Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 50. Miscellaneous Antimicrobial Agents & Urinary Antiseptics

Miscellaneous Antimicrobial Agents & Urinary Antiseptics: Introduction

This chapter includes miscellaneous agents that have antibacterial activity, urinary tract and other antiseptics, and disinfectants.

High-Yield Terms to Learn

Antiseptic An agent used to inhibit bacterial growth in vitro and in vivo Disinfectant An agent used to kill microorganisms in an inanimate environment Sterilization Procedures that kill microorganisms on instruments and dressings; methods include autoclaving, dry heat, and exposure to ethylene oxide Chlorine demand The amount of chlorine bound to organic matter in water and thus unavaIlable for antimicrobial activity

Miscellaneous Antimicrobial Agents

This group includes imidazoles that have activity against several bacteria and protozoans, a drug that acts only on gram-positive cocci, and polypeptides that act on gram-negative bacilli.

Metronidazole and Tinidazole

Mechanisms

Metronidazole and tinidazole are imidazole derivatives with activity against protozoa and bacteria. The drugs undergo a reductive bioactivation of their nitro group by ferredoxin (present in anaerobic parasites) to form reactive cytotoxic products that interfere with nucleic acid synthesis.

Pharmacokinetics

Metronidazole and tinidazole are effective orally and are distributed widely to tissues, achieving cerebrospinal fluid (CSF) levels similar to those in the blood. Metronidazole can also be given intravenously and is available in topical formulations. Elimination of the drugs require hepatic metabolism, and dosage reduction may be needed in patients with liver dysfunction. Tinidazole has a long elimination half-life permitting once-daily dosing.

Clinical Use

As an antibacterial agent, metronidazole has greatest activity against Bacteroides and Clostridium. It is the drug of choice for treatment of pseudomembranous colitis resulting from C difficile and is effective in anaerobic or mixed intra-abdominal infections and in brain abscess. Tinidazole has similar activity versus anaerobic bacteria. Metronidazole is also used for infections involving Gardnerella vaginalis and in regimens for the eradication of Helicobacter pylori in gastric ulcers. As antiprotozoal drugs, metronidazole and tinidazole are effective drugs in trichomoniasis, giardiasis, and the treatment of intestinal amebiasis and amebic hepatic abscess.

Toxicity

Adverse effects include gastrointestinal irritation, headache, and dark coloration of urine. More serious toxicity includes leukopenia, dizziness, and ataxia. Opportunistic fungal infections may occur during treatment with metronidazole and tinidazole. Drug interactions with metronidazole include a disulfiram-like reaction with ethanol and potentiation of coumarin anticoagulant effects. Although metronidazole and tinidazole are not contraindicated in pregnancy, the drugs should be used with caution.

Mupirocin

Mechanisms

Mupirocin is a natural product from Pseudomonas fluorescens. It acts on gram-positive cocci and inhibits protein synthesis by specifically binding to isoleucyl-tRNA synthetase.

Pharmacokinetics and Clinical Use

Mupirocin is used topically and is not absorbed. This drug is indicated for impetigo caused by staphylococci (including methicillin-resistant strains), -hemolytic streptococci, and Streptococcus pyogenes. It is also used intranasally to eliminate staphylococcal carriage by patients and medical personnel.

Toxicity

Local itching and burning sensations are common. Mupirocin may also cause rash, erythema, and contact dermatitis.

Polymyxins

Mechanisms

The polymyxins are polypeptides that are bactericidal against gram-negative bacteria. These drugs act like cationic detergents, disrupting bacterial cell membranes. They also bind and inactivate endotoxin.

Clinical Use

Because of toxicity, clinical applications of the polymyxins are usually limited to topical therapy of resistant gram-negative infections, including those caused by Enterobacter and Pseudomonas. A parenteral form is also available.

Toxicity

If used partenterally or absorbed into the systemic circulation, adverse effects include neurotoxicity (paresthesias, dizziness, ataxia) and acute renal tubular necrosis (hematuria, proteinuria, nitrogen retention).

Urinary Antiseptics

Urinary antiseptics are oral drugs that are rapidly excreted into the urine and act there to suppress bacteriuria. The drugs lack systemic antibacterial effects but may be toxic. Urinary antiseptics are often administered with acidifying agents because low pH is an independent inhibitor of bacterial growth in urine.

Nitrofurantoin

This drug is active against many urinary tract pathogens (but not Proteus or Pseudomonas), and resistance emerges slowly. Single daily doses of the drug can prevent recurrent urinary tract infections, and acidification of the urine enhances its activity. The drug is active orally and is excreted in the urine via filtration and secretion; toxic levels may occur in the blood of patients with renal dysfunction. Adverse effects of nitrofurantoin include gastrointestinal irritation, skin rashes, pulmonary infiltrates, phototoxicity, neuropathies, and hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Nalidixic Acid

This quinolone drug acts against many gram-negative organisms (but not Proteus or Pseudomonas) by mechanisms that may involve acidification or inhibition of DNA gyrase. Resistance emerges rapidly. The drug is active orally and is excreted in the urine partly unchanged and partly as the inactive glucuronide. Toxic effects include gastrointestinal irritation, glycosuria, skin rashes, phototoxicity, visual disturbances, and CNS stimulation. Nitrofurantoin may antagonize the action of nalidixic acid.

Methenamine

Methenamine mandelate and methenamine hippurate combine urine acidification with the release of the antibacterial compound formaldehyde at pH levels lower than 5.5. These drugs are not usually active against Proteusbecause these organisms alkalinize the urine. Insoluble complexes form between formaldehyde and sulfonamides, and the drugs should not be used together.

Disinfectants, Antiseptics, & Sterilants

Although the terms are often used interchangeably, a disinfectant is a compound that is used to kill microorganisms in an inanimate environment, whereas an antiseptic is one that is used to inhibit bacterial growth both in vitro and in contact with the surfaces of living tissues. Disinfectants and antiseptics do not have selective toxicity. Most antiseptics delay wound healing. Sterilants kill both vegetative cells and spores when applied to materials for appropriate times and temperatures.

Alcohols, Aldehydes, and Acids

Ethanol (70%) and isopropanol (70-90%) are effective skin antiseptics because they denature microbial proteins. Formaldehyde, which also denatures proteins, is too irritating for topical use but is a disinfectant for instruments. Acetic acid (1%) is used in surgical dressings and has activity against gram-negative bacteria, including Pseudomonas, when used as a urinary irrigant and in the external ear. Salicylic acid and undecylenic acid are useful in the treatment of dermatophyte infections.

Halogens

Iodine tincture is an effective antiseptic for intact skin and, although it can cause dermatitis, is commonly used in preparing the skin before taking blood samples. Iodine complexed with povidone ( povidone-iodine ) is widely used, particularly as a preoperative skin antiseptic, but solutions can become contaminated with aerobic gram-negative bacteria.

Hypochlorous acid, formed when chlorine dissolves in water, is antimicrobial. This is the basis for the use of chlorine and halazone in water purification. Organic matter binds chlorine, thus preventing antimicrobial actions. In a given water sample, this process is referred to as the chlorine demand because the chlorine-binding capacity of the organic material must be exceeded before bacterial killing is accomplished. Many preparations of chlorine for water purification do not eradicate all bacteria or entamoeba cysts.

Sodium hypochlorite is the active component in household bleach, a 1:10 dilution of which is recommended by the Centers for Disease Control and Prevention (CDC) for the disinfection of blood spills that may contain HIV or hepatitis B virus (HBV).

Oxidizing Agents

Hydrogen peroxide exerts a short-lived antimicrobial action through the release of molecular oxygen. The agent is used as a mouthwash, for cleansing wounds, and for disinfection of contact lenses. Potassium permanganate is an effective bactericidal agent but has the disadvantage of causing persistent brown stains on skin and clothing.

Heavy Metals

Mercury and silver precipitate proteins and inactivate sulfhydryl groups of enzymes but are used rarely because of toxicity. Organic mercurials such as nitromersol and thimerosal frequently cause hypersensitivity reactions but continue to be used as preservatives for vaccines, antitoxins, and immune sera. Merbromin is a weak antiseptic and stains tissues a bright red color. In the past silver nitrate was commonly used for prevention of neonatal gonococcal ophthalmia, but it has been largely replaced by topical antibiotics. Silver sulfadiazine (a sulfonamide) is used to decrease bacterial colonization in burns.

Chlorinated Phenols

Owing to its toxicity, phenol itself is used only as a disinfectant of inanimate objects. Mixtures of phenolic derivatives are used in antiseptics but can cause skin irritation. Hexachlorophene has been widely used in surgical scrub routines and in deodorant soaps, where it forms antibacterial deposits on the skin, decreasing the population of resident bacteria. Repeated use on the skin in infants can lead to absorption of the drug, resulting in CNS white matter degeneration. Antiseptic soaps may also contain other chlorinated phenols such as triclocarban and chlorhexidine. Chlorhexidine is mainly active against gram-positive cocci and is commonly used in hospital scrub routines to cleanse skin sites. All antiseptic soaps may cause allergies or photosensitization.

Ectoparasiticides

Lindane (hexachlorocyclohexane) is used to treat infestations with mites or lice and is also an agricultural insecticide. The agent can be absorbed through the skin; if excessive amounts are applied, toxic effects, including blood dyscrasias and convulsions, may occur. Crotamiton is a scabicide with some antipruritic effects, which can be used as an alternative to lindane. Allergic contact hypersensitivity may occur. Permethrin is used topically in pediculosis and scabies; adverse effects include transient burning, stinging, and pruritus. The organophosphate cholinesterase inhibitor malathion is also used topically in pediculosis.

Cationic Surfactants

Benzalkonium chloride and cetylpyridinium chloride are used as disinfectants of surgical instruments and surfaces such as floors and bench tops. Because they are effective against most bacteria and fungi and are not irritating, they are also used as antiseptics. However, when used on the skin, the antimicrobial action of these agents is antagonized by soaps and multivalent cations. The CDC has recommended that benzalkonium chloride and similar quaternary compounds not be used as antiseptics because outbreaks of infection have resulted from growth of gram-negative bacteria (eg, Pseudomonas) in such antiseptic solutions.

Checklist

When you complete this chapter, you should be able to:

 Identify the clinical uses of metronidazole and its characteristic pharmacokinetics and toxicities.

 Describe the antimicrobial activity and clinical uses of daptomycin.

 List the clinical uses of mupirocin and polymyxins.

 Identify the major urinary antiseptics and their characteristic adverse effects.

 List the agents used as antiseptics and disinfectants and point out their limitations.

Drug Summary Table: Miscellaneous Antimicrobial Agents

Subclass Mechanism of Action Effects Clinical Applications & Pharmacokinetics Toxicities & Interactions Nitroimidazoles Metronidazole Tinidazole Disrupt electron transport Bactericidal vs anaerobic bacteria and certain protozoa Anaerobic bacterial infections and Clostridium difficile colitis; oral/IV, hepatic clearance Tinidazole: Longer half-life Gastrointestinal (GI) upsets, metallic taste, neuropathy; disulfiram-like interaction with alcohol Urinary antiseptics Nitrofurantoin Methenamine salts Not identified (nitrofurantoin); forms formaldehyde in urine (methenamine) Bactericidal or bacteriostatic Simple urinary tract (UT) infections and prophylaxis; methenamine is used for suppression in UT infections Oral, low blood levels, high urine levels; GI upset; neuropathy (nitrofurantoin)



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