Anti-infective Agents

Bacterial Morphology

• Bacteria are classified by bacterial shape and colony arrangement

• Cocci are spherical in shape and usually arranged in pairs (diplo), chains (strepto), or clusters (staphylo)

• Bacilli are rod-like in shape

• Spirilla are curved and rod-like in shape

Gram Staining• Gram staining classification is based on ability of

the bacterial membrane to stain either red or blue• Bacteria that take up the red stain are classified as

gram positive, Gm(+)• Bacteria that take up the blue stain are classified as

gram negative, Gm(-)• Gm(-) bacteria have an additional outer

lipopolysaccharide membrane layer (endotoxin) that is toxic and that can produce endotoxic shock

Antibacterial Chemotherapy• Defined as the use of drugs to kill or inhibit

the growth of infectious bacteria

• Bactericidal drugs kill the bacteria

• Bacteriostatic drugs inhibit the growth of bacteria and body defenses and immune mechanisms are required to rid the body of infecting bacteria

Antibacterial Spectrum

• Refers to the range of bacteria that are killed or inhibited by any antibacterial drug

• Narrow spectrum drugs are effective against a limited number of different bacterial species

• Broad spectrum drugs are effective against a wide range of different bacterial species

Bacterial Resistance• Bacteria have the ability to produce proteins that help

them resist antimicrobial drug actions• Some bacteria produce beta-lactamase enzymes that

inactivate penicillins and cephalosporins • Some bacteria produce proteins that prevent drugs

from penetrating the bacterial membrane or proteins that remove the drugs once they have passed through the bacterial membrane

• When bacterial resistance occurs other drugs must be used to treat the infection

Penicillins

• Bacteriocidal drugs that inhibit cell wall synthesis• 1st generation drugs have a narrow spectrum and

indicated mostly for Gm(+) infections• 2nd generation drugs have a wider spectrum that

includes most common Gm(+) / Gm(-) bacterial infections

• 3rd and 4th generation drugs have a broad spectrum and are effective against most Gm(-) bacteria

Cephalosporins

• Bacteriocidal drugs that inhibit cell wall synthesis• 1st generation drugs are effective against most

common Gm(+) and Gm(-) bacteria• 2nd, 3rd, and 4th generation cephalosporins have

increasing activity against Gm(-) bacteria• Cephalosporins are the drugs of choice for

infections caused by Klebsiella pneumoniae• Cephalosporins are more resistant to inactivating

beta-lactamase enzymes than penicillins

Adverse Effects Common to Penicillins and Cephalosporins

• Minor GI disturbances and diarrhea• Hypersensitivity or allergic reactions that

include delayed skin reactions or immediate anaphylactic reactions

• Higher dosages may cause bleeding problems• Higher dosages may cause CNS disturbances

and possible seizures

Aminoglycosides

• Classified as broad spectrum antibiotics• Bacteriocidal drugs that inhibit bacterial

protein synthesis• Administered IM or IV for systemic effects • Usually the drugs of choice for serious

gram negative infections• Nephrotoxicity and ototoxicity are the most

serious adverse effects

Tetracyclines

• Basteriostatic drugs that inhibit bacterial protein synthesis

• Administered orally, but not with dairy or antacid products

• Doxycycline is the most widely used tetracycline and usually taken once per day

• Adverse effects include GI disturbances, rash, and photosensitivity

• Tetracyclines are contraindicated during pregnancy, nursing, and in children < age 8

Sulfonamides

• Bacteriostatic drugs that inhibit bacterial folic acid synthesis

• Sulfonamides are mainly indicated for treatment of urinary tract infections

• Trimethoprim/sulfamethoxazole has a broad antibacterial spectrum and many indications

• Adverse effects include rash, allergy, blood disorders, and renal tubule damage

Macrolide Antibiotics

• Bacteriostatic drugs that inhibit bacterial protein synthesis, effective with oral administration

• Erythromycin often used in penicillin allergic patients for minor ear and throat infections

• Azithromycin and clarithromycin have a broader antibacterial spectrum and clinical uses

• Adverse effects include heartburn, rashes, and GI disturbances

Fluroquinolones

• Bactericidal drugs that inhibit an enzyme essential to the function of bacterial DNA

• Administered orally• Indicated for a wide variety of urinary, soft tissue,

bone, and respiratory infections• Adverse effects include GI disturbances, rash,

photosensitivity, and joint pain• Contraindicated in pregnancy and young children

Miscellaneous Antimicrobials

• Chloramphenicol is reserved for serious infections such as typhoid fever and meningitis

• Clindamycin indicated for Gm(+) and anaerobic infections

• Vancomycin indicated for resistant Gm(+) staphylococcal infections

• Quinupristin-dalfopristin and linezolid indicated for Gm(+) infections resistant to vancomycin

Drugs Used to Treat Tuberculosis

• Tuberculosis requires prolonged treatment with multiple drugs, usually 3 or 4 different drugs

• The first line drug regimen includes isoniazid, rifampin, pyrazinamide, and ethambutol

• After 2–4 months of treatment ethambutol and pyrazinamide are usually eliminated

• Isoniazid and rifampin therapy is continued for 6–12 months

• Drug resistance is a major problem

Anti-viral and Anti-fungal drugs

Clinical Indication

Antifungal drugs

Prevention or treatment of mild to severe fungal infections

Antiviral drugs

Prevention and treatment of viral infections, especially seriously ill and elderly patients

Fungal InfectionsInfections Site Drug Action Systemic Blood, brain, lungs fungicidalaspergillosis amphotericin B,histoplasmosis ketaconazolecandidiasis miconazolecryptococcosis nystatin

Dermatophytic Hair, skin, nails fungicidalAthlete’s foot haloproginRingworm tolnaftate

fungistaticgriseofulvin

Candida albicans Skin fungicidalmucous membranes ketaconazolevagina miconazole

nystatin

Mechanism of Antifungal Action

Fungicidal: Capable of killing fungi

Drugs bind to fungal membranes and increase permeability,nutrients leak out, and fungi die

Drugs: amphotericin B, ketaconazole, miconazole, nystatin

Fungistatic: Limits the growth of active fungi but does not eradicate the microorganisms

Drug binds to keratin in the skin and hair so fungi cannot enter the tissue and undergo further growth

Drug: griseofulvin

Contraindications

Antifungal drugs are contraindicated in

patients with history of hypersensitivity

Griseofulvin is contraindicated in patients with Porphyria and hepatic failure. It should not be used during pregnancy

Viral Diseases Acquired immunityProtection against developing a clinical viral infectionobtained by • experiencing the infection

or• vaccination with the weakened or dead virus

The immune system produces proteins that recognize viruses at the next infection and inhibit viral interaction with the host cells

Examples- smallpox, chicken pox, measles, polio

Viral Diseases

No immunity transferred with infection• Influenza• Herpes simplex• Human immunodeficiency virus (HIV)

– virus goes undetected within the human cells for years

– virus attacks the lymphocytes – progressive immunosuppression– opportunistic infections develop– clinical signs and symptoms characterize

AIDS (acquired immunodeficiency syndrome)

Propagation of Viruses• Totally dependent on the metabolic system of

the human host cells

• Attach to cell membranes to inject viral DNA or RNA into the cell

• Enter nucleus to direct production of more viruses according to the nucleic acid blue print

• Cells rupture to “shed” new viruses to infect other host cells

Antiviral DrugsInfluenzaAmantadine, rimantadine

HIVDidanosine, lamivudine, saquinavir, zidovudine

CytomegalovirusCidofovir, foscarnet, ganciclovir

Genital Herpes, Herpes zoster, chicken poxAcyclovir, famciclovir, valacyclovir

Herpes simplex keratitisIdoxuridine, trifluridine, vidarabine

Antiviral Drugs—Mechanisms of Action• Inhibition of cell penetrationAmantadine stops Asian strain (A2) when administered prophylactically (20 hrs ahead)

• Transcription of viral proteinsDidanosine, lamivudine, stavudine, zalcitabine, zidovudineinhibit reverse transcriptase so HIV RNA cannot be duplicated

• Inhibition of viral synthesisAcyclovir, idoxuridine, vidarabine incorporate into HIV DNA and impair protein synthesis

• Protease inhibitorsIndinavir, ritonavir, saguinavir inhibit HIV proteases that are essential to make HIV infectious

Special ConsiderationsHIV protease inhibitors inhibit liver metabolism centers (P450) so that other medications mayaccumulate in the blood because of blocked ordelayed metabolism

Renal impairment will cause antiviral drugs toaccumulate in the blood. Dose adjustment will be required

Amantadine and rimantidine doses must be reduced in theelderly where renal clearance has decreased

Anti-HIV Drugs Adverse Effects

• Nausea Nephrotoxicity• Gastritis Inhibition of hepatic metabolism• Vomiting anemias• Diarrhea• Headache• Confusion• Dizziness• Insomnia• Arthralgia• Allergic reactions, edema, rash• Hypertension

Characteristics of AntimalarialsHighly bound to plasma proteinsMetabolized in the liverProduce antiinflammatory response in

immuno/inflammatory conditions e.g. rheumatoid arthritis, lupus, polymositis

Relax skeletal muscleStimulate contraction of uterine muscleDepress cardioconduction (increase PR & QT

intervals on the ECG)

Adverse Effects of AntimalarialsAdverse effects are related to the magnitude of the dose

and chronic use of the drugs• Nausea• Diarrhea• Headache• Blurred vision• Vertigo• Rash• Cinchonism – sensitive individuals experience

ringing in the ears (tinnitus) and headache from CNS stimulation

Protozoal DysentaryGiardia lamblia and Entameba histolytica enter

the gastrointestinal tract

Symptoms of acute infectionIrritation of intestinal tissueInflammation and painSpasm of anal sphincter (tenesmus)DiarrheaFatigue and muscle weakness Loss of body water and electrolytes

Chronic Entamebic Dysentary

Entamebic histolytica can burrow into the wall of the liver creating an inflammation and abscess in the absence of other typical symptoms

Antidysentery DrugsParomomycinTetracyclines

Metronidazole

Chloroquine, iodoquinol

Antibiotics inhibit the growth of intestinal bacteria that provide critical nutrients to the protozoa

Antibiotic that distributes to all tissues including bone, bile, liver abscesses and intestines to reach all protozoa. Amebicidal.

Attach to protozoa DNA and impair critical protein synthesis

Parasitic Worm Infestation

• Pinworms

• Roundworms

• Tapeworms

Enter the gastrointestinal tract with food or soil containing worm eggs

Worms hatch with the intestines

Worms are shed in the feces

Symptoms of Worm Infestation Common symptoms

Diarrhea

Nausea

Loss of appetite

Abdominal cramping

Itching (anus)

Hookworms, tapeworms Perforate intestines Blood loss Anemia

Anthelmintic Drugs

• Pinworms, roundwormsMebendazole, pyrantil pamoate,

thiabendazole

• Tapeworms Praziquantel

Anthelmintic Drugs

• Remain within the intestine

• Decrease worm motility by paralyzing theparasites’ muscles

• Peristalsis and laxatives move the worms and eggs out of the intestines

Anthelmintic Drugs: Adverse Effects• Nausea

• Fever

• Headache

• Cramps

• Diarrhea

• Tinnitus

• Hypotension

Antiseptics and Disinfectants

Clinical Indication

Prevent or control infection of living (antiseptics) surfaces and nonliving (disinfectants) surfaces including:

• countertops, floors, equipment, instruments

• skin, mucous membranes

Forms of Antiseptics & DisinfectantsChemical solutions containing

• Alcohols (ethanol, isopropanol)• Aldehydes (formaldehyde)• Halogenated compounds (iodine)• Iodophors (povidone-iodine)• Phenols (hexachlorophene, triclosan)• Oxidizers (hydrogen peroxide)• Heavy metals (silver nitrate, mercurial)• Quaternary ammoniums (benzalkonium chloride)

Method or Route of Administration

Topical application or wash-down surfaces

• Swab, sponge, scrub• Mouthwash (occasionally)

Cidal- Kills the microorganisms e.g., bacteriocidal, virucidal, germicidal

Static- Inhibit or slow the growth of microorganisms but does not eradicate all organisms e.g. bacteriostatic, fungistatic

Sterilization- complete eradication of all microorganisms

Spectrum of activity- broad (or narrow) indicates the potency to eliminate a large variety of organism types (or limited in the type of microorganisms it affects)

Terminology

Nosocomial – infection acquired while staying in a hospital or institution such as nursing home

Irrigation – method of washing a fluid antiseptic over the tissue(s) to remove the organisms

Active vehicle – the solution used to dissolve an antiseptic has separate definite ability to destroy microorganisms

Topical – applied to a surface, not swallowed or injected

Systemic – reaches the blood stream (circulation) after administration

Terminology

Main Uses

• Reduce the need for antibiotics by eliminating potential pathogenic infectious organic material on nonliving surfaces

• Reduce the growth and contamination of wounds (burns, skin ulcers)

• Eliminate microorganism from entering punctures encountered in procedures such as spinal, regional anesthesia, blood draws for clinical laboratory analysis

Adverse Effects

• Dry skin, rash, hypersensitivity • Eczamoid dermatitis (high dose long term exposure)• Hypothyroidism (iodine absorption)• Neurotoxicitity (hexachlorophene)

From Topical Application

From Internal Absorption• Anorexia • Vomiting• Internal cramping• Convulsions• Death