mechanism of action is bactericidal and disrupts cell-wall synthesis.
• Classified into four separate groups based on their spectrum of activity.
• Substituted for penicillin when allergy or resistance is suspected.
• Bacterial resistance exists for cephalosporins, influencing their use.
• First-generation cephalosporins such as cephalexin and cefazolin.
• First-generation cephalosporins are used to treat gram-positive and gram-negative infections, especially K. pneumoniae.
• Second-generation cephalosporins include cefaclor and cefoxitin, have a broader spectrum.
• Second-generation cephalosporins are indicated when first-generation cephalosporins are not effective.
• Second-generation cephalosporins treats B. fragilis, S. marcescens, H. influenzae, and N. gonorrhoeae.
• Third-generation cephalosporins include cefixime, cefdinir, ceftriaxone, ceftazidime, and ceftazidime/avibactam, have a broader spectrum than second-generation antibiotics.
• Third-generation cephalosporins have a longer duration of action.
• Third-generation cephalosporins treat serious gram-negative infections.
• Third-generation cephalosporins can cross the blood-brain barrier.
• Fourth-generation cephalosporins includes cefepime and ceftolozone/tazobactam.
• Fourth-generation cephalosporins have greater resistance to beta-lactamase.
• Fifth-generation cephalosporins include ceftaroline.
• Adverse effects include Gl disturbances, nephrotoxicity, and a disulfiram reaction with alcohol.
• Use is avoided in patients with anaphylactic reactions or hives from penicillin due to potential allergy.

Aminoglycosides

• Effective against gram-negative bacilli but are inactive against anaerobic organisms.
• Bacteriostatic, achieving this by inhibiting protein synthesis.
• Poorly absorbed in the GI tract, making them suitable for abdominal surgery.
• Systemic treatment requires injection because of poor GI absorption.
• Adverse effects, when taken orally, include nausea, vomiting, and diarrhea.
• Adverse effects when injected include nephrotoxicity and ototoxicity.
• Aminoglycosides should not be given during pregnancy.
• Aminoglycosides should not be given with general anesthetics.
• Can lead to muscular blockage and permanent paralysis.
• Amikacin (Amikin): Reserved for serious gram-negative infections, especially those resistant to tobramycin or gentamicin.
• Gentamicin (Garamycin): Reserved for serious gram-negative infections, but can produce ototoxicity.
• Kanamycin (Kantrex): Limited to oral use before intestinal surgery because of toxicity.
• Neomycin: Used orally before intestinal surgery and topically for skin and ocular infections.
• Spectinomycin (Trobicin): Structurally related to aminoglycosides, administered IM for resistant gonorrhea.
• Streptomycin: Used in the treatment of tuberculosis, plague, and tularemia.
• Tobramycin (Nebcin): Reserved for serious gram-negative infections, particularly Pseudomonas aeruginosa.

Tetracyclines

• Broad-spectrum antibiotics that work by interfering with protein synthesis and are bacteriostatic.
• Effective against both gram-positive and gram-negative bacteria.
• Indicated for Rocky Mountain spotted fever, cholera, urethritis, and Lyme disease.
• Tigecycline is specifically used for MRSA.
• Absorption can be inhibited by calcium, antacids, and mineral supplements.
• Common adverse effects include nausea, vomiting, diarrhea, fungal superinfections, and photosensitivity.
• Tetracyclines bind to calcium and are deposited in growing bones and teeth, they can cause mottling and stunted growth.
• Doxycycline (Vibramycin): Highest incidence of phototoxicity, available in 100mg dose taken once per day.
• Demeclocycline (Declomycin): Most frequently used tetracycline, available in 150 mg every 6 hours or 300 mg BID, food doesn't affect absorption.
• Minocycline (Minocin): Highest incidence of vestibular side effects, available in 100 mg every 12 hrs.
• Tetracycline (Sumycin): Absorption decreased by food, available in 250–500 mg every 6 hrs.
• Tigecycline (Tygacil): IV only with 100-mg loading dose, then 50 mg every 12 hrs and is active against many resistant strains.

Sulfonamides

• Synthetic drugs primarily used in topical burn creams and for treating urinary and GI tract infections.
• Mechanism of action is bacteriostatic, as they block the synthesis of folic acid.
• Common adverse effects include nausea, vomiting, diarrhea, crystalluria.
• Other adverse effects include allergic reactions (rash and photosensitivity) and Stevens-Johnson syndrome.
• Drug interactions can occur with anticoagulants and hypoglycemics.
• Trimethoprim increases the effectiveness of sulfonamides by further inhibiting folic acid synthesis.
• Sulfonamides, including trimethoprim-sulfamethoxazole (TMP/SMZ), are effective against a broad spectrum of gram-positive and gram-negative bacteria.
• Used for respiratory, urinary, GI, ear, sinus, and pneumonial infections.
  • Mafenide (Sulfamylon): Used in burn cases to prevent infection. (Topical)
  • Silver sulfadiazine: Used in burn cases to prevent infection. (Topical)
  • Sulfacetamide (Sulamyd): Used for ocular infections. (Topical)
  • Sulfamethoxazole: Treats urinary tract infections. (Intermediate acting)
  • Sulfasalazine (Azulfidine): Treats ulcerative colitis. (Long acting)
  • Sulfisoxazole: Treats urinary tract infections. (Short acting)
  • Trimethoprim-sulfamethoxazole (Bactrim, Septra): Treats respiratory, urinary infections. (Synergistic action)

Macrolide Antibiotics

• Bacteriostatic and inhibit protein synthesis.
  • Erythromycin: Effective treatment for Legionnaire's disease and genital infections caused by C. trachomatis.
  • Azithromycin: Long half-life, useful for ear and respiratory infections.
  • Clarithromycin: More potent than erythromycin and treats the same bacteria, also effective against Lyme disease.
  • Telithromycin: Antibacterial spectrum similar to azithromycin and clarithromycin, and is indicated for respiratory infections.

Fluoroquinolone Antimicrobials

• Synthetic antimicrobials with a broad-spectrum activity, primarily targeting gram-negative bacteria.
• Well-absorbed in the body.
  • Ciprofloxacin: Bactericidal. It inhibits bacteria's ability to replicate and is useful treatment of urinary, respiratory, bone, and soft tissue infections.
• Common adverse effects include headache, dizziness, Gl disturbances, and photosensitivity.
• Less common adverse effects are aortic dissection and tendon rupture.
• Has evidence that suggests it can cause cartilage defects, tendonitis, and joint pain.
• Not recommended for children or pregnant women.
  • Ciprofloxacin (Cipro): Administered PO, IV, BID. Highest activity against gram-negative organisms treats anthrax, resistant tuberculosis
  • Gemifloxacin (Factive): Administered PO, once/day. Has increased gram-positive activity and treats respiratory infections
  • Levofloxacin (Levaquin): Administered PO, IV, once/day. Has increased gram-positive activity and treats respiratory and urinary infections
  • Delafloxacin (Baxdela): Administered PO, IV, twice daily. Treats respiratory and skin structure infections
  • Moxifloxacin (Avelox): Administered PO, IV, once/day. Has increased gram-positive activity and treats respiratory and anaerobic infections
  • Norfloxacin (Noroxin): Administered PO, BID. Treats urinary tract infections
  • Ofloxacin (Floxin): Administered PO, BID. Treats urinary tract infections

Miscellaneous Antimicrobial Drugs

• Chloramphenicol: Broad-spectrum antibiotic used for serious or life-threatening infections, and inhibits cell-wall synthesis.
• Clindamycin: Bacteriostatic, inhibits protein synthesis. It is effective against gram-positive and anaerobic organisms.

Miscellaneous Antimicrobials

• Metronidazole: Bactericidal, effective against bacteria and protozoa, used against anaerobic bacteria.
• Vancomycin: Bactericidal, interferes with cell-wall synthesis and is indicated for treating resistant staphylococcal infections (MRSA).

Antitubercular Drugs

• Used to treat tuberculosis, an infection caused by M. tuberculosis.
• Tuberculosis usually affects the lungs, but can spread to other body areas.
• Combination therapy is the best approach due to an increase in bacterial resistance to drug therapy.
  • Isoniazid (INH): Bactericidal, inhibits cell-wall synthesis. Common adverse effects include peripheral neuritis and hepatitis.
  • Rifampin: Inhibits enzyme required for RNA and has a wider antibacterial spectrum than isoniazid.
  • Ethambutol: A bacteriostatic drug which inhibits cell-wall synthesis and side effects such as fever, rash, and Gl disturbances.
  • Pyrazinamide: A derivative of nicotinamide, effects increased by acidic conditions. Common adverse effects include hepatotoxicity, hyperuricemia, and symptoms of gout.
  • Aminosalicylic acid (Paser): Mechanism of action, Bacteriostatic, inhibits folic acid synthesis and the toxicity is GI disturbances and hypersensitivity reactions.
  • Capreomycin (Capastat): The mechanism of action is, Bacteriostatic, inhibits protein synthesis and the toxicity is ototoxicity and nephrotoxicity.
  • Cycloserine (Seromycin): The mechanism of action, Bacteriostatic, inhibits cell-wall synthesis and the toxicity is peripheral neuropathy, CNS disturbances.
  • Ethionamide (Trecator-SC): The mechanism of action, Bacteriostatic, blocks synthesis mycolic acid and the toxicity is neurotoxicity, GI disturbances, and GI disturbances.

Preferred Therapies

• Upper respiratory infections: Amoxicillin and amoxicillin plus clavulanic acid / Second-generation cephalosporins or azithromycin and clarithromycin.
• Community-acquired pneumonia: Macrolides, azithromycin, or clarithromycin / Second-generation cephalosporins and doxycycline.
• Urinary tract infections: Trimethoprim/sulfamethoxazole / Fluoroquinolones.
• Gonococcal infections: Cephalosporins / Cefixime or ceftriaxone.
• Syphilis infections: Benzathine penicillin / Ceftriaxone and doxycycline.
• Chlamydial infections: Azithromycin or doxycycline.