Pharmacology_Katzung

Pharmacology_Katzung. Owing to their significant toxicity with systemic administration (especially nephrotoxicity), polymyxins were, until recently, largely restricted to topical use. Ointments containing polymyxin B, 5000 units/g, in mixtures with bacitracin or neomycin (or both) are commonly applied to infected superficial skin lesions. Emergence of strains of Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae that are resistant to all other agents has renewed interest in polymyxins as parenteral agents for salvage therapy of infections caused by these organisms. Urinary antiseptics are oral agents that exert antibacterial activity in the urine but have little or no systemic antibacterial effect. Their usefulness is limited to lower urinary tract infections.


Pharmacology_Katzung

Pharmacology_Katzung. Urinary antiseptics are oral agents that exert antibacterial activity in the urine but have little or no systemic antibacterial effect. Their usefulness is limited to lower urinary tract infections. At therapeutic doses, nitrofurantoin is bactericidal for many Gram-positive and Gram-negative bacteria; however, P aeruginosa and many strains of Proteus are inherently resistant. Nitrofurantoin has a complex mechanism of action that is not fully understood. Antibacterial activity appears to correlate with rapid intracellular conversion of nitrofurantoin to highly reactive intermediates by bacterial reductases. These intermediates react non-specifically with many ribosomal proteins and disrupt metabolic processes and the synthesis of proteins, RNA, and DNA. It is not known which of the multiple actions of nitrofurantoin is primarily responsible for its bactericidal activity.


Pharmacology_Katzung

Pharmacology_Katzung. There is no cross-resistance between nitrofurantoin and other antimicrobial agents, and resistance emerges slowly. As resistance to trimethoprim-sulfamethoxazole and fluoroquinolones has become more common in Escherichia coli, nitrofurantoin has become an important alternative oral agent for treatment of uncomplicated urinary tract infection.


Pharmacology_Katzung

Pharmacology_Katzung. Nitrofurantoin is well absorbed after ingestion. It is metabolized and excreted so rapidly that no systemic antibacterial action is achieved. The drug is excreted into the urine by both glomerular filtration and tubular secretion. With average daily doses, concentrations of 200 mcg/mL are reached in urine. In renal failure, urine levels are insufficient for antibacterial action, but high blood levels may cause toxicity. Nitrofurantoin is contraindicated in patients with significant renal insufficiency. Traditional recommendations are to avoid use in patients with creatinine clearance <60 mL/min; however, some data suggest short-term nitrofurantoin treatment is acceptable in patients with creatinine clearance >30 mL/min.


Pharmacology_Katzung

Pharmacology_Katzung. The dosage for urinary tract infection in adults is 100 mg orally taken four times daily. A long-acting formulation (Macrobid) can be taken twice daily. Each long-acting capsule contains two forms of nitrofurantoin. Macrocrystalline nitrofurantoin, which has slower dissolution and absorption than nitrofurantoin monohydrate, constitutes 25%. The remaining 75% is nitrofurantoin monohydrate contained in a powder blend, which, upon exposure to gastric and intestinal fluids, forms a gel matrix that releases nitrofurantoin over time. The drug should not be used to treat upper urinary tract infection. It is desirable to keep urinary pH below 5.5, which greatly enhances drug activity. A single daily dose of nitrofurantoin, 100 mg, can prevent recurrent urinary tract infections in some women.


Pharmacology_Katzung

Pharmacology_Katzung. Anorexia, nausea, and vomiting are the principal side effects of nitrofurantoin. Neuropathies and pulmonary toxicities may occur, particularly with prolonged use or in patients with renal impairment. Hemolytic anemia can occur in patients with glucose-6-phosphate dehydrogenase deficiency. Nitrofurantoin antagonizes the action of nalidixic acid. Rashes, pulmonary infiltration and fibrosis, and other hypersensitivity reactions have been reported. Methenamine mandelate is the salt of mandelic acid and methenamine and possesses properties of both of these urinary antiseptics. Methenamine hippurate is the salt of hippuric acid and methenamine. Below pH 5.5, methenamine releases formaldehyde, which is antibacterial (see Aldehydes, below). Oral mandelic acid or hippuric acid is absorbed and excreted unchanged in the urine. These drugs are bactericidal for some Gram-negative bacteria when urine pH is less than 5.5.


Pharmacology_Katzung

Pharmacology_Katzung. Methenamine mandelate, 1 g four times daily, or methenamine hippurate, 1 g twice daily by mouth (in children age 6 to 12 years, 500 mg four times daily or twice daily, respectively), is used only as a urinary antiseptic to prevent, not treat, symptomatic urinary tract infection. Acidifying agents (eg, ascorbic acid, 4–12 g/d) may be given to lower urinary pH below 5.5. Sulfonamides should not be given at the same time because they may form an insoluble compound with the formaldehyde released by methenamine. Persons taking methenamine mandelate may exhibit falsely elevated tests for catecholamine metabolites. ■ DISINFECTANTS, ANTISEPTICS, & STERILANTS


Pharmacology_Katzung

Pharmacology_Katzung. ■ DISINFECTANTS, ANTISEPTICS, & STERILANTS Disinfectants are chemical agents or physical procedures that inhibit or kill microorganisms (Table 50–1). Antiseptics are disinfecting chemical agents with sufficiently low toxicity for host cells that they can be used directly on skin, mucous membranes, or wounds. Sterilants kill both vegetative cells and spores when applied to materials for appropriate times and temperatures. Some of the terms used in this context are defined in Table 50–2.


Pharmacology_Katzung

Pharmacology_Katzung. Disinfection prevents infection by reducing the number of potentially infective organisms by killing, removing, or diluting them. Disinfection can be accomplished by application of chemical agents or use of physical agents such as ionizing radiation, dry or moist heat, or superheated steam (autoclave, 120°C) to kill microorganisms. Often a combination of agents is used, eg, water and moderate heat over time (pasteurization); ethylene oxide and moist heat (a sterilant); or addition of disinfectant to a detergent. Prevention of infection also can be achieved by washing, which dilutes the potentially infectious organism.


Pharmacology_Katzung

Pharmacology_Katzung. Hand hygiene is probably the most important means of preventing transmission of infectious agents from person to person or from regions of high microbial load, eg, mouth, nose, or gut, to potential sites of infection. Alcohol-based hand rubs and soap and warm water are used to remove bacteria. Skin disinfectants along with detergent and water are usually used preoperatively as a surgical scrub for surgeons’ hands.


Pharmacology_Katzung

Pharmacology_Katzung. Evaluation of effectiveness of antiseptics, disinfectants, and sterilants, although seemingly simple in principle, is very complex. Factors in any evaluation include the intrinsic resistance of the microorganism, the number of microorganisms present, mixed populations of organisms, amount of organic material present (eg, blood, feces, tissue), concentration and stability of disinfectant or sterilant, time and temperature of exposure, pH, and hydration and binding of the agent to surfaces. Specific, standardized assays of activity are defined for each use. Toxicity for humans also must be evaluated. In the USA, the Environmental Protection Agency (EPA) regulates disinfectants and sterilants and the FDA regulates antiseptics. Users of antiseptics, disinfectants, and sterilants need to consider their short-term and long-term toxicity because they may have general biocidal activity and may accumulate in the TABLE 50–1 Activities of disinfectants.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 50–1 Activities of disinfectants. Bacteria Viruses Other Gram-Positive Gram-Negative Acid-Fast Spores Lipophilic Hydrophilic Fungi Amebic Cysts Prions Alcohols (isopropanol, HS HS S R S V — — R conc, concentration; HS, highly susceptible; MS, moderately susceptible; —, no data; R, resistant; S, susceptible; V, variable. environment or in the body. Disinfectants and antiseptics may also become contaminated by resistant microorganisms—eg, spores, P aeruginosa, or Serratia marcescens—and actually transmit infection. Most topical antiseptics interfere with wound healing to some degree. Cleansing of wounds with soap and water may be less damaging than the application of antiseptics. Some of the chemical classes of antiseptics, disinfectants, and sterilants are described briefly in the text that follows. The reader is referred to the general references for descriptions of physical disinfection and sterilization methods.


Pharmacology_Katzung

Pharmacology_Katzung. The two alcohols most frequently used for antisepsis and disinfection are ethanol and isopropyl alcohol (isopropanol). They are rapidly active, killing vegetative bacteria, Mycobacterium TABLE 50–2 Commonly used terms related to chemical and physical killing of microorganisms. Antisepsis Application of an agent to living tissue for the purpose of preventing infection Decontamination Process that produces marked reduction in number or activity of microorganisms Disinfection Chemical or physical treatment that destroys most vegetative microbes and viruses, but not spores, in or on inanimate surfaces Sanitization Reduction of microbial load on an inanimate surface to a level considered acceptable for public health purposes


Pharmacology_Katzung

Pharmacology_Katzung. Sterilization A process intended to kill or remove all types of microorganisms, including spores, and usually including viruses, with an acceptably low probability of their survival tuberculosis, and many fungi, and inactivating lipophilic viruses. The optimum bactericidal concentration is 60–90% by volume in water. They probably act by denaturation of proteins. They are not used as sterilants because they are not sporicidal, do not penetrate protein-containing organic material, and may not be active against hydrophilic viruses. Their skin-drying effect can be alleviated by addition of emollients to the formulation. Use of alcohol-based hand rubs has been shown to reduce transmission of health care–associated bacterial pathogens and is recommended by the Centers for Disease Control and Prevention (CDC) as the preferred method of hand decontamination in health care settings. Alcohol-based hand rubs are ineffective against spores of C difficile, and handwashing with soap and water is


Pharmacology_Katzung

Pharmacology_Katzung. Prevention (CDC) as the preferred method of hand decontamination in health care settings. Alcohol-based hand rubs are ineffective against spores of C difficile, and handwashing with soap and water is required for decontamination after caring for a patient with infection from this organism.


Pharmacology_Katzung

Pharmacology_Katzung. Alcohols are flammable and must be stored in cool, well-ventilated areas. They must be allowed to evaporate before cautery, electrosurgery, or laser surgery. Alcohols may be damaging if applied directly to corneal tissue. Therefore, instruments such as tonometers that have been disinfected in alcohol should be rinsed with sterile water, or the alcohol should be allowed to evaporate before they are used.


Pharmacology_Katzung

Pharmacology_Katzung. Chlorhexidine is a cationic biguanide with very low water solubility. Water-soluble chlorhexidine digluconate is used in water-based formulations as an antiseptic. It is active against vegetative bacteria and mycobacteria and has variable activity against fungi and viruses. It strongly adsorbs to bacterial membranes, causing leakage of small molecules and precipitation of cytoplasmic proteins. It is active at pH 5.5–7.0. Chlorhexidine gluconate is slower in its action than alcohols, but, because of its persistence, it has residual activity, producing bactericidal action equivalent to alcohols. It is most effective against Gram-positive cocci and less active against Gram-positive and Gram-negative rods. Spore germination is inhibited by chlorhexidine. Chlorhexidine digluconate is resistant to inhibition by blood and organic materials. However, anionic and nonionic agents in moisturizers, neutral soaps, and surfactants may neutralize its action. Chlorhexidine digluconate formulations of


Pharmacology_Katzung

Pharmacology_Katzung. to inhibition by blood and organic materials. However, anionic and nonionic agents in moisturizers, neutral soaps, and surfactants may neutralize its action. Chlorhexidine digluconate formulations of 4% concentration have slightly greater antibacterial activity than newer 2% formulations. The combination of chlorhexidine gluconate in 70% alcohol, available in some countries including the USA, is the preferred agent for skin antisepsis in many surgical and percutaneous procedures. The advantage of this combination over povidone-iodine may derive from its more rapid action after application, its retained activity after exposure to body fluids, and its persistent activity on the skin. Chlorhexidine has a very low skin-sensitizing or irritating capacity. Oral toxicity is low because it is poorly absorbed from the alimentary tract. Chlorhexidine must not be used during surgery on the middle ear because it causes sensorineural deafness. Similar neural toxicity may be encountered during


Pharmacology_Katzung

Pharmacology_Katzung. poorly absorbed from the alimentary tract. Chlorhexidine must not be used during surgery on the middle ear because it causes sensorineural deafness. Similar neural toxicity may be encountered during neurosurgery.


Pharmacology_Katzung

Pharmacology_Katzung. Iodine in a 1:20,000 solution is bactericidal in 1 minute and kills spores in 15 minutes. Tincture of iodine USP contains 2% iodine and 2.4% sodium iodide in alcohol. It is the most active antiseptic for intact skin. It is not commonly used due to serious hypersensitivity reactions and staining of clothing and dressings. Iodophors are complexes of iodine with a surface-active agent such as polyvinyl pyrrolidone (PVP; povidone-iodine). Iodophors retain the activity of iodine. They kill vegetative bacteria, mycobacteria, fungi, and lipid-containing viruses. They may be sporicidal with prolonged exposure. Iodophors can be used as antiseptics or disinfectants, the latter containing more iodine. The amount of free iodine is low, but it is released as the solution is diluted. An iodophor solution must be diluted according to the manufacturer’s directions to obtain full activity.


Pharmacology_Katzung

Pharmacology_Katzung. Iodophors are less irritating and less likely to produce skin hypersensitivity than tincture of iodine. They require drying time on skin before becoming active, which can be a disadvantage. Although iodophors have a somewhat broader spectrum of activity than chlorhexidine, including sporicidal action, they lack its persistent activity on skin.


Pharmacology_Katzung

Pharmacology_Katzung. Chlorine is a strong oxidizing agent and universal disinfectant that is commonly provided as a 5.25% sodium hypochlorite solution, a typical formulation for household bleach. Because formulations may vary, the exact concentration should be verified on the label. A 1:10 dilution of household bleach (producing a 0.525% concentration) provides 5000 ppm of available chlorine. The CDC recommends this concentration for disinfection of blood spills. Less than 5 ppm kills vegetative bacteria, whereas up to 5000 ppm is necessary to kill bacterial spores. A concentration of 1000–10,000 ppm is tuberculocidal. One hundred ppm kills vegetative fungal cells in 1 hour, but fungal spores require 500 ppm. Viruses are inactivated by 200–500 ppm. Dilutions of sodium hypochlorite made up in pH 7.5–8.0 tap water retain their activity for months when kept in tightly closed, opaque containers. Frequent opening and closing of the container reduces the activity markedly.


Pharmacology_Katzung

Pharmacology_Katzung. Because chlorine is inactivated by blood, serum, feces, and protein-containing materials, surfaces should be cleaned before chlorine disinfectant is applied. Undissociated hypochlorous acid (HOCl) is the active biocidal agent. When pH is increased, the less active hypochlorite ion, OCl –, is formed. When hypochlorite solutions contact formaldehyde, the carcinogen bischloromethyl is formed. Rapid evolution of irritating chlorine gas occurs when hypochlorite solutions are mixed with acid and urine. Solutions are corrosive to aluminum, silver, and stainless steel. Alternative chlorine-releasing compounds include chlorine dioxide and chloramine-T. These agents have a prolonged bactericidal action.


Pharmacology_Katzung

Pharmacology_Katzung. Alternative chlorine-releasing compounds include chlorine dioxide and chloramine-T. These agents have a prolonged bactericidal action. Phenol itself (perhaps the oldest of the surgical antiseptics) is no longer used even as a disinfectant because of its corrosive effect on tissues, its toxicity when absorbed, and its carcinogenic effect. These adverse actions are diminished by forming derivatives in which a functional group replaces a hydrogen atom in the aromatic ring. The phenolic agents most commonly used are o-phenylphenol, o-benzyl-p-chlorophenol, and p-tertiary amylphenol. Mixtures of phenolic derivatives are often used. Some of these are derived from coal tar distillates, eg, cresols and xylenols. Skin absorption and skin irritation still occur with these derivatives, and appropriate care is necessary in their use. Detergents are often added to formulations to clean and remove organic material that may decrease the activity of a phenolic compound.


Pharmacology_Katzung

Pharmacology_Katzung. Phenolic compounds disrupt cell walls and membranes, precipitate proteins, and inactivate enzymes. They are bactericidal (including mycobacteria) and fungicidal and are capable of inactivating lipophilic viruses. They are not sporicidal. Dilution and time of exposure recommendations of the manufacturer must be followed. Phenolic disinfectants are used for hard surface decontamination in hospitals and laboratories, eg, floors, beds, and counter or bench tops. They are not recommended for use in nurseries and especially near infants, where their use has been associated with hyperbilirubinemia. Use of hexachlorophene as a skin disinfectant has caused cerebral edema and seizures in premature infants and, occasionally, in adults. It is no longer available in the United States.


Pharmacology_Katzung

Pharmacology_Katzung. The quaternary ammonium compounds (“quats”) are cationic surface-active detergents. The active cation has at least one long water-repellent hydrocarbon chain, which causes the molecules to concentrate as an oriented layer on the surface of solutions and colloidal or suspended particles. The charged nitrogen portion of the cation has high affinity for water and prevents separation out of solution. The bactericidal action of quaternary compounds has been attributed to inactivation of energy-producing enzymes, denaturation of proteins, and disruption of the cell membrane. These agents are fungistatic and sporistatic and also inhibit algae. They are bactericidal for Gram-positive bacteria and moderately active against Gram-negative bacteria. Lipophilic viruses are inactivated. They are not tuberculocidal or sporicidal, and they do not inactivate hydrophilic viruses. Quaternary ammonium compounds bind to the surface of colloidal protein in blood, serum, and milk and to the fibers in


Pharmacology_Katzung

Pharmacology_Katzung. not tuberculocidal or sporicidal, and they do not inactivate hydrophilic viruses. Quaternary ammonium compounds bind to the surface of colloidal protein in blood, serum, and milk and to the fibers in cotton, mops, cloths, and paper towels used to apply them, which can cause inactivation of the agent by removing it from solution. They are inactivated by anionic detergents (soaps), by many nonionic detergents, and by calcium, magnesium, ferric, and aluminum ions.


Pharmacology_Katzung

Pharmacology_Katzung. Quaternary compounds are used for sanitation of noncritical surfaces (floors, bench tops, etc). Their low toxicity has led to their use as sanitizers in food production facilities. The CDC recommends that quaternary ammonium compounds such as benzalkonium chloride not be used as antiseptics because several outbreaks of infections have occurred that were due to growth of Pseudomonas and other Gram-negative bacteria in quaternary ammonium antiseptic solutions.


Pharmacology_Katzung

Pharmacology_Katzung. Formaldehyde and glutaraldehyde are used for disinfection or sterilization of instruments such as fiberoptic endoscopes, respiratory therapy equipment, hemodialyzers, and dental instruments that cannot withstand exposure to the high temperatures of steam sterilization. They are not corrosive for metal, plastic, or rubber. These agents have a broad spectrum of activity against microorganisms. They act by alkylation of chemical groups in proteins and nucleic acids. Failures of disinfection or sterilization can occur as a result of dilution below the known effective concentration, the presence of organic material, and the failure of liquid to penetrate into small channels in the instruments. Automatic circulating baths are available that increase penetration of aldehyde solution into the instrument while decreasing exposure of the operator to irritating fumes.


Pharmacology_Katzung

Pharmacology_Katzung. Formaldehyde is available as a 40% weight per volume solution in water (100% formalin). An 8% formaldehyde solution in water has a broad spectrum of activity against bacteria, fungi, and viruses. Sporicidal activity may take as long as 18 hours. Its rapidity of action is increased by solution in 70% isopropanol. Formaldehyde solutions are used for high-level disinfection of hemodialyzers, preparation of vaccines, and preservation and embalming of tissues. The 4% formaldehyde (10% formalin) solutions used for fixation of tissues and embalming may not be mycobactericidal.


Pharmacology_Katzung

Pharmacology_Katzung. Glutaraldehyde is a dialdehyde (1,5-pentanedial). Solutions of 2% weight per volume glutaraldehyde are most commonly used. The solution must be alkalinized to pH 7.4–8.5 for activation. Activated solutions are bactericidal, sporicidal, fungicidal, and viricidal for both lipophilic and hydrophilic viruses. Glutaraldehyde has greater sporicidal activity than formaldehyde, but it may have less tuberculocidal activity. Lethal action against mycobacteria and spores may require prolonged exposure. Once activated, solutions have a shelf life of 14 days, after which polymerization reduces activity. Other means of activation and stabilization can increase the shelf life. Because glutaraldehyde solutions are frequently reused, the most common reason for loss of activity is dilution and exposure to organic material. Test strips to measure residual activity are recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Formaldehyde has a characteristic pungent odor and is highly irritating to respiratory mucous membranes and eyes at concentrations of 2–5 ppm. The U.S. Occupational Safety and Health Administration (OSHA) has declared that formaldehyde is a potential carcinogen and has established an employee exposure standard that limits the 8-hour time-weighted average (TWA) exposure to 0.75 ppm. Protection of health care workers from exposure to glutaraldehyde concentrations greater than 0.2 ppm is advisable. Increased air exchange, enclosure in hoods with exhausts, tight-fitting lids on exposure devices, and use of protective personal equipment such as goggles, respirators, and gloves may be necessary to achieve these exposure limits.


Pharmacology_Katzung

Pharmacology_Katzung. Ortho-phthalaldehyde (OPA) is a phenolic dialdehyde chemical sterilant with a spectrum of activity comparable to glutaraldehyde, although it is several times more rapidly bactericidal. OPA solution typically contains 0.55% OPA. Its label claim is that high-level disinfection can be achieved in 12 minutes at room temperature compared with 45 minutes for 2.4% glutaraldehyde. Unlike glutaraldehyde, OPA requires no activation, is less irritating to mucous membranes, and does not require exposure monitoring. It has good materials compatibility and an acceptable environmental safety profile. OPA is useful for disinfection or sterilization of endoscopes, surgical instruments, and other medical devices.


Pharmacology_Katzung

Pharmacology_Katzung. Electrolysis of saline yields a mixture of oxidants, primarily hypochlorous acid and chlorine, with potent disinfectant and sterilant properties. The solution generated by the process, which has been commercialized and marketed as Sterilox for disinfection of endoscopes and dental materials, is rapidly bactericidal, fungicidal, tuberculocidal, and sporicidal. High-level disinfection is achieved with a contact time of 10 minutes. The solution is nontoxic and nonirritating and requires no special disposal precautions. The peroxygen compounds, hydrogen peroxide and peracetic acid, have high killing activity and a broad spectrum against bacteria, spores, viruses, and fungi when used in appropriate concentration. They have the advantage that their decomposition products are not toxic and do not injure the environment. They are powerful oxidizers that are used primarily as disinfectants and sterilants.


Pharmacology_Katzung

Pharmacology_Katzung. Hydrogen peroxide is a very effective disinfectant when used for inanimate objects or materials with low organic content such as water. Systems that produce hydrogen peroxide vapor or dry mist are now available for room decontamination in healthcare facilities. Organisms that produce the enzymes catalase and peroxidase rapidly degrade hydrogen peroxide. The innocuous degradation products are oxygen and water. Concentrated solutions containing 90% weight per volume H2O2 are prepared electrochemically. When diluted in high-quality deionized water to 6% and 3% and put into clean containers, the products remain stable. Concentrations of 10–25% hydrogen peroxide are sporicidal. Vapor phase hydrogen peroxide (VPHP) is a cold gaseous sterilant that has the potential to replace the toxic or carcinogenic gases ethylene oxide and formaldehyde. VPHP does not require a pressurized chamber and is active at temperatures as low as 4°C and concentrations as low as 4 mg/L. It is incompatible with


Pharmacology_Katzung

Pharmacology_Katzung. gases ethylene oxide and formaldehyde. VPHP does not require a pressurized chamber and is active at temperatures as low as 4°C and concentrations as low as 4 mg/L. It is incompatible with liquids and cellulose products. It penetrates the surface of some plastics. Automated equipment using vaporized hydrogen peroxide or hydrogen peroxide mixed with formic acid is available for sterilizing endoscopes.


Pharmacology_Katzung

Pharmacology_Katzung. Peracetic acid (CH3COOOH) is prepared commercially from hydrogen peroxide, acetic acid, and a catalyst such as sulfuric acid. It is explosive in the pure form. It is usually used in dilute solution and transported in containers with vented caps to prevent increased pressure as oxygen is released. Peracetic acid is more active than hydrogen peroxide as a bactericidal and sporicidal agent. Concentrations of 250–500 ppm are effective against a broad range of bacteria in 5 minutes at pH 7.0 at 20°C. Bacterial spores are inactivated by 500–30,000 ppm peracetic acid. Only slightly increased concentrations are necessary in the presence of organic matter. Viruses require variable exposures. Enteroviruses require 2000 ppm for 15–30 minutes for inactivation.


Pharmacology_Katzung

Pharmacology_Katzung. An automated machine that uses buffered peracetic acid liquid of 0.1–0.5% concentration has been developed for sterilization of medical, surgical, and dental instruments. Peracetic acid sterilization systems have also been adopted for hemodialyzers. The food processing and beverage industries use peracetic acid extensively because the breakdown products in high dilution do not produce objectionable odor, taste, or toxicity, and rinsing is not necessary. Peracetic acid is a potent tumor promoter but a weak carcinogen. It is not mutagenic in the Ames test. Ultraviolet irradiation is used in some health care facilities as an alternate mode of disinfection for patient care areas. It is typically employed via an automated system, allowing for less staff exposure to decontamination products. It has rapid cidal activity against numerous pathogens, providing effective decontamination for most vegetative bacteria in less than 25 minutes and against C. difficile in less than one hour.


Pharmacology_Katzung

Pharmacology_Katzung. Heavy metals, principally mercury and silver, are now rarely used as disinfectants. Mercury is an environmental hazard, and some pathogenic bacteria have developed plasmid-mediated resistance to mercurials. Hypersensitivity to thimerosal is common, possibly in up to 40% of the population. These compounds are absorbed from solution by rubber and plastic closures. Thimerosal 0.001– 0.004% is still used safely as a preservative of vaccines, antitoxins, and immune sera. Although a causative link to autism has never been established and the original claim was found to be fraudulent, thimerosal-free vaccines are available for use in children and pregnant women.


Pharmacology_Katzung

Pharmacology_Katzung. Inorganic silver salts are strongly bactericidal. Silver nitrate, 1:1000, had been most commonly used, particularly as a preventive for gonococcal ophthalmitis in newborns. Antibiotic ointments have replaced silver nitrate for this indication. Silver sulfadiazine slowly releases silver and is used to suppress bacterial growth in burn wounds (see Chapter 46). For many years, pressurized steam (autoclaving) at 120°C for 30 minutes has been the basic method for sterilizing instruments and other heat-resistant materials. When autoclaving is not possible, as with lensed instruments and materials containing plastic and rubber, ethylene oxide—diluted with either fluorocarbon or carbon dioxide to diminish explosive hazard—has been used at 440–1200 mg/L at 45–60°C with 30–60% relative humidity. The higher concentrations have been used to increase penetration.


Pharmacology_Katzung

Pharmacology_Katzung. Ethylene oxide is classified as a mutagen and carcinogen. The OSHA permissible exposure limit (PEL) for ethylene oxide is 1 ppm calculated as a time-weighted average. Alternative sterilants now being used increasingly include vapor-phase hydrogen peroxide, peracetic acid, ozone, gas plasma, chlorine dioxide, formaldehyde, and propylene oxide. Each of these sterilants has potential advantages and problems. Automated peracetic acid systems are being used increasingly for high-level decontamination and sterilization of endoscopes and hemodialyzers because of their effectiveness, automated features, and the low toxicity of the residual products of sterilization.


Pharmacology_Katzung

Pharmacology_Katzung. Disinfectants are used as preservatives to prevent the overgrowth of bacteria and fungi in pharmaceutical products, laboratory sera and reagents, cosmetic products, and contact lenses. Multi-use vials of medication that may be reentered through a rubber diaphragm, eye drops, and nose drops require preservatives. Preservatives should not be irritating or toxic to tissues to which they will be applied, they must be effective in preventing growth of microorganisms likely to contaminate solutions, and they must have sufficient solubility and stability to remain active. Commonly used preservative agents include organic acids such as benzoic acid and salts, the parabens, (alkyl esters of p-hydroxybenzoic acid), sorbic acid and salts, phenolic compounds, quaternary ammonium compounds, alcohols, and mercurials such as thimerosal in 0.001–0.004% concentration.


Pharmacology_Katzung

Pharmacology_Katzung. • Tinidazole: Oral; similar to metronidazole but dosed once daily; approved for trichomonas, giardiasis, and amebiasis • Methenamine hippurate and methenamine mandelate: Oral; release formaldehyde at acidic pH in the urine; used only for prophylaxis, not treatment, of urinary tract infections Colistimethate sodium Generic, Coly-Mycin M Methenamine hippurate Generic, Hiprex Metronidazole Generic, Flagyl, Metro Nitrofurantoin Generic, Macrodantin, Macrobid Methenamine mandelate Generic, Mandelamine Mupirocin Generic, Bactroban, Centany Polymyxin B (Polymyxin B sulfate) Generic DISINFECTANTS, ANTISEPTICS, & STERILANTS Benzalkonium Generic, Zephiran Chlorhexidine gluconate topical Generic, Hibiclens, Betasept, others Chlorhexidine gluconate, oral rinse: 0.12% Peridex, Periogard Iodine aqueous Generic, Lugol’s Solution Nitrofurazone Generic, Furacin


Pharmacology_Katzung

Pharmacology_Katzung. Chlorhexidine gluconate, oral rinse: 0.12% Peridex, Periogard Iodine aqueous Generic, Lugol’s Solution Nitrofurazone Generic, Furacin Bischoff WE et al: Handwashing compliance by health care workers: The impact of introducing an accessible, alcohol-based hand antiseptic. Arch Intern Med 2000;160:1017. Chambers HF, Winston LG: Mupirocin prophylaxis misses by a nose. Ann Intern Med 2004;140:484. Gordin FM et al: Reduction in nosocomial transmission of drug-resistant bacteria after introduction of an alcohol-based hand-rub. Infect Control Hosp Epidemiol 2005;26:650. Hoonmo LK, DuPont HL: Rifaximin: A unique gastrointestinal-selective antibiotic for enteric diseases. Curr Opin Gastroenterol 2010;26:17. Humphreys PN: Testing standards for sporicides. J Hosp Infect 2011;77:193. Louie TJ et al: Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422. Medical Letter: Tinidazole (Tindamax)—a new anti-protozoal drug. Med Lett Drugs Ther 2004;46:70.


Pharmacology_Katzung

Pharmacology_Katzung. Medical Letter: Tinidazole (Tindamax)—a new anti-protozoal drug. Med Lett Drugs Ther 2004;46:70. Meyer GW: Endoscope disinfection. www.uptodate.com/contents/endoscopedisinfection. UpToDate 2017. Noorani A et al: Systematic review and meta-analysis of preoperative antisepsis with chlorhexidine versus povidone-iodine in clean-contaminated surgery. Br J Surg 2010;97:1614. Rutala WA, Weber DJ: Disinfection and sterilization in health care facilities: an overview and current issues. Infect Dis Clin N Am 2016;30:609. Rutala WA, Weber DJ: New disinfection and sterilization methods. Emerg Infect Dis 2001;7:348. Widmer AF, Frei R: Decontamination, disinfection, and sterilization. In: Murray PR et al (editors): Manual of Clinical Microbiology, 7th ed. American Society for Microbiology, 1999. Povidone-iodine Generic, Betadine Silver nitrate Generic Thimerosal Generic, Mersol


Pharmacology_Katzung

Pharmacology_Katzung. Povidone-iodine Generic, Betadine Silver nitrate Generic Thimerosal Generic, Mersol The patient may be treated with oral metronidazole, which is an appropriate drug for mild to moderate cases of C difficile infection. Oral vancomycin is also a reason-able alternative and is the preferred treatment for severe cases and for older patients. Fidaxomicin is an effective treatment for C. difficile infection, but it is more expen-sive than other first-line medications. The room should be cleaned with a bleach solution (5000 ppm) because it is sporicidal. Other sporicidal disinfectants also may be effective. Clinical Use of Antimicrobial Agents Harry W. Lampiris, MD, & Daniel S. Maddix, PharmD


Pharmacology_Katzung

Pharmacology_Katzung. A 65-year-old man undergoes cystoscopy because of the presence of microscopic hematuria in order to rule out urologic malignancy. The patient has mild dysuria and pyuria and empirically receives oral therapy with cip-rofloxacin for presumed urinary tract infection prior to the procedure and tolerates the procedure well. Approxi-mately 48 hours after the procedure, the patient presents to the emergency department with confusion, dysuria and chills. Physical exam reveals a blood pressure of 90/50, pulse of 120, temperature of 38.5° C and respira-tory rate of 24. The patient is disoriented but the physical exam is otherwise unremarkable. Laboratory test shows WBC 24,000/mm3 and elevated serum lactate; urinalysis shows 300 WBC per high power field and 4+ bacteria. What possible organisms are likely to be responsible for the patient’s symptoms? At this point, what antibiotic(s) would you choose for initial therapy of this potentially life-threatening infection?


Pharmacology_Katzung

Pharmacology_Katzung. The development of antimicrobial drugs represents one of the most important advances in therapeutics, both in the control or cure of serious infections and in the prevention and treatment of infectious complications of other therapeutic modalities such as cancer chemotherapy, immunosuppression, and surgery. However, evidence is overwhelming that antimicrobial agents are vastly overprescribed in outpatient settings in the USA, and the availability of antimicrobial agents without prescription in many developing countries has—by facilitating the development of resistance—already severely limited therapeutic options in the treatment of life-threatening infections. Therefore, the clinician should first determine whether antimicrobial therapy is warranted for a given patient. The specific questions one should ask include the following: 1. Is an antimicrobial agent indicated on the basis of clinical findings? Or is it prudent to wait until such clinical findings become apparent? 2.


Pharmacology_Katzung

Pharmacology_Katzung. Is an antimicrobial agent indicated on the basis of clinical findings? Or is it prudent to wait until such clinical findings become apparent? 2. Have appropriate clinical specimens been obtained to establish a microbiologic diagnosis? 3. What are the likely etiologic agents for the patient’s illness? 4. What measures should be taken to protect individuals exposed to the index case to prevent secondary cases, and what measures should be implemented to prevent further exposure? 5. Is there clinical evidence (eg, from well-executed clinical trials) that antimicrobial therapy will confer clinical benefit for the patient? Once a specific cause is identified based on specific microbiologic tests, the following further questions should be considered: 1. If a specific microbial pathogen is identified, can a narrower-spectrum agent be substituted for the initial empiric drug? 2. Is one agent or a combination of agents necessary? 3.


Pharmacology_Katzung

Pharmacology_Katzung. If a specific microbial pathogen is identified, can a narrower-spectrum agent be substituted for the initial empiric drug? 2. Is one agent or a combination of agents necessary? 3. What are the optimal dose, route of administration, and duration of therapy? 4. What specific tests (eg, susceptibility testing) should be undertaken to identify patients who will not respond to treatment? 5.


Pharmacology_Katzung

Pharmacology_Katzung. 4. What specific tests (eg, susceptibility testing) should be undertaken to identify patients who will not respond to treatment? 5. What adjunctive measures can be undertaken to eradicate the infection? For example, is surgery feasible for removal of devitalized tissue or foreign bodies—or drainage of an abscess—into which antimicrobial agents may be unable to penetrate? Is it possible to decrease the dosage of immunosuppressive therapy in patients who have undergone organ transplantation? Is it possible to reduce morbidity or mortality due to the infection by reducing host immunologic response to the infection (eg, by the use of corticosteroids for the treatment of severe Pneumocystis jiroveci pneumonia or meningitis due to Streptococcus pneumoniae)?


Pharmacology_Katzung

Pharmacology_Katzung. Antimicrobial agents are frequently used before the pathogen responsible for a particular illness or the susceptibility to a particular antimicrobial agent is known. This use of antimicrobial agents is called empiric (or presumptive) therapy and is based on experience with a particular clinical entity. The usual justification for empiric therapy is the hope that early intervention will improve the outcome; in the best cases, this has been established by placebo-controlled, double-blind, prospective clinical trials. For example, treatment of febrile episodes in neutropenic cancer patients with empiric antimicrobial therapy has been demonstrated to have impressive morbidity and mortality benefits even though the specific bacterial agent responsible for fever is determined for only a minority of such episodes.


Pharmacology_Katzung

Pharmacology_Katzung. Finally, there are many clinical entities, such as certain episodes of community-acquired pneumonia, in which it is difficult to identify a specific pathogen. In such cases, a clinical response to empiric therapy may be an important clue to the likely pathogen. Frequently, the signs and symptoms of infection diminish as a result of empiric therapy, and microbiologic test results become available to establish a specific microbiologic diagnosis. At the time that the pathogenic organism responsible for the illness is identified, empiric therapy is optimally modified to definitive therapy, which is typically narrower in coverage and is given for an appropriate duration based on the results of clinical trials, or experience when clinical trial data are not available. Approach to Empiric Therapy Initiation of empiric therapy should follow a specific and systematic approach. A. Formulate a Clinical Diagnosis of Microbial Infection


Pharmacology_Katzung

Pharmacology_Katzung. Approach to Empiric Therapy Initiation of empiric therapy should follow a specific and systematic approach. A. Formulate a Clinical Diagnosis of Microbial Infection Using all available data, the clinician should determine that there is a clinical syndrome compatible with infection (eg, pneumonia, cellulitis, sinusitis). B. Obtain Specimens for Laboratory Examination Examination of stained specimens by microscopy or simple examination of an uncentrifuged sample of urine for white blood cells and bacteria may provide important immediate etiologic clues. Cultures of selected anatomic sites (blood, sputum, urine, cerebrospinal fluid, and stool) and nonculture methods (antigen testing, polymerase chain reaction, and serology) also may confirm specific etiologic agents. C. Formulate a Microbiologic Diagnosis


Pharmacology_Katzung

Pharmacology_Katzung. C. Formulate a Microbiologic Diagnosis The history, physical examination, and immediately available laboratory results (eg, Gram stain of urine or sputum) may provide highly specific information. For example, in a young man with urethritis and a Gram-stained smear from the urethral meatus demonstrating intracellular Gram-negative diplococci, the most likely pathogen is Neisseria gonorrhoeae. In the latter instance, however, the clinician should be aware that a significant number of patients with gonococcal urethritis have negative Gram stains for the organism and that a significant number of patients with gonococcal urethritis harbor concurrent chlamydial infection that is not demonstrated on the Gram-stained smear. D. Determine the Necessity for Empiric Therapy


Pharmacology_Katzung

Pharmacology_Katzung. D. Determine the Necessity for Empiric Therapy Whether to initiate empiric therapy is an important clinical decision based partly on experience and partly on data from clinical trials. Empiric therapy is indicated when there is a significant risk of serious morbidity or mortality if therapy is withheld until a specific pathogen is detected by the clinical laboratory. In other settings, empiric therapy may be indicated for public health reasons rather than for demonstrated superior outcome of therapy in a specific patient. For example, urethritis in a young sexually active man usually requires treatment for N gonorrhoeae and Chlamydia trachomatis despite the absence of microbiologic confirmation at the time of diagnosis. Because the risk of noncompliance with follow-up visits in this patient population may lead to further transmission of these sexually transmitted pathogens, empiric therapy is warranted. E. Institute Treatment


Pharmacology_Katzung

Pharmacology_Katzung. E. Institute Treatment Selection of empiric therapy may be based on the microbiologic diagnosis or a clinical diagnosis without available microbiologic clues. If no microbiologic information is available, the antimicrobial spectrum of the agent or agents chosen must necessarily be broader, taking into account the most likely pathogens responsible for the patient’s illness. Choice of Antimicrobial Agent


Pharmacology_Katzung

Pharmacology_Katzung. Choice of Antimicrobial Agent Selection from among several drugs depends on host factors that include the following: (1) concomitant disease states (eg, AIDS, neutropenia due to the use of cytotoxic chemotherapy, organ transplantation, severe chronic liver or kidney disease) or the use of immunosuppressive medications; (2) prior adverse drug effects; (3) impaired elimination or detoxification of the drug (may be genetically predetermined but more frequently is associated with impaired renal or hepatic function due to underlying disease); (4) age of the patient; (5) pregnancy status; and (6) epidemiologic exposure (eg, exposure to a sick family member or pet, recent hospitalization, recent travel, occupational exposure, or new sexual partner).


Pharmacology_Katzung

Pharmacology_Katzung. Pharmacologic factors include (1) the kinetics of absorption, distribution, and elimination; (2) the ability of the drug to be delivered to the site of infection; (3) the potential toxicity of an agent; and (4) pharmacokinetic or pharmacodynamic interactions with other drugs. Knowledge of the susceptibility of an organism to a specific agent in a hospital or community setting is important in the selection of empiric therapy. Pharmacokinetic differences among agents with similar antimicrobial spectrums may be exploited to reduce the frequency of dosing (eg, ceftriaxone, ertapenem, or daptomycin may be conveniently given once every 24 hours). Finally, increasing consideration is being given to the cost of antimicrobial therapy, especially when multiple agents with comparable efficacy and toxicity are available for a specific infection. Changing from intravenous to oral antibiotics for prolonged administration can be particularly cost-effective.


Pharmacology_Katzung

Pharmacology_Katzung. Brief guides to empiric therapy based on presumptive microbial diagnosis and site of infection are given in Tables 51–1 and 51–2. Properly obtained and processed specimens for culture frequently yield reliable information about the cause of infection. The lack of a confirmatory microbiologic diagnosis may be due to the following: 1. Sample error, eg, obtaining cultures after antimicrobial agents have been administered, inadequate volume or quantity of specimen obtained, or contamination of specimens sent for culture 2. Noncultivable or slow-growing organisms (Histoplasma capsulatum, Bartonella or Brucella species), in which cultures are often discarded before sufficient growth has occurred for detection 3. Requesting bacterial cultures when infection is due to other organisms 4.


Pharmacology_Katzung

Pharmacology_Katzung. Requesting bacterial cultures when infection is due to other organisms 4. Not recognizing the need for special media or isolation techniques (eg, charcoal yeast extract agar for isolation of Legionella species, shell-vial tissue culture system for rapid isolation of cytomegalovirus) Even in the setting of a classic infectious disease for which isolation techniques have been established for decades (eg, pneumococcal pneumonia, pulmonary tuberculosis, streptococcal pharyngitis), the sensitivity of the culture technique may be inadequate to identify all cases of the disease. Testing bacterial pathogens in vitro for their susceptibility to antimicrobial agents is extremely valuable in confirming susceptibility, ideally to a narrow-spectrum nontoxic antimicrobial drug.


Pharmacology_Katzung

Pharmacology_Katzung. Testing bacterial pathogens in vitro for their susceptibility to antimicrobial agents is extremely valuable in confirming susceptibility, ideally to a narrow-spectrum nontoxic antimicrobial drug. Tests measure the concentration of drug required to inhibit growth of the organism (minimal inhibitory concentration [MIC]) or to kill the organism (minimal bactericidal concentration [MBC]). The results of these tests can then be correlated with known drug concentrations in various body compartments. Only MICs are routinely measured in most infections, whereas in infections in which bactericidal therapy is required for eradication of infection (eg, meningitis, endocarditis, sepsis in the granulocytopenic host), MBC measurements occasionally may be useful. A. Beta-Lactamase Assay


Pharmacology_Katzung

Pharmacology_Katzung. A. Beta-Lactamase Assay For some bacteria (eg, Haemophilus species), the susceptibility patterns of strains are similar except for the production of β lactamase. In these cases, extensive susceptibility testing may not be required, and a direct test for β lactamase using a chromogenic β-lactam substrate (nitrocefin disk) may be substituted. B. Synergy Studies Synergy studies are in vitro tests that attempt to measure synergistic, additive, indifferent, or antagonistic drug interactions. In general, these tests have not been standardized and have not correlated well with clinical outcome. (See section on Antimicrobial Drug Combinations for details.) MONITORING THERAPEUTIC RESPONSE: DURATION OF THERAPY


Pharmacology_Katzung

Pharmacology_Katzung. MONITORING THERAPEUTIC RESPONSE: DURATION OF THERAPY The therapeutic response may be monitored microbiologically or clinically. Cultures of specimens taken from infected sites should eventually become sterile or demonstrate eradication of the pathogen and are useful for documenting recurrence or relapse. Follow-up cultures may also be useful for detecting superinfections or the development of resistance. Clinically, the patient’s systemic manifestations of infection (malaise, fever, leukocytosis) should abate, and the clinical findings should improve (eg, as shown by clearing of radiographic infiltrates or lessening hypoxemia in pneumonia).


Pharmacology_Katzung

Pharmacology_Katzung. The duration of definitive therapy required for cure depends on the pathogen, the site of infection, and host factors (immunocompromised patients generally require longer courses of treatment). Precise data on duration of therapy exist for some infections (eg, streptococcal pharyngitis, syphilis, gonorrhea, tuberculosis, and cryptococcal meningitis). In many other situations, duration of therapy is determined empirically. Minimizing duration of antimicrobial therapy for specific infections is an intervention that may help prevent the development of antimicrobial resistance. For many infections, a combined medical-surgical approach may be required for clinical cure. Clinical Failure of Antimicrobial Therapy When the patient has an inadequate clinical or microbiologic response to antimicrobial therapy selected by in vitro susceptibility testing, systematic investigation should be undertaken to TABLE 51–1 Empiric antimicrobial therapy based on microbiologic etiology.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 51–1 Empiric antimicrobial therapy based on microbiologic etiology. TABLE 51–1 Empiric antimicrobial therapy based on microbiologic etiology. (Continued) Suspected or Proven Disease or Pathogen Drugs of First Choice Alternative Drugs 1Trimethoprim-sulfamethoxazole (TMP-SMZ) is a mixture of one part trimethoprim plus five parts sulfamethoxazole.


Pharmacology_Katzung

Pharmacology_Katzung. 2First-generation cephalosporins: cefazolin for parenteral administration; cefadroxil or cephalexin for oral administration. Second-generation cephalosporins: cefuroxime for par enteral administration; cefaclor, cefuroxime axetil, cefprozil for oral administration. Third-generation cephalosporins: ceftazidime, cefotaxime, ceftriaxone for parenteral admin istration; cefixime, cefpodoxime, ceftibuten, cefdinir, cefditoren for oral administration. Fourth-generation cephalosporin: cefepime for parenteral administration. Cephamycins: cefoxitin and cefotetan for parenteral administration. 3Quinolones: ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin. Norfloxacin is not effective for the treatment of systemic infections. Gemifloxacin, levofloxacin, and moxifloxacin have excellent activity against pneumococci. Ciprofloxacin and levofloxacin have good activity against Pseudomonas aeruginosa. 4Macrolides: azithromycin, clarithromycin, dirithromycin, erythromycin.


Pharmacology_Katzung

Pharmacology_Katzung. have excellent activity against pneumococci. Ciprofloxacin and levofloxacin have good activity against Pseudomonas aeruginosa. 4Macrolides: azithromycin, clarithromycin, dirithromycin, erythromycin. 5Generally, streptomycin and gentamicin are used to treat infections with Gram-positive organisms, whereas gentamicin, tobramycin, and amikacin are used to treat infections with Gram-negatives. 6Carbapenems: doripenem, ertapenem, imipenem, meropenem. Ertapenem lacks activity against enterococci, Acinetobacter, and P aeruginosa. 7Antipseudomonal penicillin: piperacillin, piperacillin/tazobactam, ticarcillin/clavulanic acid. 8See footnote 3 in Table 51–2 for guidelines on the treatment of penicillin-resistant pneumococcal meningitis. 9Parenteral nafcillin or oxacillin; oral dicloxacillin. 10There is no regimen that is reliably bactericidal for vancomycin-resistant enterococcus for which there is extensive clinical experience; daptomycin has bactericidal activity in vitro. Regimens that have


Pharmacology_Katzung

Pharmacology_Katzung. is no regimen that is reliably bactericidal for vancomycin-resistant enterococcus for which there is extensive clinical experience; daptomycin has bactericidal activity in vitro. Regimens that have been reported to be efficacious include nitrofurantoin (for urinary tract infection); potential regimens for bacteremia include daptomycin, linezolid, and dalfopristin/quinupristin. 11Echinocandins: anidulafungin, caspofungin, micafungin.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 51–2 Empiric antimicrobial therapy based on site of infection. Child H influenzae, pneumococcus, Ceftriaxone or cefotaxime ± Chloramphenicol, meropenem meningococcus vancomycin3 1See footnote 9, Table 51–1. 2See footnote 2, Table 51–1. 3When meningitis with penicillin-resistant pneumococcus is suspected, empiric therapy with this regimen is recommended. 4Erythromycin, clarithromycin, or azithromycin (an azalide) may be used. 5Quinolones used to treat pneumonococcal infections include levofloxacin, moxifloxacin, and gemifloxacin. 6Adjunctive immunomodulatory drugs such as drotrecogin-alfa can also be considered for patients with severe sepsis. determine the cause of failure. Errors in susceptibility testing are rare, but the original results should be confirmed by repeat testing. Drug dosing and absorption should be scrutinized and tested directly using serum measurements, pill counting, or directly observed therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The clinical data should be reviewed to determine whether the patient’s immune function is adequate and, if not, what can be done to maximize it. For example, are adequate numbers of granulocytes present and is undiagnosed immunodeficiency, malignancy, or malnutrition present? The presence of abscesses or foreign bodies should also be considered. Finally, culture and susceptibility testing should be repeated to determine whether superinfection has occurred with another organism or whether the original pathogen has developed drug resistance. The time course of drug concentration is closely related to the antimicrobial effect at the site of infection and to any toxic effects. Pharmacodynamic factors include pathogen susceptibility testing, drug bactericidal versus bacteriostatic activity, drug synergism, antagonism, and postantibiotic effects. Together with pharmacokinetics, pharmacodynamic information permits the selection of optimal antimicrobial dosage regimens.


Pharmacology_Katzung

Pharmacology_Katzung. Antibacterial agents may be classified as bacteriostatic or bactericidal (Table 51–3). For agents that are primarily bacteriostatic, inhibitory drug concentrations are much lower than bactericidal drug concentrations. In general, cell wall-active agents are bactericidal, and drugs that inhibit protein synthesis are bacteriostatic. The classification of antibacterial agents as bactericidal or bacteriostatic has limitations. Some agents that are considered to be bacteriostatic may be bactericidal against selected organisms. On the other hand, enterococci are inhibited but not killed by vancomycin, penicillin, or ampicillin used as single agents.


Pharmacology_Katzung

Pharmacology_Katzung. Bacteriostatic and bactericidal agents are equivalent for the treatment of most infectious diseases in immunocompetent hosts. Bactericidal agents should be selected over bacteriostatic ones in circumstances in which local or systemic host defenses are impaired. Bactericidal agents are required for treatment of endocarditis and other endovascular infections, meningitis, and infections in neutropenic cancer patients. Bactericidal agents can be divided into two groups: agents that exhibit concentration-dependent killing (eg, aminoglycosides and quinolones) and agents that exhibit time-dependent killing TABLE 51–3 Bactericidal and bacteriostatic antibacterial agents.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 51–3 Bactericidal and bacteriostatic antibacterial agents. (eg, β-lactams and vancomycin). For drugs whose killing action is concentration-dependent, the rate and extent of killing increase with increasing drug concentrations. Concentration-dependent killing is one of the pharmacodynamic factors responsible for the efficacy of once-daily dosing of aminoglycosides. For drugs whose killing action is time-dependent, bactericidal activity continues as long as serum concentrations are greater than the MBC.


Pharmacology_Katzung

Pharmacology_Katzung. Persistent suppression of bacterial growth after limited exposure to an antimicrobial agent is known as the postantibiotic effect (PAE). The PAE can be expressed mathematically as follows: where T is the time required for the viable count in the test (in vitro) culture to increase tenfold above the count observed immediately before drug removal and C is the time required for the count in an untreated culture to increase tenfold above the count observed immediately after completion of the same procedure used on the test culture. The PAE reflects the time required for bacteria to return to logarithmic growth.


Pharmacology_Katzung

Pharmacology_Katzung. Proposed mechanisms include (1) slow recovery after reversible nonlethal damage to cell structures; (2) persistence of the drug at a binding site or within the periplasmic space; and (3) the need to synthesize new enzymes before growth can resume. Most antimicrobials possess significant in vitro PAEs (≥1.5 hours) against susceptible Gram-positive cocci (Table 51–4). Antimicrobials TABLE 51–4 Antibacterial agents with in vitro postantibiotic effects ≥1.5 hours. with significant PAEs against susceptible Gram-negative bacilli are limited to carbapenems and agents that inhibit protein or DNA synthesis.


Pharmacology_Katzung

Pharmacology_Katzung. with significant PAEs against susceptible Gram-negative bacilli are limited to carbapenems and agents that inhibit protein or DNA synthesis. In vivo PAEs are usually much longer than in vitro PAEs. This is thought to be due to postantibiotic leukocyte enhancement (PALE) and exposure of bacteria to subinhibitory antibiotic concentrations. The efficacy of once-daily dosing regimens is in part due to the PAE. Aminoglycosides and quinolones possess concentration-dependent PAEs; thus, high doses of aminoglycosides given once daily result in enhanced bactericidal activity and extended PAEs. This combination of pharmacodynamic effects allows aminoglycoside serum concentrations that are below the MICs of target organisms to remain effective for extended periods of time. Route of Administration


Pharmacology_Katzung

Pharmacology_Katzung. Route of Administration Many antimicrobial agents have similar pharmacokinetic properties when given orally or parenterally (ie, tetracyclines, trimethoprim-sulfamethoxazole, quinolones, metronidazole, clindamycin, rifampin, linezolid, and fluconazole). In most cases, oral therapy with these drugs is equally effective, is less costly, and results in fewer complications than parenteral therapy. The intravenous route is preferred in the following situations: for critically ill patients; (2) for patients with bacterial meningitis or endocarditis; (3) for patients with nausea, vomiting, gastrectomy, ileus, or diseases that may impair oral absorption; and when giving antimicrobials that are poorly absorbed following oral administration.


Pharmacology_Katzung

Pharmacology_Katzung. Various diseases and physiologic states alter the pharmacokinetics of antimicrobial agents. Impairment of renal or hepatic function may result in decreased elimination. Table 51–5 lists drugs that require dosage reduction in patients with renal or hepatic insufficiency. Failure to reduce antimicrobial agent dosage in such patients may cause toxic effects. Conversely, patients with burns, cystic fibrosis, or trauma may have increased dosage requirements for selected agents. The pharmacokinetics of antimicrobials is also altered in the elderly (see Chapter 60), in neonates (see Chapter 59), and in pregnancy. Most antimicrobial agents are well distributed to most body tissues and fluids. Penetration into the cerebrospinal fluid is an exception. Most do not penetrate uninflamed meninges to an appreciable extent. In the presence of meningitis, however, the cerebrospinal fluid concentrations of many antimicrobials increase (Table 51–6).


Pharmacology_Katzung

Pharmacology_Katzung. Monitoring Serum Concentrations of Antimicrobial Agents For most antimicrobial agents, the relation between dose and therapeutic outcome is well established, and serum concentration monitoring is unnecessary for these drugs. To justify routine serum concentration monitoring, it should be established (1) that a direct relationship exists between drug concentrations and efficacy or toxicity; (2) that substantial interpatient variability exists in serum concentrations on standard doses; (3) that a small difference exists between therapeutic and toxic serum concentrations; (4) that the clinical efficacy or toxicity of the drug is delayed or difficult to measure; and (5) that an accurate assay is available. In clinical practice, serum concentration monitoring is routinely performed on patients receiving aminoglycosides or vancomycin. Flucytosine serum concentration monitoring has been shown to reduce toxicity when doses are adjusted to maintain peak concentrations below 100 mcg/mL.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 51–5 Antimicrobial agents that require dosage adjustment or are contraindicated in patients with renal or hepatic impairment. Acyclovir, amantadine, aminoglycosides, aztreonam, carbapenems, cephalosporins,1 clarithromycin, colistin, cycloserine, dalbavancin, daptomycin, didanosine, emtricitabine, ethambutol, ethionamide, famciclovir, fluconazole, flucytosine, foscarnet, ganciclovir, lamivudine, oseltamivir, penicillins,2 peramivir, polymyxin B, pyrazinamide, quinolones,3 ribavirin, rifabutin, rimantadine, stavudine, telavancin, telbivudine, telithromycin, tenofovir, terbinafine, trimethoprimsulfamethoxazole, valacyclovir, vancomycin, zidovudine


Pharmacology_Katzung

Pharmacology_Katzung. Cidofovir, methenamine, Abacavir, atazanavir, caspofungin, nalidixic acid, nitrofurantoin, chloramphenicol, clindamycin, sulfonamides (long-acting), erythromycin, fosamprenavir, indinavir, tetracyclines4 metronidazole, rimantadine, tigecycline 1Except ceftriaxone. 2Except antistaphylococcal penicillins (eg, nafcillin and dicloxacillin). 3Except moxifloxacin. 4Except doxycycline and minocycline. TABLE 51–6 Cerebrospinal fluid (CSF) penetration of selected antimicrobials.


Pharmacology_Katzung

Pharmacology_Katzung. Owing to the large number of antimicrobials available, it is usually possible to select an effective alternative in patients who develop serious drug toxicity (Table 51–1). However, for some infections there are no effective alternatives to the drug of choice. For example, in patients with neurosyphilis who have a history of anaphylaxis to penicillin, it is necessary to perform skin testing and desensitization to penicillin. It is important to obtain a clear history of drug allergy and other adverse drug reactions. A patient with a documented antimicrobial allergy should carry a card with the name of the drug and a description of the reaction. Cross-reactivity between penicillins and cephalosporins is less than 10%. Cephalosporins may be administered to patients with penicillin-induced maculopapular rashes but should be avoided in patients with a history of penicillin-induced immediate hypersensitivity reactions. On the other hand, aztreonam does not cross-react with penicillins and


Pharmacology_Katzung

Pharmacology_Katzung. rashes but should be avoided in patients with a history of penicillin-induced immediate hypersensitivity reactions. On the other hand, aztreonam does not cross-react with penicillins and can be safely administered to patients with a history of penicillin-induced anaphylaxis. For mild reactions, it may be possible to continue therapy with use of adjunctive agents or dosage reduction.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse reactions to antimicrobials occur with increased frequency in several groups, including neonates, geriatric patients, renal failure patients, and AIDS patients. Dosage adjustment of the drugs listed in Table 51–5 is essential for the prevention of adverse effects in patients with renal failure. In addition, several agents are contraindicated in patients with renal impairment because of increased rates of serious toxicity (Table 51–5). See the preceding chapters for discussions of specific drugs. Most infections should be treated with a single antimicrobial agent. Although indications for combination therapy exist, antimicrobial combinations are often overused in clinical practice. The unnecessary use of antimicrobial combinations increases toxicity and costs and may occasionally result in reduced efficacy due to antagonism of one drug by another. Antimicrobial combinations should be selected for one or more of the following reasons: 1.


Pharmacology_Katzung

Pharmacology_Katzung. To provide broad-spectrum empiric therapy in seriously ill patients. 2. To treat polymicrobial infections (such as intra-abdominal abscesses, which typically are due to a combination of anaerobic and aerobic Gram-negative organisms, and enterococci). The antimicrobial combination chosen should cover the most common known or suspected pathogens but need not cover all possible pathogens. The availability of antimicrobials with excellent polymicrobial coverage (eg, β-lactamase inhibitor combinations or carbapenems) may reduce the need for combination therapy in the setting of polymicrobial infections. 3. To decrease the emergence of resistant strains. The value of combination therapy in this setting has been clearly demonstrated for tuberculosis. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 3. To decrease the emergence of resistant strains. The value of combination therapy in this setting has been clearly demonstrated for tuberculosis. 4. To decrease dose-related toxicity by using reduced doses of one or more components of the drug regimen. The use of flucytosine in combination with amphotericin B for the treatment of cryptococcal meningitis in non-HIV-infected patients allows for a reduction in amphotericin B dosage with decreased amphotericin B–induced nephrotoxicity. 5. To obtain enhanced inhibition or killing. This use of antimicrobial combinations is discussed in the paragraphs that follow.


Pharmacology_Katzung

Pharmacology_Katzung. 5. To obtain enhanced inhibition or killing. This use of antimicrobial combinations is discussed in the paragraphs that follow. When the inhibitory or killing effects of two or more antimicrobials used together are significantly greater than expected from their effects when used individually, synergism is said to result. Synergism is marked by a fourfold or greater reduction in the MIC or MBC of each drug when used in combination versus when used alone. Antagonism occurs when the combined inhibitory or killing effects of two or more antimicrobial drugs are significantly less than observed when the drugs are used individually. Mechanisms of Synergistic Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanisms of Synergistic Action The need for synergistic combinations of antimicrobials has been clearly established for the treatment of enterococcal endocarditis. Bactericidal activity is essential for the optimal management of bacterial endocarditis. Penicillin or ampicillin in combination with gentamicin or streptomycin is superior to monotherapy with a penicillin or vancomycin. When tested alone, penicillins and vancomycin are only bacteriostatic against susceptible enterococcal isolates. When these agents are combined with an aminoglycoside, however, bactericidal activity results. The addition of gentamicin or streptomycin to penicillin allows for a reduction in the duration of therapy for selected patients with viridans streptococcal endocarditis.


Pharmacology_Katzung

Pharmacology_Katzung. Other synergistic antimicrobial combinations have been shown to be more effective than monotherapy with individual components. Trimethoprim-sulfamethoxazole has been successfully used in the treatment of bacterial infections and P jiroveci (carinii) pneumonia. *β-Lactamase inhibitors restore the activity of intrinsically active but hydrolyzable β lactams against organisms such as Staphylococcus aureus and Bacteroides fragilis. Three major mechanisms of antimicrobial synergism have been established: 1. Blockade of sequential steps in a metabolic sequence: Trimethoprim-sulfamethoxazole is the best-known example of this mechanism of synergy (see Chapter 46). Blockade of the two sequential steps in the folic acid pathway by trimethoprimsulfamethoxazole results in a much more complete inhibition of growth than achieved by either component alone. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Inhibition of enzymatic inactivation: Enzymatic inactivation of β-lactam antibiotics is a major mechanism of antibiotic resistance. Inhibition of β lactamase by β-lactamase inhibitor drugs (eg, sulbactam) results in synergism. 3. Enhancement of antimicrobial agent uptake: Penicillins and other cell wall-active agents can increase the uptake of aminoglycosides by a number of bacteria, including staphylococci, enterococci, streptococci, and P aeruginosa. Enterococci are thought to be intrinsically resistant to aminoglycosides because of permeability barriers. Similarly, amphotericin B is thought to enhance the uptake of flucytosine by fungi. Mechanisms of Antagonistic Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanisms of Antagonistic Action There are few clinically relevant examples of antimicrobial antagonism. The most striking example was reported in a study of patients with pneumococcal meningitis. Patients who were treated with the combination of penicillin and chlortetracycline had a mortality rate of 79% compared with a mortality rate of 21% in patients who received penicillin monotherapy (illustrating the first mechanism set forth below). The use of an antagonistic antimicrobial combination does not preclude other potential beneficial interactions. For example, rifampin may antagonize the action of anti-staphylococcal penicillins or vancomycin against staphylococci. However, the aforementioned antimicrobials may prevent the emergence of resistance to rifampin.


Pharmacology_Katzung

Pharmacology_Katzung. Two major mechanisms of antimicrobial antagonism have been established: 1. Inhibition of cidal activity by static agents: Bacteriostatic agents such as tetracyclines and chloramphenicol can * Pneumocystis jiroveci is a fungal organism found in humans (P carinii infects animals) that responds to antiprotozoal drugs. See Chapter 52. antagonize the action of bactericidal cell wall-active agents because cell wall-active agents require that the bacteria be actively growing and dividing. 2. Induction of enzymatic inactivation: Some Gram-negative bacilli, including Enterobacter species, P aeruginosa, Serratia marcescens, and Citrobacter freundii, possess inducible β-lactamases. β-Lactam antibiotics such as imipenem, cefoxitin, and ampicillin are potent inducers of β-lactamase production. If an inducing agent is combined with an intrinsically active but hydrolyzable β-lactam such as piperacillin, antagonism may result.


Pharmacology_Katzung

Pharmacology_Katzung. Antimicrobial agents are effective in preventing infections in many settings. Antimicrobial prophylaxis should be used in circumstances in which efficacy has been demonstrated and benefits outweigh the risks of prophylaxis. Antimicrobial prophylaxis may be divided into surgical prophylaxis and nonsurgical prophylaxis. Surgical wound infections are a major category of nosocomial infections. The estimated annual cost of surgical wound infections in the USA is more than $1.5 billion. The National Research Council (NRC) Wound Classification Criteria have served as the basis for recommending antimicrobial prophylaxis. NRC criteria consist of four classes (see Box: National Research Council [NRC] Wound Classification Criteria).


Pharmacology_Katzung

Pharmacology_Katzung. The Study of the Efficacy of Nosocomial Infection Control (SENIC) identified four independent risk factors for postoperative wound infections: operations on the abdomen, operations lasting more than 2 hours, contaminated or dirty wound classification, and at least three medical diagnoses. Patients with at least two SENIC risk factors who undergo clean surgical procedures have an increased risk of developing surgical wound infections and should receive antimicrobial prophylaxis. Surgical procedures that necessitate the use of antimicrobial prophylaxis include contaminated and clean-contaminated operations, selected operations in which postoperative infection may be catastrophic such as open heart surgery, clean procedures that involve placement of prosthetic materials, and any procedure in an immunocompromised host. The operation should carry a significant risk of postoperative site infection or cause significant bacterial contamination.


Pharmacology_Katzung

Pharmacology_Katzung. General principles of antimicrobial surgical prophylaxis include the following: 1. The antibiotic should be active against common surgical wound pathogens; unnecessarily broad coverage should be avoided. 2. The antibiotic should have proved efficacy in clinical trials. 3. The antibiotic must achieve concentrations greater than the MIC of suspected pathogens, and these concentrations must be present at the time of incision. TABLE 51–7 Recommendations for surgical antimicrobial prophylaxis.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 51–7 Recommendations for surgical antimicrobial prophylaxis. Clean: Elective, primarily closed procedure; respiratory, gastrointestinal, biliary, genitourinary, or oropharyngeal tract not entered; no acute inflammation and no break in technique; expected infection rate ≤ 2%. Clean contaminated: Urgent or emergency case that is otherwise clean; elective, controlled opening of respiratory, gastrointestinal, biliary, or oropharyngeal tract; minimal spillage or minor break in technique; expected infection rate ≤ 10%. Contaminated: Acute nonpurulent inflammation; major technique break or major spill from hollow organ; penetrating trauma less than 4 hours old; chronic open wounds to be grafted or covered; expected infection rate about 20%. Dirty: Purulence or abscess; preoperative perforation of respiratory, gastrointestinal, biliary, or oropharyngeal tract; penetrating trauma more than 4 hours old; expected infection rate about 40%. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. The shortest possible course—ideally a single dose—of the most effective and least toxic antibiotic should be used. 5. The newer broad-spectrum antibiotics should be reserved for therapy of resistant infections. 6. If all other factors are equal, the least expensive agent should be used.


Pharmacology_Katzung

Pharmacology_Katzung. The proper selection and administration of antimicrobial prophylaxis are of utmost importance. Common indications for surgical prophylaxis are shown in Table 51–7. Cefazolin is the prophylactic agent of choice for head and neck, gastroduodenal, biliary tract, gynecologic, and clean procedures. Local wound infection patterns should be considered when selecting antimicrobial prophylaxis. The selection of vancomycin over cefazolin may be necessary in hospitals with high rates of methicillin-resistant S aureus or S epidermidis infections. The antibiotic should be present in adequate concentrations at the operative site before incision and throughout the procedure; initial dosing is dependent on the volume of distribution, peak levels, clearance, protein binding, and bioavailability. Parenteral agents should be administered during the interval beginning 60 minutes before incision. In cesarean section, the antibiotic is administered after umbilical cord clamping. For many antimicrobial


Pharmacology_Katzung

Pharmacology_Katzung. agents should be administered during the interval beginning 60 minutes before incision. In cesarean section, the antibiotic is administered after umbilical cord clamping. For many antimicrobial agents, doses should be repeated if the procedure exceeds 2–6 hours in duration. Single-dose prophylaxis is effective for most procedures and results in decreased toxicity and antimicrobial resistance.


Pharmacology_Katzung

Pharmacology_Katzung. Improper administration of antimicrobial prophylaxis leads to excessive surgical wound infection rates. Common errors in antibiotic prophylaxis include selection of the wrong antibiotic, administering the first dose too early or too late, failure to repeat doses during prolonged procedures, excessive duration of prophylaxis, and inappropriate use of broad-spectrum antibiotics. Nonsurgical prophylaxis includes the administration of antimicrobials to prevent colonization or asymptomatic infection as 1In conjunction with mechanical bowel preparation. TABLE 51–8 Recommendations for nonsurgical antimicrobial prophylaxis. 1Prophylaxis is recommended for the following: dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa, and invasive procedure of the respiratory tract that involves incision or biopsy of the respiratory mucosa, such as tonsillectomy and adenoidectomy.


Pharmacology_Katzung

Pharmacology_Katzung. 2Prophylaxis should be targeted to those with the following risk factors: prosthetic heart valves, previous bacterial endocarditis, congenital cardiac malformations, cardiac transplantation patients who develop cardiac valvulopathy. 3Highly active antiretroviral therapy. See aidsinfo.nih.gov/ for updated guidelines. well as the administration of drugs following colonization by or inoculation of pathogens but before the development of disease. Nonsurgical prophylaxis is indicated in individuals who are at high risk for temporary exposure to selected virulent pathogens and in patients who are at increased risk for developing infection Baddour LM et al: Infective endocarditis: Diagnosis, antimicrobial therapy, and management of complications. Circulation 2015;132:1435.


Pharmacology_Katzung

Pharmacology_Katzung. Baddour LM et al: Infective endocarditis: Diagnosis, antimicrobial therapy, and management of complications. Circulation 2015;132:1435. Baron EJ et al: Guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). Clin Infect Dis 2013;57:e22. Blumberg HM et al: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603. Boucher HW: 10 × ‘20 Progress—Development of new drugs active against gram-negative bacilli: An update from the Infectious Diseases Society of America. Clin Infect Dis 2013;56:1685. Bratzler DW et al: Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70:195.


Pharmacology_Katzung

Pharmacology_Katzung. Bratzler DW et al: Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70:195. Chow AW et al: IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis 2012;54:e72. Holmes AH et al: Understanding the mechanisms and drivers of antimicrobial resistance. Lancet 2016;387:176. Kalil AC et al: Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical practice guidelines by the Infectious Disease Society of America and the American Thoracic Society. Clin Infect Dis 2016;63:e61. Kaye KS, Kaye D: Antibacterial therapy and newer agents. Infect Dis Clin North Am 2009;23:757. Mandell LA et al: Infectious Diseases Society of America/American Thoracic Society Consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27.


Pharmacology_Katzung

Pharmacology_Katzung. Mandell LA et al: Infectious Diseases Society of America/American Thoracic Society Consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27. because of underlying disease (eg, immunocompromised hosts). Prophylaxis is most effective when directed against organisms that are predictably susceptible to antimicrobial agents. Common indications and drugs for nonsurgical prophylaxis are listed in Table 51–8.


Pharmacology_Katzung

Pharmacology_Katzung. Martin RF: Surgical infections. Surg Clin North Am 2014;94:1135. Mirakian R et al: Management of allergy to penicillins and other beta-lactams. Clin Exp Allergy 2015;45:300. National Nosocomial Infections Surveillance System: National Nosocomial Infections Surveillance (NNIS) System Report, Data Summary from January 1992–June 2004, issued October 2004. Am J Infect Control 2004;32:470. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents: Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Peleg AY et al: Hospital-acquired infections due to gram negative bacteria. N Engl


Pharmacology_Katzung

Pharmacology_Katzung. J Med 2010;362:1804. Simons FE: Anaphylaxis. J Allergy Clin Immunol 2010;125(Suppl 2):S161. Spellberg B et al: The future of antibiotics and resistance. N Engl J Med 2013;368:299. Tunkel AR et al: Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267. Wilson W et al: Prevention of infective endocarditis: Guidelines from the American Heart Association. Circulation 2007;116:1736. Workowski KA, Bolan GA: Sexually transmitted diseases treatment guidelines 2015. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2015;64(RR-3):1.


Pharmacology_Katzung

Pharmacology_Katzung. This patient is experiencing a post-procedure urinary tract infection which may have been introduced into his bloodstream at the time of his cystoscopy. It is likely that the patient is experiencing a sepsis-like syndrome and has a systemic infection with a uropathogen that is resistant to the antibiotic that he has received. Pos-sible bacteria that may be responsible for the patient’s symptoms are methicillin-resistant Staphylococcus aureus, Enterococcus sp., and enteric Gram-negative rods that are resistant to ciprofloxacin such as ESBL-positive E coli or Klebsiella pneumoniae, or other hospital-acquired Gram negative organisms such as Pseudomonas aeruginosa. The patient was treated with vancomycin and meropenem, and blood and urine cultures were both positive for ESBL-positive E coli that was resistant to ciprofloxacin. The patient defervesced and hemodynamically stabilized over the subsequent 48 hours. ESBL-positive E coli is an emerging urinary tract pathogen that may be acquired


Pharmacology_Katzung

Pharmacology_Katzung. was resistant to ciprofloxacin. The patient defervesced and hemodynamically stabilized over the subsequent 48 hours. ESBL-positive E coli is an emerging urinary tract pathogen that may be acquired in the outpatient setting, and oral antibiotic therapy may not reliably be effective; empiric therapy with a carbapenem (ertapenem, doripenem, meropenem, imipenem) is recom-mended for serious infections due to this organism.


Pharmacology_Katzung

Pharmacology_Katzung. Philip J. Rosenthal, MD A 5-year-old American girl presents with a 1-week history of intermittent chills, fever, and sweats. She had returned home 2 weeks earlier after leaving the USA for the first time to spend 3 weeks with her grandparents in Nigeria. She received all standard childhood immunizations, but no additional treat-ment before travel, since her parents have returned to their native Nigeria frequently without medical consequences. Three days ago, the child was seen in an outpatient clinic and diagnosed with a viral syndrome. Examination reveals a lethargic child, with a temperature of 39.8°C (103.6°F) and splenomegaly. She has no skin rash or lymphadenopathy. Ini-tial laboratory studies are remarkable for hematocrit 29.8%, platelets 45,000/mm3, creatinine 2.5 mg/dL (220 μmol/L), and mildly elevated bilirubin and transaminases. A blood smear shows ring forms of Plasmodium falciparum at 1.5% parasit-emia. What treatment should be started?


Pharmacology_Katzung

Pharmacology_Katzung. Malaria is the most important parasitic disease of humans and causes hundreds of millions of illnesses per year. Four species of plasmodium typically cause human malaria: Plasmodium falciparum, P vivax, P malariae, and P ovale. A fifth species, P knowlesi, is primarily a pathogen of monkeys but has recently been recognized to cause illness, including severe disease, in humans in Asia. Although all of the latter species may cause significant illness, P falciparum is responsible for the majority of serious complications and deaths. Drug resistance is an important therapeutic problem, most notably with P falciparum.


Pharmacology_Katzung

Pharmacology_Katzung. An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection (Figure 52–1). Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Repeated cycles of infection can lead to the infection of many erythrocytes and serious disease. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.


Pharmacology_Katzung

Pharmacology_Katzung. In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most drugs, and relapses can occur after therapy directed against erythrocytic parasites. Eradication of both erythrocytic and hepatic parasites is required to cure these infections.


Pharmacology_Katzung

Pharmacology_Katzung. Several classes of antimalarial drugs are available (Table 52–1 and Figure 52–2). Drugs that eliminate developing or dormant liver forms are called tissue schizonticides; those that act on erythrocytic parasites are blood schizonticides; and those that kill sexual stages and prevent transmission to mosquitoes are gametocides. No single available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages. Few available agents are causal prophylactic drugs, ie, capable of preventing erythrocytic infection. However, all effective chemoprophylactic agents kill erythrocytic parasites before they increase sufficiently in number to cause clinical disease.


Pharmacology_Katzung

Pharmacology_Katzung. BloodschizonticideTissueschizonticideBloodGametocideLiverSchizontsHypnozoitesFIGURE 52–1 Life cycle of malaria parasites. Only the asexual erythrocytic stage of infection causes clinical malaria. All effective antimalarial treatments are blood schizonticides that kill this stage. (Reproduced from Baird JK: Effectiveness of antimalarial drugs. N Engl J Med 2005;352:1565.)


Pharmacology_Katzung

Pharmacology_Katzung. When patients are counseled on the prevention of malaria, it is imperative to emphasize measures to prevent mosquito bites (eg, with insect repellents, insecticides, and bed nets), because parasites are increasingly resistant to multiple drugs and no chemoprophylactic regimen is fully protective. Current recommendations from the U.S. Centers for Disease Control and Prevention (CDC) include the use of chloroquine for chemoprophylaxis in the few areas infested by only chloroquine-sensitive malaria parasites (principally Hispaniola and Central America west of the Panama Canal), and mefloquine, Malarone, * or doxycycline for most other malarious areas, with doxycycline preferred for areas with a high prevalence of multidrug-resistant falciparum malaria (principally border areas of Thailand) (Table 52–2). CDC recommendations should be checked regularly (Phone: 770-488-7788; after hours 770-488-7100; Internet: www.cdc.gov/malaria), because these may change in response to changing resistance


Pharmacology_Katzung

Pharmacology_Katzung. 52–2). CDC recommendations should be checked regularly (Phone: 770-488-7788; after hours 770-488-7100; Internet: www.cdc.gov/malaria), because these may change in response to changing resistance patterns and increasing experience with new drugs. In some circumstances, it may be appropriate for travelers to carry supplies of drugs with them in case they develop a febrile illness when medical attention is unavailable. Regimens for self-treatment include new artemisinin-based combination therapies (see below), which are widely available internationally (and, in the case of Coartem†, in the USA); Malarone; mefloquine; and quinine. Most authorities do not recommend routine terminal chemoprophylaxis with primaquine to eradicate dormant hepatic stages of P vivax and P ovale after travel, but this may be appropriate in some circumstances, especially for travelers with major exposure to these parasites.


Pharmacology_Katzung

Pharmacology_Katzung. Multiple drugs are available for the treatment of malaria that presents in the USA (Table 52–3). Most nonfalciparum infections and falciparum malaria from areas without known resistance should be treated with chloroquine. For vivax malaria from areas with suspected chloroquine resistance, including Indonesia and Papua New Guinea, other therapies effective against falciparum malaria may be used. Vivax and ovale malaria should subsequently be treated with primaquine to eradicate liver forms. Uncomplicated falciparum malaria from most areas is most often treated with Malarone, but new artemisinin-based combinations are increasingly the international standard of care, and one combination, Coartem, is now available in the USA. Other agents that are generally effective against resistant falciparum malaria include mefloquine, quinine, and halofantrine, all of which have toxicity concerns at treatment dosages. Severe falciparum malaria is treated with intravenous artesunate, quinidine, or


Pharmacology_Katzung

Pharmacology_Katzung. malaria include mefloquine, quinine, and halofantrine, all of which have toxicity concerns at treatment dosages. Severe falciparum malaria is treated with intravenous artesunate, quinidine, or quinine (intravenous quinine is not available in the USA).


Pharmacology_Katzung

Pharmacology_Katzung. Chloroquine has been a drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s, but its usefulness against P falciparum has been seriously compromised by drug resistance. It remains the drug of choice in the treatment of sensitive P falciparum and other species of human malaria parasites. Chloroquine is a synthetic 4-aminoquinoline (Figure 52–2) formulated as the phosphate salt for oral use. It is rapidly and almost completely absorbed from the gastrointestinal tract, reaches maximum plasma concentrations in about 3 hours, and is rapidly distributed to the tissues. It has a very large apparent volume of distribution of 100–1000 L/kg and is slowly released from tissues and metabolized. Chloroquine is principally excreted in the urine with an initial half-life of 3–5 days but a much longer terminal elimination half-life of 1–2 months.


Pharmacology_Katzung

Pharmacology_Katzung. When not limited by resistance, chloroquine is a highly effective blood schizonticide. Chloroquine is not reliably active against liver stage parasites or gametocytes. The drug probably acts by concentrating in parasite food vacuoles, preventing the biocrystallization * Malarone is a proprietary formulation of atovaquone plus proguanil. †Coartem is a proprietary formulation of artemether and lumefantrine. FIGURE 52–2 Structural formulas of some antimalarial drugs. of the hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to the buildup of free heme.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 52–2 Structural formulas of some antimalarial drugs. of the hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to the buildup of free heme. Resistance to chloroquine is now very common among strains of P falciparum and uncommon but increasing for P vivax. In P falciparum, mutations in a putative transporter, PfCRT, are the primary mediators of resistance. Chloroquine resistance can be reversed by certain agents, including verapamil, desipramine, and chlorpheniramine, but the clinical value of resistance-reversing drugs is not established.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Treatment—Chloroquine is the drug of choice in the treatment of uncomplicated nonfalciparum and sensitive falciparum malaria. It rapidly terminates fever (usually in 24–48 hours) and clears parasitemia (in 48–72 hours) caused by sensitive parasites. Chloroquine has been replaced by other drugs, principally artemisinin-based combination therapies, as the standard therapy to treat falciparum malaria in most endemic countries. Chloroquine does not eliminate dormant liver forms of P vivax and P ovale, and for that reason primaquine must be added for the radical cure of these species. 2. Chemoprophylaxis—Chloroquine is the preferred chemoprophylactic agent in malarious regions without resistant falciparum malaria. Eradication of P vivax and P ovale requires a course of primaquine to clear hepatic stages. TABLE 52–1 Major antimalarial drugs. 1Not available in the USA. 2Available in the USA only as the fixed combination Coartem.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 52–1 Major antimalarial drugs. 1Not available in the USA. 2Available in the USA only as the fixed combination Coartem. 3. Amebic liver abscess—Chloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy with metronidazole (see below).


Pharmacology_Katzung

Pharmacology_Katzung. 3. Amebic liver abscess—Chloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy with metronidazole (see below). Chloroquine is usually very well tolerated, even with prolonged use. Pruritus is common, primarily in Africans. Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon. Dosing after meals may reduce some adverse effects. Rare reactions include hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons, impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension, and electrocardiographic changes. The long-term administration of high doses of chloroquine for rheumatologic diseases (see Chapter 36) can result in irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy, but these are rarely seen with standard-dose weekly


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 52–2 Drugs for the prevention of malaria in travelers.1 1Recommendations may change, as resistance to all available drugs is increasing. See text for additional information on toxicities and cautions. For additional details and pediatric dosing, see CDC guidelines (phone: 877-FYI-TRIP; www.cdc.gov). Travelers to remote areas should consider carrying effective therapy (see text) for use if they develop a febrile illness and cannot reach medical attention quickly. 2Areas without known chloroquine-resistant P falciparum are Central America west of the Panama Canal, Haiti, Dominican Republic, Egypt, and most malarious countries of the Middle East. Malarone or mefloquine are currently recommended for other malarious areas except for border areas of Thailand, where doxycycline is recommended.