CLINICAL PHARMACOLOGY OF ANTISEPTICS AND ENZYME DRUGS. CLINICAL PHARMACOLOGY OF DRUGS WITH INFLUENCE ON METABOLISM IN SOLID DENTAL TISSUES (MEDICINES WITH PHOSPHORUS, CALCIUM AND FLUORIDE)
Disinfectants are strong chemical agents that inhibit or kill microorganisms
Antiseptics are disinfecting 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.
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,
Handwashing is 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. Soap and warm water efficiently and effectively remove bacteria. Skin disinfectants along with detergent and water are usually used preoperatively as a surgical scrub for surgeons’ hands and the patient’s surgical incision.
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. The Environmental Protection Agency (EPA) regulates disinfectants and sterilants and the Food and Drug Administration 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 environment or in the body of the patient or caregiver using the agent. Disinfectants and antiseptics may also become contaminated by resistant microorganisms¾eg, spores, P aeruginosa, or Serratia marcescens¾and actually transmit infection. Most topical antiseptics interfere with wound healing to some degree. Simple cleansing with soap and water is less damaging than antiseptics to wounds. Topical antibiotics with a narrow spectrum of action and low toxicity (eg, bacitracin and mupirocin) can be used for temporary control of bacterial growth and are generally preferred to antiseptics. Methenamine mandelate releases formaldehyde in a low antibacterial concentration at acid pH and can be an effective urinary antiseptic for long-term control of urinary tract infections.
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.
The two alcohols most frequently used for antisepsis and disinfection are ethanol and isopropyl alcohol (isopropanol). They are rapidly active, killing vegetative bacteria, Mycobacterium 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, may not be active against hydrophilic viruses, and lack residual action because they evaporate completely. The alcohols are useful in situations in which sinks with running water are not available for washing with soap and water. Their skin-drying effect can be partially alleviated by addition of emollients to the formulation. Use of alcohol-based hand rubs has been shown to reduce transmission of nosocomial bacterial pathogens and is recommended by the Centers for Disease Control and Prevention (CDC) as the preferred method of hand decontamination. Alcohol-based hand rubs are ineffective against spores of Clostridium difficile and assiduous handwashing with a disinfectant soap and water is still required for decontamination after caring for a patient with infection from this organism.
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.
CHLORHEXIDINE
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 moderate 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 when used repeatedly, 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 4% concentration have slightly greater antibacterial activity thaewer 2% formulations. Chlorhexidine 0.5% in 70% alcohol formulations are available in some countries. 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 neurosurgery.
1. Iodine
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 because of serious hypersensitivity reactions that may occur and because of its staining of clothing and dressings.
2. Iodophors
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 upon 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.
Iodophors are less irritating and less likely to produce skin hypersensitivity than tincture of iodine. They act as rapidly as chlorhexidine and have a broader spectrum of action, including sporicidal action, but they lack the persistent action of chlorhexidine.
3. Chlorine
Chlorine is a strong oxidizing agent and universal disinfectant that is most 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 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 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 5.25% 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.
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 bis-chloromethyl 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 retain chlorine longer and have a prolonged bactericidal action.
PHENOLICS
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.
Phenolic compounds disrupt cell walls and membranes, precipitate proteins, and inactivate enzymes. They are bactericidal (including mycobacteria) and fungicidal and they 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 iurseries and especially in bassinets, where their use has been associated with hyperbilirubinemia. Use of hexachlorophene as a skin disinfectant has caused cerebral edema and convulsions in premature infants and occasionally in adults.
QUATERNARY AMMONIUM COMPOUNDS
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 bacteriostatic, 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 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.
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. 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.
PEROXYGEN COMPOUNDS
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.
Hydrogen peroxide is a very effective disinfectant when used for inanimate objects or materials with low organic content such as water. Organisms with the enzymes catalase and peroxidase rapidly degrade hydrogen peroxide. The innocuous degradation products are oxygen and water. Concentrated solutions containing 90% w/v H2O2 are prepared electrochemically. When diluted in high-quality deionized water to 6% and 3% and put into clean containers, they remain stable. Hydrogen peroxide has been proposed for disinfection of respirators, acrylic resin implants, plastic eating utensils, soft contact lenses, and cartons intended to contain milk or juice products. 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 liquids and cellulose products. It penetrates the surface of some plastics. Automated equipment using vaporized hydrogen peroxide (eg, Sterrad) or hydrogen peroxide mixed with formic acid (Endoclens) is available for sterilizing endoscopes.
Peracetic acid (CH3COOOH) is prepared commercially from 90% hydrogen peroxide, acetic acid, and sulfuric acid as a catalyst. 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.
An automated machine (Steris) 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. Because rinsing is not necessary in this use, time and money are saved.
Peracetic acid is a potent tumor promoter but a weak carcinogen. It is not mutagenic in the Ames test.
HEAVY METALS
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. Nevertheless, thimerosal 0.001-0.004% is still used as a preservative of vaccines, antitoxins, and immune sera.
Inorganic silver salts are strongly bactericidal. Silver nitrate, 1:1000, has been most commonly used, particularly as a preventive for gonococcal ophthalmitis iewborns. Antibiotic ointments have replaced silver nitrate for this indication. Silver sulfadiazine slowly releases silver and is used to suppress bacterial growth in burn wounds.
Oral Inflammation
Oral inflammation is the basis of gingivitis and periodontitis; it is caused by bacteria that initiate the destruction of gingival tissue and compromise periodontal attachment. Bacteria adhere to oral surfaces and aggregate to produce plaque, or dental biofilm, that are complex and physically structured microbial communities able to harvest several pathogenic species in large numbers. Dental biofilm is largely composed of polysaccharides that form a physical barrier which protects bacteria from the effects of antibiotics, antiseptics, and host defense mechanisms.
The pathogenic bacteria in the periodontium have the ability to evade the host defense mechanisms that would routinely control such infections and prevent disease. This breakdown in the host defense mechanism appears as an inflammatory response, which can itself contribute to tissue pathology, promoting the release of tissue-derived enzymes that destroy the extracellular matrix and bone. Antigens released by bacterial cells stimulate the production of antibodies which are not effective at killing bacteria within biofilm, but may form immune complexes that further damage surrounding tissues.
The main underlying concepts for the treatment of oral inflammation are summarized in the figure at right. Therapy is targeted at three interdependent components to prevent initiation or halt progression of oral inflammation. Treatment requirements and effectiveness are modulated by genetic and environmental factors. The first component is to remove dental biofilm and reduce the levels of bacteria, which also changes the composition of the oral microflora. The second component involves the modulation of the host response (inflammation) by limiting the production of antibodies and the release of proteinase caused by bacterial tissue invasion. The last component involves alteration of the oral microhabitat by modifying the physical features that facilitate the growth and accumulation of bacteria.
Several factors can contribute to oral inflammation (see table overleaf). Some factors can be modified to minimize the risk of oral diseases and improve control of oral inflammation, while others will help to define an individual treatment plan for optimal oral health.
Management of the Patient with Oral Inflammation
The optimal strategy to eliminate dental biofilm from the oral cavity has four dimensions: physical removal of dental biofilm; destruction of the remaining bacteria using antimicrobial agents; routine oral hygiene habits; and patient education.
Instrumentation and Physical Removal of Biofilm
Dental biofilm offers remarkable resistance to host defense mechanisms and antibacterial agents. The most effective method to disrupt dental biofilm is through mechanical means, such as the use of power and hand instrumentation, and oral physiotherapy aids such as toothbrushes, floss, and other interdental devices. Mechanical alteration of dental biofilm disrupts the bacterial structure and is essential in dislodging bacteria, reducing plaque, preventing dental calculus, and maintaining subgingival bacteria at a level below that which is capable of initiating inflammation.
Alteration of the microenvironment surrounding the subgingival microbiota can affect numbers, proportions, and prevalence of bacterial species present in the oral cavity. Some physical features predisposing to the accumulation of plaque, such as over-contoured crowns, open or overhanging margins, narrow embrasure space, open contacts, caries, or tooth malposition, should be preventively corrected to improve the patient’s ability to remove the biofilm. Gingival deformities hindering biofilm control should be corrected by adequate surgery to reduce the potential for plaque accumulation. Daily removal of supragingival plaque reduces gingival inflammation and also controls the amount of subgingival plaque. It also can significantly reduce the proportion of known periodontal pathogens such as B. forsythus, P. gingivalis, and A. actinomycetemcomitans.
Antibacterial Agents
Despite frequent mechanical cleaning, the rapid multiplication rates of bacteria warrant consistent efforts to decrease these pathogens to baseline levels. Use of topical oral rinses containing antibacterial agents, such as chlorhexidine (Peridex®, PerioGard®) or essential oils (Listerine®), or of an antibacterial dentifrice (Colgate® Total®), will help to prevent or delay bacterial accumulation and dental biofilm formation. Daily brushing with Colgate Total, which is the only toothpaste in the U.S. that contains the antibacterial agent triclosan, has been shown to reduce the growth of oral bacteria and the formation of plaque. It uses a patented copolymer to improve retention of the bactericide triclosan to oral surfaces, providing 12- hour antibacterial action. In addition, it provides direct inhibition of potent inflammatory mediators, thus affecting the inflammation process as well. Topical agents improve the control of supragingival plaque, which will also have indirect effects on subgingival plaque.
Individualized Patient Oral Hygiene Program
A long-term treatment plan for managing chronic oral inflammation should include regular maintenance care by an oral healthcare professional for thorough elimination of dental biofilm and calculus, and to perform periodic evaluation of the periodontal status. Frequency of visits (every three to six months) depends on the patient’s condition and risk factors, and the extent of bacterial infection, oral inflammation, and periodontal disease. Diagnosis of the periodontal condition is based on traditional clinical assessments, including the presence of clinical signs of inflammation (gingival bleeding), probing depth, loss of clinical attachment, radiographic findings and various symptoms such as pain, ulceration, and amount of observable plaque and calculus. An accurate diagnosis of periodontal disease severity is essential for selecting an appropriate treatment and maintenance strategy for a given patient. For the patient with gingivitis, a combination of routine personal plaque control in combination with professional removal of plaque, calculus, and local contributing factors may be needed to reduce inflammation. At-home use of an antimicrobial toothpaste containing triclosan/copolymer (Colgate Total) has been shown to improve the outcome of a gingivitis treatment regimen and reduce oral inflammation.
Self-Care Communication and Education
Control of oral inflammation essentially relies on preventive measures to inhibit dental biofilm accumulation, and can be achieved by maintaining good oral hygiene involving daily flossing and brushing with an antibacterial antiplaque toothpaste.
An individualized treatment plan is needed to monitor the maintenance of the oral environment and the progression of oral inflammation. Frequent followup evaluation of a patient’s condition to determine the need for further treatment is recommended. Communication between practitioners and patients is an essential aspect of oral inflammation management. Oral healthcare professionals should advise patients on how to modify risk factors to reduce oral inflammation. Cessation of smoking, a key risk factor for oral disease, should be advocated.
A good plaque control program, coupled with regular periodontal maintenance by an oral healthcare professional and reduction of risk factors, can effectively manage oral inflammation in the majority of patients
As dental caries is one of the most common diseases worldwide, oral health care professionals are always looking to add new, effective instruments to their caries management armamentarium. The availability of calcium and phosphate in the remineralization process is essential. A variety of calcium phosphate technologies are currently available in professionally-dispensed and over-the-counter oral health care products that may help limit the progression of carious lesions and enhance the repair of early lesions already present.
ENAMEL AND DENTAL DECAY
Enamel, with its epithelial structure is the body’s most mineralized tissue. Apatite crystals represent 96% of the weight.
Unlike what they appear to be, they do not constitute an inert and impenetrable structure.
Microscopically, they show a microporous aspect that offers diffusion channels along the sheath of the framework prisms.
A more detailed investigation allows us to distinguish the presence of the following components:
-hydroxyapatite precursors
-calcium phosphate apatite crystals with a composition close to hydroxyapatite
-organic material around the sheath of the prisms
-fluoroapatites
-fluoride hydroxyapatites
-impurities: carbonate, carbonated apatites, adsorbed magnesium, adsorbed calcium
-diphosphonate dihydrate
-octocalcium phosphate.
The newly emerged tooth has not yet reached its definitive degree of mineralization. It presents a more porous enamel surface than a mature tooth.
Moreover, mineral density varies on the same tooth: Cervical enamel is less dense than occlusal enamel. hrough buccal environment, the post eruptive maturation is dependent on buccal fluids and mineral ions (calcium and phosphate). We can observe a succession of demineralization an mineralization cycles that iormal conditions, lead to a decrease in porosity and surface irregularity. We must notice that the porous surface of a young enamel is more sensitive to acids produced by bacterian glycolysis.
When the tooth has matured, mineral exchanges continue for its whole life between the enamel surface and ions included in buccal fluids. pH, phosphates and calcium concentrations regulate these exchanges. With a 7-pH, a reduced number of calcium ions is sufficient to maintain the stability of enamel. The more the pH decreases, the more calcium ions are needed to avoid apatite demineralization. 5.5 is the critical pH value under which hydroxyapatite dissolution is irreversible. The result is a calcium and phosphate leakage around the tooth. The 5.5 pH does not damage fluoroapatite which begins to dissolve when pH reaches 4.6. The initial carious lesion is materialized by a break of the balance of the demineralization – remineralization cycle of enamel surface.
Demineralization:
Mineral ions are lost by enamel: the pH decreases and the buccal environment does not provide enough replacement ions. Remineralization: Mineral ions precipitate on enamel. There is a sufficient concentration in buccal fluids and the pH remains above the critical threshold of apatite dissolution. Decay process: Tooth decay begins on the subsurface of enamel with a widening of intercrystal compartments and a dissolution of apatite crystals by acids produced from bacteria. This is macroscopically materialized by white spots.Dissolution occurs along the edges of the prisms round the sheaths which favour the acid spread. The progress of the lesion always precedes that of the bacteria. At this stage, tooth decay is reversible if the buccal fluids bring enough mineral elements as such as calcium phosphate to the enamel surface.The lesion can be stopped but a complete remineralization is an exception. A demineralized subsurface under a mineralized surface remains.In the cement which is less mineralized than the enamel, the evolution of the decay is faster. FLUORIDE AND DECAY PREVENTION
The enamel surface can also be enriched with fluoridated calcium phosphate which is more resistant to acids. Fluorine has a significant function in the prevention of tooth decay. It also helps to increase mineral density of the tooth during all its construction. There are two ways to administer fluoride:
-Taking fluoride tablets
-Topical application on dental surfaces with fluoride gel in a mould (mouth tray) or with tooth pastes.
Fluoride in oral taking
Fluoride taken in tabletform will integrate into apatite crystals during amelogenesis in order to increase their density and thus to produce a better protection against tooth decay. However, this prevention is more theorical than real. If oral hygiene is defective and the patient’s diet rich in refined sugar, nothing will stop the development of dental plaque and decay will progress. The purpose of systemic fluoration is to obtain development of fluoroapatites and fluorohydroxyapatites.Let’s keep in mind that fluoride is naturally part of food :it can be found in spring waters, green tea, salmon, spinach and lettuce.For spring waters, the concentrations vary according to the springs.Eventually, fluoride can be added to food (salt). So, before any prescription, it is necessary to assess the daily fluoride ingestion, to avoid fluorosis. Recommended prescriptions in the absence of fluoride contained in food:
– 6 -> 24 months_: ▪Without fluoridated salt : 0,05 mg/kg/day.
– ▪With fluoridated salt: 0,025 mg/kg/day_
– 2 -> 4 years_: 0,05 mg/kg/day__
– 4 -> 8 years_: 0,05 to 0,075 mg/kg/day.
Overdose leads to fluorosis whose degree depends on the level of the poisoning. The first sign is a white spot on the enamel. A chalky slit enamel is the effect of the process growth. At a further stage, the enamel has disappeared and the coronary morphology is atypical. Finally, poisoning can have serious consequences. The lethal dose is 15 mg/kg for children and 32 to 64 mg/kg for adults.European authorities do not recommend fluoride systemic between 0 and 6 months.For spring waters, recommended concentrations are between 0.7 mg/L and 1.3 mg/L. Fluoride in topical application.Fluoride systemically incorporated is not sufficient to protect surfaces efficiently during the demineralization stages.Fluoride in the interface enamel-oral environment is more efficient in the remineralization process.Fluoride in topical application has a triple effect:
– Inhibition of enamel demineralization by acids.
– Disturbance of tooth decay bacterial growth and metabolism.
– Activation of the fluoride crystals precipitation on the enamel surfaces.
We commonly use preparations including sodium fluoride and calcium fluoride.The application is carried out after descaling and drying out the surfaces which need to be protected.The product is applied in a thin layer with a brush or a cotton bud (cotton wad).The prophylaxy is carried out every 6 months.It is accepted that the decrease of the tooth decay index in industrialized countries is the outcome of topical fluoride common use.With this type of fluorine supply, overdosing is avoided in decay prophylaxy.Topical application after orofacial radiotherapy.A topical fluorine daily use is recommended for patients undergoing head and neck radiotherapy.This application which lasts five minutes, aims at thwarting the unwanted effects of irradiations on salivary glands. It must be prescribed for life. It insures an efficient protection against hyposaliva and acidity. This application must necessarily be carried out with a soft plaster mouth tray. The molecule which is used, is a blend of sodium fluoride and ammonium bifluoride. The mouth tray and the oral cavity will be carefully washed 30mn after the end of the application.For children, this prescription will be adapted with a tooth paste whose fluoride concentration is higher than the recommended standard. If the child is between 6 and 10 years old, the application will be substituted by a daily fluoride mouth rinse.
Fluoride and tooth pastes
There are 2 types of fluoride molecules incorporated in tooth paste.
Inorganic molecules: – sodium fluoride (NaF)
– tin fluoride (SnF2)
– sodium mono fluoro phosphate (Na2FPO3)
Organic molecules: – Aminfluoride (AmF297)
– Nicomethanolfluorhydrate
A new evidence based study has concluded that the clinical efficiency of sodium fluoride is undisputable.
Tooth paste dosage
Tooth pastes have no toxicity risks but allergies are possible. Until the age of 10, children swallow 44 percent of tooth paste. This explains the different dosages in fluoride.
Tooth pastes which benefit from a sale authorization, offer 3 dosages:
– 2 for children: 250 or 600 ppm
– 1 for adults: 2500 ppm
Tooth pastes without sale authorization do not exceed 1500 ppm.
European Directives advise the following dosages for a fluoride tooth paste:
– 2 to 6 years old: 450 ppm
– after 6: 1250 ppm.
It has not been proved that prophylactic efficiency is proportional to fluoride concentration.
Comparative studies between the use of pastes with doses up to 1000-, 1500- and 2500 ppm have not enabled it to be determined which concentration offers the best protection against tooth decay.
European Directives recommend tooth brushing with an up to 500 ppm fluoride paste as soon as the first temporary molars have emerged, and to reserve fluoride systemic use to patients with a high risk of tooth decay after a fluoride assessment.
The Role of Fluoride
Tooth enamel begins to demineralize in the presence of bacteria-produced acid once the oral cavity’s pH level drops below 5.5 and demineralization eliminates the calcium and phosphate ions that compose enamel’s hydroxyapatite. In the remineralization process, calcium and phosphate ions are redeposited into the tooth mineral. Fluoride contributes to the remineralization process in several ways. It accumulates on the surface of the enamel crystal, which cre-ates a physical barrier that makes the tooth more acid resistant. The negatively charged fluoride ion attracts the positively charged cal- cium during this repair process, ultimately changing carbonated apatite to a fluorapatite- like form that is larger and stronger than the original hydroxyapatite.2 Fluoride may also provide antimicrobial effects through the inhi- bition of bacterial intracellular enzymes. Although fluoride serves as a catalyst for rem- ineralization, remineralization will not occur unless adequate amounts of calcium and phosphate ions are available.
For patients at risk of dental caries, the availability of calcium and phosphate ions is important. Calcium and phosphate from outside sources may be able to alter the cariogenic potential of dental plaque biofilm. Calcium phosphate products claim to enhance the bioavailability of calcium and phosphate ions. In theory, this aids in the enhancement of remineralization. Four types of calcium phosphate-based technologies are currently available in the United States: amorphous calcium phosphate (ACP), casein phosphopeptide amorphous calcium phosphate (CPP-ACP or Recaldent®), calcium sodium phosphosilicate (CSP or NovaMin®), and tri-calcium phosphate (TCP). Table 1 provides a list of products that contain these technologies. The use of calcium phosphate products in caries management is considered an “off-label” use because some of these products are accepted by the Food and Drug Administration (FDA) as tooth polishing or desensitizing ingredients only, rather than agents of remineralization.
Amorphous Calcium Phosphate
ACP technology was developed in 1991 by the American Dental Association’s (ADA) Paffenbarger Research Center. ACP contains the same minerals found in hydroxyapatite and aims, in the presence of fluoride, to speed up remineralization. ACP technology is considered unstablized because a calcium salt and a phosphate salt are delivered separately (eg, through a dual-barrel syringe). This delivery system allows for the precipitation of ACP at the tooth surface. Because it is not a premixed calcium phosphate compound, when ACP is introduced onto a tooth surface, a reservoir of calcium and phosphate ions forms. Rapid deposition of new mineral then may fill surface defects on the original tooth surface.
ACP is available in a variety of products, including dentifrices, prophy pastes, fluoride varnish, fluoride gels, pit and fissure sealant materials, desensitizing agents, cements, and tooth whitening agents. In a dentifrice, ACP, with fluoride, enhances remineralization and forms a strong bond to the dentin, becoming an intrinsic part of the tooth. Sealants containing ACP promote in situ remineralization of artificially-induced carious lesions on smooth enamel surfaces, although not significantly more than sealants containing fluoride. Prophy paste with added calcium, phosphate, and fluoride has the potential to form ACP on the tooth surface. ACP-containing orthodontic com- posite resins may reduce enamel decalcification in patients with poor oral hygiene without dam- aging the cement’s shear bond strength. The addition of ACP in carbamide peroxide whitening agents may reduce transient tooth sensitivity caused by the whitening process.
Most studies in support of ACP are animal model, in vitro, or in situ caries model studies. Although the use of ACP to assist in the remineralization process shows promise, more clinical trial research is needed. One clinical trial demonstrated a significant decrease in root caries among 44 high-risk head and neck radiation patients with the use of a dual phase ACP dentifrice containing 1,100 ppm sodium fluoride in comparison to a toothpaste containing 1,100 ppm sodium fluoride only.
Casein Phosphopeptide Amorphous Calcium Phosphate or Recaldent
Casein (milk protein) was first investigated as a way to reduce caries as early as 1946. The University of Melbourne, Australia, and the Victorian Dairy Industry Authority, Abbotsford, Australia, are credited with the patent for the CPP-ACP complex and its trademark Recaldent. The FDA designated Recaldent as a “generally recognized as safe” (GRAS) ingredient to add to food products in 1999.
CPP-ACP is referred to as stabilized ACP and is a complex of casein phosphopeptides that stabilize an amorphous form of calcium phosphate to maintain the calcium and phosphate ions, ensuring their delivery into the tooth structure before they precipitate or crystallize. CPP-ACP readily binds to the surface of the tooth as well as to the bacterial plaque surrounding the tooth. The CPP-ACP complex also acts as a reservoir of bioavailable calcium and phosphate. Under acidic conditions, CPP-ACP releases calcium and phosphate to enhance remineraliza- tion. Recently, CPP-ACP added to milk and hard candy (not available in United States) significantly remineralized enamel subsur- face carious lesions in situ.
Products containing CPP-ACP that are currently on the market in the United States include one professionally-dispensed cream available with and without added fluoride and one chewing gum. The use of a CPPACP cream has demonstrated significant regression of white-spot lesions in postorthodontic populations. A recent in situ study using CPP-ACP combined with 900 ppm fluoride found that the combination offered a higher remineralization potential than CPP-ACP alone.23 Gum with added CPP-ACP demonstrated higher amounts of remineralization of enamel subsurface lesions in situ than sugar-free gum alone. A true milk allergy (casein) is a contraindica- tion to using a product containing CPP-ACP.
As with ACP, the majority of investigations of CPP-ACP are animal model, in vitro, and in situ caries model studies. Although lower level evidence, published case reports are growing. A recent 2-year clinical trial conducted on 2,000 children demonstrated that CPP-ACP in a sugar-free chewing gum slowed progression and enhanced regression of approximal caries compared to a sugar-free control gum. To achieve this benefit, participants in the study chewed the gum for 10 minutes, three times a day. More clinical trial research is needed to quantify that CPP-ACP can prevent or reverse carious lesions or the dental caries process.
Calcium Sodium Phosphosilicate or Novamin
CSP belongs to a class of compounds called bioactive glass that have been available since the late 1960s to help regenerate bone. CSP reacts in an aqueous environment, so when exposed to saliva, ions of calcium, phosphate, and sodium are released. The sodium helps buffer the acid and then with time, the calcium and phosphate ions are available to assist in remineralization. Originally developed for the treatment of dentinal hypersensitivity, a series of in vitro and in situ studies suggest that CSP has the ability to prevent dentin demineralization, remineralize root carious lesions, heal white spot lesions, and fill demineralized lesions.
Most products available with CSP claim a reduction in tooth sensitivity and include toothpastes, desensitizing toothpastes, one prophy paste, and one air polishing powder. Added to a commercially available dentifrice containing strontium chloride (SrCl2), the CSP-containing paste was superior in reducing pain from air and cold water stimulus compared with the SrCl2 and placebo group. This reduction in pain was confirmed in a recent 6-week clinical trial where a 5% CSP paste reduced the visual analog scale score more than a toothpaste containing 5% potassium nitrate or a placebo.
The use of CSP in an air polishing powder demonstrated a significant reduction in cold pain stimulus compared with sodium bicarbonate air polishing powder at a 10-day recall. An in vitro study suggested teeth polished with a prophy paste and an air polishing powder both containing CSP were effective in reducing the dentin permeability of acid-treated dentin, with the air polishing powder being the most effective. High fluoride toothpaste (2,800 ppm and 5,000 ppm) promoted remineralization and inhibited demineralization more effectively than a CSP toothpaste. No published data are available yet about the combination of high fluoride toothpaste (5,000 ppm) and CSP.
Much of the research conducted about CSP has looked at its role as a desensitizing agent rather than its ability to enhance remineralization and prevent demineralization. At this time, there are no published animal model or clinical studies supporting its anticariogenic effects. One published report details a series of in vitro studies and one in situ caries model study.
Tri-Calcium Phosphate
TCP is a new hybrid material created with a milling technique that fuses beta tricalcium phosphate (ß-TCP) and sodium lauryl sulfate or fumaric acid. This blending results in a “functionalized” calcium and a “free” phosphate, designed to increase the efficacy of fluoride remineralization. ß-TCP, which is commonly used in FDA-approved orthopedic applications to boost bone growth, is similar to apatite structure and possesses unique calcium environments capable of reacting with fluoride and enamel. While the phosphate floats free, these exposed calcium environments are protected, preventing the calcium from prematurely interacting with fluoride. TCP provides catalytic amounts of calcium to boost fluoride efficacy and may be welldesigned to coexist with fluoride in a mouthrinse or dentifrice because it will not react before reaching the tooth surface.36 When TCP finally comes into contact with the tooth surface and is moistened by saliva, the protective barrier breaks down, making the calcium, phosphate, and fluoride ions available to the teeth. The fluoride and calcium then react with weakened enamel to provide a seed for enhanced mineral growth relative to fluoride alone.
Products available with TCP include a 5,000 ppm sodium fluoride dentifrice and a 5% sodium fluoride varnish. One study that investigated the toothpaste found that it delivered more high-quality mineral above the surface and deep in the carious lesions, and provided superior surface and subsurface remineralization compared to a 5,000 ppm fluoride product alone. Another study found that the TCP toothpaste showed better subsurface remineralization when compared to a CPP-ACP-containing product. There are no published studies yet about TCP added to fluoride varnish.
Conclusion
Dental caries remains a complex, multifactorial, and infectious bacterial biofilm disease that involves two continuous processes—demineralization and remineralization of the tooth surface. The goal of remineralization therapy should be to strengthen teeth. Along with an under- standing of the patient’s caries risk and an adequate anti-plaque self-care program, successful management of the dental caries infection over a lifetime can be accomplished using evidence-based, clinically effective methods and products. Calcium phosphate products may offer patients added protection against the progression or repair of carious lesions, but more in vivo clinical trials are needed to determine their short-term and long-term effects and to establish their clinical relevance.
Despite their growing popularity, calcium phosphate products are not for every patient and should not be used as a substitute for fluoride. For patients with normal salivary flow and composition, sufficient calcium and phosphate ions are already present to assist the body in the remineralization process, thus making the need for additional calcium and phosphate unnecessary. In this case, the use of low level fluoride should be recommended. In patients with salivary hypofunction including low flow, low pH, and poor buffering capacity, the use of agents containing bioavailable calcium and phosphate may be beneficial.
Antimicrobial drugs are used to prevent or treat infections caused by pathogenic (disease-producing) microorganisms. The human body and the environment contain many microorganisms, most of which live in a state of balance with the human host and do not cause disease. When the balance is upset and infection occurs, characteristics of the infecting microorganism(s) and the adequacy of host defense mechanisms are major factors in the severity of the infection and the person’s ability to recover. Conditions that impair defense mechanisms increase the incidence and severity of infections and impede recovery. In addition, use of antimicrobial drugs may lead to serious infections caused by drug-resistant microorganisms.
To help prevent infectious diseases and participate effectively in antimicrobial drug therapy, the nurse must be knowledgeable about microorganisms, host responses to microorganisms, and antimicrobial drugs.
Terms and Concepts
Several terms are used to describe these drugs. Anti-infective and antimicrobial include antibacterial, antiviral, and antifungal drugs; antibacterial and antibiotic usually refer only to drugs used in bacterial infections. Most of the drugs in this section are antibacterials. Antiviral and antifungal drugs are discussed in Chapters 39 and 40, respectively. Additional terms for antibacterial drugs include broad spectrum, for those effective against several groups of microorganisms, and narrow spectrum, for those effective against a few groups. The action of an antibacterial drug is usually described as bactericidal (kills the microorganism) or bacteriostatic (inhibits growth of the microorganism). Whether a drug is bactericidal or bacteriostatic often depends on its concentration at the infection site and the susceptibility of the microorganism to the drug. Successful treatment with bacteriostatic antibiotics depends on the ability of the host’s immune system to eliminate the inhibited bacteria and an adequate duration of drug therapy. Stopping an antibiotic prematurely can result in rapid resumption of bacterial growth. Bactericidal drugs are preferred in serious infections, especially in people with impaired immune function.
Actions of antibacterial drugs on bacterial cells
Mechanisms of Action
Most antibiotics act on a specific target in the bacterial cell. Almost any structure unique to bacteria, such as proteins or nucleic acids, can be a target for antibiotics. Specific mechanisms include the following:
1. Inhibition of bacterial cell wall synthesis or activation of enzymes that disrupt bacterial cell walls (eg, penicillins, cephalosporins, vancomycin)
2. Inhibition of protein synthesis by bacteria or production of abnormal bacterial proteins (eg, aminoglycosides, clindamycin, erythromycin, tetracyclines). These drugs bind irreversibly to bacterial ribosomes, intracellular structures that synthesize proteins. When antimicrobial drugs are bound to the ribosomes, bacteria cannot synthesize the proteins necessary for cell walls and other structures.
3. Disruption of microbial cell membranes (eg, antifungals)
4. Inhibition of organism reproduction by interfering with nucleic acid synthesis (eg, fluoroquinolones, rifampin, anti–acquired immunodeficiency syndrome antivirals)
5. Inhibition of cell metabolism and growth (eg, sulfonamides, trimethoprim)
INDICATIONS FOR USE
Antimicrobial drugs are used to treat and prevent infections. Because laboratory tests (except Gram’s stain and a rapid test for group A streptococci) to identify causative organisms usually take 24 hours or longer, empiric therapy against the most likely pathogens is often begun. Once organisms are identified, more specific therapy is instituted. Prophylactic therapy is recommended to prevent:
1. Group A streptococcal infections and possibly rheumatic fever, rheumatic heart disease, and glomerulonephritis. Penicillin is commonly used.
2. Bacterial endocarditis in clients with cardiac valvular disease who are having dental, surgical, or other invasive procedures
3. Tuberculosis. Isoniazid is used.
4. Perioperative infections in high-risk clients (eg, those whose resistance to infection is lowered because of age, poor nutrition, disease, or drugs) and for high-risk surgical procedures (eg, cardiac or GI surgery, certain orthopedic procedures, organ transplants)
5. Sexually transmitted diseases (eg, gonorrhea, syphilis, chlamydial infections) after exposure has occurred
6. Recurrent urinary tract infections in premenopausal, sexually active women. A single dose of trimethoprimsulfamethoxazole, cinoxacin, or cephalexin, taken after
sexual intercourse, is often effective.
Rational Use of Antimicrobial Drugs
Antimicrobials are among the most frequently used drugs worldwide. Their success in saving lives and decreasing severity and duration of infectious diseases has encouraged their extensive use. Authorities believe that much antibiotic use involves overuse, misuse, or abuse of the drugs. That is, an antibiotic is not indicated at all or the wrong drug, dose, route, or duration is prescribed. Inappropriate use of antibiotics increases adverse drug effects, infections with drugresistant microorganisms, and health care costs. In addition, it decreases the number of effective drugs for serious or
antibiotic-resistant infections. Guidelines to promote more appropriate use of the drugs include:
1. Avoid the use of broad-spectrum antibacterial drugs to treat trivial or viral infections; use narrow-spectrum agents when likely to be effective.
2. Give antibacterial drugs only when a significant bacterial infection is diagnosed or strongly suspected or when there is an established indication for prophylaxis. These drugs are ineffective and should not be used to treat viral infections.
3. Minimize antimicrobial drug therapy for fever unless other clinical manifestations or laboratory data indicate infection.
4. Use the drugs along with other interventions to decrease microbial proliferation, such as universal precautions, medical isolation techniques, frequent and thorough handwashing, and preoperative skin and bowel cleansing.
5. Follow recommendations of the Centers for Disease Control and Prevention for prevention and treatment of infections, especially those caused by drug-resistant organisms (eg, gonorrhea, penicillin-resistant streptococcal infections, methicillin-resistant staphylococcal infections, vancomycin-resistant enterococcal infections, and MDR-TB).
6. Consult infectious disease physicians, infection control nurses, and infectious disease pharmacists about local patterns of drug-resistant organisms and treatment of complicated infections.
Drug Selection
Once an infection requiring treatment is diagnosed, numerous factors influence the choice of an antimicrobial drug or combination of drugs.
Initial, empiric therapy. Because most laboratory tests to definitively identify causative organisms and to determine susceptibility to antibiotics require 48 to 72 hours, the physician usually prescribes for immediate administration a drug that is likely to be effective. This empiric therapy is based on an informed estimate of the most likely pathogen, given the client’s signs and symptoms and apparent site of infection. A single broad-spectrum antibiotic or a combination of drugs is often chosen.
Culture and susceptibility studies allow the therapist to “match the drug to the bug.” Culture identifies the causative organism; susceptibility tests determine which drugs are likely to be effective against the organism. Culture and susceptibility studies are especially important with suspected gram-negative infections because of the high incidence of drugresistant microorganisms. However, drug-resistant gram-positive organisms are being identified with increasing frequency.
When a specific organism is identified by a laboratory culture, tests can be performed to measure the organism’s susceptibility to particular antibiotics. Laboratory reports indicate whether the organism is susceptible (S) or resistant (R) to the tested drugs. One indication of susceptibility is the minimum inhibitory concentration (MIC). The MIC is the lowest concentration of an antibiotic that prevents visible growth of microorganisms. Some laboratories report MIC instead of, or in addition to, susceptible (S) or resistant (R). Susceptible organisms have low or moderate MICs that can be attained by giving usual doses of an antimicrobial agent. For the drug to be effective, serum and tissue concentrations should usually exceed the MIC of an organism for a period of time. How much and how long drug concentrations need to exceed the MIC depend on the drug class and the bacterial species. With betalactam agents (eg, penicillins, cephalosporins), the drug concentration usually needs to be maintained above the MIC of the infecting organism for a majority of the dosing interval. With the aminoglycosides (eg, gentamicin, others), the drug concentration does not need to be maintained above the MIC for the entire dosing interval.
Aminoglycosides have a postantibiotic effect, defined as a persistent effect of an antimicrobial on bacterial growth after brief exposure of the organisms to a drug. Some studies demonstrate that large doses of aminoglycosides, given once daily, are as effective as more frequent dosing and may cause less nephrotoxicity. Resistant organisms have high MICs and may require higher concentrations of drug than can be achieved in the body, even with large doses. In some cases the minimum bactericidal concentration (MBC) is reported, indicating no growth of the organism in the presence of a particular antibiotic. The MBC is especially desirable for infected hosts with impaired immune functions.
Clients’ responses to antimicrobial therapy cannot always be correlated with the MIC of an infecting pathogen. Thus, reports of drug susceptibility testing must be applied in the context of the site of infection, the characteristics of the drug, and the clinical status of the client.
Knowledge of antibiotic resistance patterns in the community and agency. Because these patterns change, continuing efforts must be made. Pseudomonas aeruginosa is resistant to many antibiotics. Those strains resistant to gentamicin may be susceptible to amikacin, ceftazidime, imipenem, or aztreonam. Some gramnegative organisms have become increasingly resistant to aminoglycosides, third-generation cephalosporins, and aztreonam, but may be susceptible to imipenem.
Knowledge of the organisms most likely to infect particular body tissues. For example, urinary tract infections are often caused by E. coli, and a drug effective against this organism is indicated.
A drug’s ability to penetrate infected tissues. Several antimicrobials are effective in urinary tract infections because they are excreted in the urine. However, the choice of an effective antimicrobial drug may be limited in infections of the brain, eyes, gallbladder, or prostate gland because many drugs are unable to reach therapeutic concentrations in these tissues.
A drug’s toxicity and the risk-to-benefit ratio. In general, the least toxic drug should always be used. However, for serious infections, more toxic drugs may be necessary.
Drug costs. If an older, less expensive drug meets the criteria for rational drug selection and is likely to be effective in a given infection, it should be used as opposed to a more expensive agent. For hospitals and nursing homes, personnel costs in relation to preparation and administration should be considered as well as purchasing costs.
Antibiotic Combination Therapy
Antimicrobial drugs are often used in combination. Indications for combination therapy may include:
• Infections caused by multiple microorganisms (eg, abdominal and pelvic infections)
• Nosocomial infections, which may be caused by many different organisms
• Serious infections in which a combination is synergistic (eg, an aminoglycoside and an antipseudomonal penicillin for pseudomonal infections)
• Likely emergence of drug-resistant organisms if a single drug is used (eg, tuberculosis). Although drug combinations to prevent resistance are widely used, the only clearly effective use is for treatment of tuberculosis.
• Fever or other signs of infection in clients whose immune systems are suppressed. Combinations of antibacterial plus antiviral and/or antifungal drugs may be needed.
Dosage
Dosage (amount and frequency of administration) should be individualized according to characteristics of the causative organism, the chosen drug, and the client’s size and condition (eg, type and severity of infection, ability to use and excrete the chosen drug). For example, dosage may need to be increased for more resistant organisms such as Pseudomonas and for infections in which antibiotics have difficulty penetrating to the site of infection (eg, meningitis). Dosage often must be reduced if the client has renal impairment or other disorders that delay drug elimination.
Route of Administration
Most antimicrobial drugs are given orally or IV for systemic infections. The route of administration depends on the client’s condition (eg, location and severity of the infection, ability to take oral drugs) and the available drug dosage forms. In serious infections, the IV route is preferred for most drugs.
Duration of Therapy
Duration of therapy varies from a single dose to years, depending on the reason for use. For most acute infections, the average duration is approximately 7 to 10 days or until the recipient has been afebrile and asymptomatic for 48 to 72 hours.
Beta-Lactam Antibacterials
Beta-lactam antibacterials derive their name from the betalactam ring that is part of their chemical structure. An intact beta-lactam ring is essential for antibacterial activity. Several gram-positive and gram-negative bacteria produce betalactamase enzymes that disrupt the beta-lactam ring and inactivate the drugs. This is a major mechanism by which microorganisms acquire resistance to beta-lactam antibiotics.
Penicillinase and cephalosporinase are beta-lactamase enzymes that act on penicillins and cephalosporins, respectively. Despite the common element of a beta-lactam ring, characteristics of beta-lactam antibiotics differ widely because of variations in their chemical structures. The drugs may differ in antimicrobial spectrum of activity, routes of administration, susceptibility to beta-lactamase enzymes, and adverse effects. Beta-lactam antibiotics include penicillins, cephalosporins, carbapenems, and monobactams.
Beta-lactam antibacterial drugs inhibit synthesis of bacterial cell walls by binding to proteins (penicillin-binding proteins) in bacterial cell membranes. This binding produces a defective cell wall that allows intracellular contents to leak out, destroying the microorganism. In sub-bactericidal concentrations, the drugs may inhibit growth, decrease viability, and alter the shape and structure of organisms. The latter characteristic may help to explain the development of mutant strains of microorganisms exposed to the drugs. Betalactam antibiotics are most effective when bacterial cells are dividing.
The penicillins are effective, safe, and widely used antimicrobial agents. The group includes natural extracts from the Penicillium mold and several semisynthetic derivatives.
When penicillin G, the prototype, was introduced, it was effective against streptococci, staphylococci, gonococci, meningococci, Treponema pallidum, and other organisms. It had to be given parenterally because it was destroyed by gastric acid, and injections were painful. With extensive use, strains of drug-resistant staphylococci appeared. Later penicillins were developed to increase gastric acid stability, betalactamase stability, and antimicrobial spectrum of activity, especially against gram-negative microorganisms. Semisynthetic derivatives are formed by adding side chains to the penicillin nucleus.
After absorption, penicillins are widely distributed and achieve therapeutic concentrations in most body fluids, including joint, pleural, and pericardial fluids and bile. Therapeutic levels are not usually obtained in intraocular and cerebrospinal fluids (CSF) unless inflammation is present because normal cell membranes act as barriers to drug penetration.
Penicillins are rapidly excreted by the kidneys and produce high drug concentrations in the urine (an exception is nafcillin, which is excreted by the liver). The most serious, and potentially fatal, adverse effect of the penicillins is hypersensitivity. Seizures, interstitial nephritis, and nephropathy may also occur.
Indications for Use
Clinical indications for use of penicillins include bacterial infections caused by susceptible microorganisms. As a class, penicillins usually are more effective in infections caused by gram-positive bacteria than those caused by gram-negative bacteria. However, their clinical uses vary significantly according to the subgroup or individual drug and microbial patterns of resistance. The drugs are often useful in skin/ soft tissue, respiratory, gastrointestinal, and genitourinary infections. However, the incidence of resistance among streptococci, staphylococci, and other microorganisms continues to grow.
Contraindications to Use
Contraindications include hypersensitivity or allergic reactions to any penicillin preparation. An allergic reaction to one penicillin means the client is allergic to all members of the penicillin class. The potential for cross-allergenicity with cephalosporins and carbapenems exists, so other alternatives should be selected in pencillin-allergic clients when possible.
Penicillinase-Resistant (Antistaphylococcal)Penicillins
This group includes four drugs (cloxacillin, dicloxacillin, nafcillin, and oxacillin) that are effective in some infections caused by staphylococci resistant to penicillin G. An older member of this group, methicillin, is no longer marketed for clinical use. However, susceptibility of bacteria to the antistaphylococcal penicillins is determined by exposing the bacteria to methicillin (methicillin-susceptible or -resistant) or oxacillin (oxacillinsusceptible or -resistant) in bacteriology laboratories. These drugs are formulated to resist the penicillinases that inactivate other penicillins. They are recommended for use in known or suspected staphylococcal infections, except for methicillin-resistant Staphylococcus aureus (MRSA) infections. Although called “methicillin-resistant,” these staphylococcal microorganisms are also resistant to other antistaphylococcal penicillins.
Aminopenicillins
Ampicillin is a broad-spectrum, semisynthetic penicillin that is bactericidal for several types of gram-positive and gramnegative bacteria. It has been effective against enterococci, Proteus mirabilis, Salmonella, Shigella, and Escherichia coli, but resistant forms of these organisms are increasing. It is ineffective against penicillinase-producing staphylococci and gonococci. Ampicillin is excreted mainly by the kidneys; thus, it is useful in urinary tract infections (UTI). Because some is excreted in bile, it is useful in biliary tract infections not caused by biliary obstruction. It is used in the treatment of bronchitis, sinusitis, and otitis media.
Extended-Spectrum (Antipseudomonal) Penicillins
The drugs in this group (carbenicillin, ticarcillin, mezlocillin, and piperacillin) have a broad spectrum of antimicrobial activity, especially against gram-negative organisms such as Pseudomonas and Proteus species and E. coli. For pseudomonal infections, one of these drugs is usually given concomitantly with an aminoglycoside or a fluoroquinolone. Carbenicillin is available as an oral formulation for UTI or prostatitis caused by susceptible pathogens. The other drugs are usually given by intermittent IV infusion, although most can be given IM.
Cephalosporins are a widely used group of drugs that are derived from a fungus. Although technically cefoxitin and cefotetan (cephamycins derived from a different fungus) and loracarbef (a carbacephem) are not cephalosporins, they are categorized with the cephalosporins because of their similarities to the group. Cephalosporins are broad-spectrum agents with activity against both gram-positive and gram-negative bacteria. Compared with penicillins, they are in general less active against gram-positive organisms but more active against gram-negative ones. Once absorbed, cephalosporins are widely distributed into most body fluids and tissues, with maximum concentrations in the liver and kidneys. Many cephalosporins do not reach therapeutic levels in CSF; exceptions are cefuroxime, a secondgeneration drug, and the third-generation agents. These drugs reach therapeutic levels when meninges are inflamed. Most cephalosporins are excreted through the kidneys. Exceptions include cefoperazone, which is excreted in bile, and ceftriaxone, which undergoes dual elimination via the biliary tract and kidneys. Cefotaxime is primarily metabolized in the liver to an active metabolite, desacetylcefotaxime, which is eliminated by the kidneys.
Clinical indications for the use of cephalosporins include surgical prophylaxis and treatment of infections of the respiratory tract, skin and soft tissues, bones and joints, urinary tract, brain and spinal cord, and bloodstream (septicemia). In most infections with streptococci and staphylococci, penicillins are more effective and less expensive. In infections caused by methicillin-resistant S. aureus, cephalosporins are not clinically effective even if in vitro testing indicates susceptibility. Infections caused by Neiserria gonorrhoeae, once susceptible to penicillin, are now preferentially treated with a third-generation cephalosporin such as ceftriaxone.
Cefepime is indicated for use in severe infections of the lower respiratory and urinary tracts, skin and soft tissue, female reproductive tract, and infebrile neutropenic clients. It may be used as monotherapy for all infections caused by susceptible organisms except P. aeruginosa; a combination of drugs should be used for serious pseudomonal infections.
A major contraindication to the use of a cephalosporin is a previous severe anaphylactic reaction to a penicillin. Because cephalosporins are chemically similar to penicillins, there is a risk of cross-sensitivity. However, incidence of cross-sensitivity is low, especially in clients who have had delayed reactions (eg, skin rash) to penicillins. Another contraindication is cephalosporin allergy. Immediate allergic reactions with anaphylaxis, bronchospasm, and urticaria occur less often than delayed reactions with skin rash, drug fever, and eosinophilia.
Carbapenems are broad-spectrum, bactericidal, beta-lactam antimicrobials. Like other beta-lactam drugs, they inhibit synthesis of bacterial cell walls by binding with penicillinbinding proteins. The group consists of three drugs.
Imipenem/cilastatin (Primaxin) is given parenterally and distributed in most body fluids. Imipenem is rapidly broken down by an enzyme (dehydropeptidase) in renal tubules and therefore reaches only low concentrations in urine. Cilastatin was synthesized to inhibit the enzyme and reduce potential renal toxicity of the antibacterial agent. Recommended doses indicate the amount of imipenem; the solution contains an equivalent amount of cilastatin.
The drug is effective in infections caused by a wide range of bacteria, including penicillinase-producing staphylococci, E. coli, Proteus species, Enterobacter–Klebsiella–Serratia species, P. aeruginosa, and Enterococcus faecalis. Its main indication for use is treatment of infections caused by organisms resistant to other drugs. Adverse effects are similar to those of other beta-lactam antibiotics, including the risk of crosssensitivity in clients with penicillin hypersensitivity. Central nervous system toxicity, including seizures, has been reported. Seizures are more likely in clients with a seizure disorder or when recommended doses are exceeded; however, they have occurred in other clients as well. To prepare the solution for IM injection, lidocaine, a local anesthetic, is added to decrease pain. This solution is contraindicated in people allergic to this type of local anesthetic or who have severe shock or heart block.
Meropenem (Merrem) has a broad spectrum of antibacterial activity and may be used as a single drug for empiric therapy before causative microorganisms are identified. It is effective against penicillin-susceptible staphylococci and S. pneumoniae, most gram-negative aerobes (eg, E. coli, H. influenzae, Klebsiella pneumoniae, P. aeruginosa), and some anaerobes, including B. fragilis. It is indicated for use in intra-abdominal infections and bacterial meningitis caused by susceptible organisms. Compared with imipenem, meropenem costs more and seems to offer no clinical advantages. Adverse effects are similar to those of imipenem.
Ertapenem (Invanz) also has a broad spectrum of antibacterial activity, although more limited than imipenem and meropenem. It is approved for complicated intra-abdominal, skin and skin structure, acute pelvic, and urinary tract infections. It can be used to treat community-acquired pneumonia caused by penicillin-susceptible S. pneumoniae. Unlike imipenem and meropenem, ertapenem does not have in vitro activity against Pseudomonas aeruginosa and Acinetobacter baumannii.
Ertapenem shares the adverse effect profile of the other carbapenems. Lidocaine is also used in preparation of the solution for IM injection, and the same cautions should be used as with imipenem.
Aztreonam (Azactam) is active against gram-negative bacteria, including Enterobacteriaceae and P. aeruginosa, and many strains that are resistant to multiple antibiotics. Activity against gram-negative bacteria is similar to that of the aminoglycosides, but the drug does not cause kidney damage or hearing loss. Aztreonam is stable in the presence of beta-lactamase enzymes. Because gram-positive and anaerobic bacteria are resistant to aztreonam, the drug’s ability to preserve normal gram-positive and anaerobic flora may be an advantage over
most other antimicrobial agents.
Indications for use include infections of the urinary tract, lower respiratory tract, skin and skin structures, as well as intra-abdominal and gynecologic infections and septicemia. Adverse effects are similar to those for penicillin, including possible hypersensitivity reactions.
Drug Selection
Choice of a beta-lactam antibacterial depends on the organism causing the infection, severity of the infection, and other factors. With penicillins, penicillin G or amoxicillin is the drug of choice in many infections; an antipseudomonal penicillin is indicated in most Pseudomonas infections; and an antistaphylococcal penicillin is indicated in staphylococcal infections. Antistaphylococcal drugs of choice are nafcillin for IV use and dicloxacillin for oral use.
With cephalosporins, first-generation drugs are often used for surgical prophylaxis, especially with prosthetic implants, because gram-positive organisms such as staphylococci cause most post-implant infections. They may also be used alone for treatment of infections caused by susceptible organisms in body sites where drug penetration and host defenses are adequate.
Cefazolin (Kefzol) is a frequently used parenteral agent. It reaches a higher serum concentration, is more protein bound, and has a slower rate of elimination than other firstgeneration drugs. These factors prolong serum half-life, so cefazolin can be given less frequently. Cefazolin may also be administered IM.
Second-generation cephalosporins are also often used for surgical prophylaxis, especially for gynecologic and colorectal surgery. They are also used for treatment of intraabdominal infections such as pelvic inflammatory disease, diverticulitis, penetrating wounds of the abdomen, and other infections caused by organisms inhabiting pelvic and colorectal areas.
Third-generation cephalosporins are recommended for serious infections caused by susceptible organisms that are resistant to first- and second-generation cephalosporins. They are often used in the treatment of infections caused by E. coli, Proteus, Klebsiella, and Serratia species, and other Enterobacteriaceae, especially when the infections occur in body sites not readily reached by other drugs (eg, CSF, bone) and in clients with immunosuppression. Although effective against many Pseudomonas strains, these drugs should not be used alone in treating pseudomonal infections because drug resistance develops.
Fourth-generation drugs are most useful in serious gramnegative infections, especially infections caused by organisms resistant to third-generation drugs. Cefepime has the same indications for use as ceftazidime, a third-generation drug.
Chloramphenicol is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome and inhibits the peptidyl transferase step of protein synthesis. Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms. It is active also against rickettsiae but not chlamydiae. Most gram-positive bacteria are inhibited at concentrations of 1-10 mcg/mL, and many gram-negative bacteria are inhibited by concentrations of 0.2-5 mcg/mL. H influenzae, N meningitidis, and some strains of bacteroides are highly susceptible, and for them chloramphenicol may be bactericidal.
KERATOLYTIC DESTRUCTIVE AGENTS
SALICYLIC ACID
Salicylic acid has been extensively used in dermatologic therapy as a keratolytic agent. The mechanism by which it produces its keratolytic and other therapeutic effects is poorly understood. The drug may solubilize cell surface proteins that keep the stratum corneum intact, thereby resulting in desquamation of keratotic debris. Salicylic acid is keratolytic in concentrations of 3-6%. In concentrations greater than 6%, it can be destructive to tissues.
Salicylism and death have occurred following topical application. In an adult,
Propylene glycol is used extensively in topical preparations because it is an excellent vehicle for organic compounds. It has recently been used alone as a keratolytic agent in 40-70% concentrations, with plastic occlusion, or in gel with 6% salicylic acid.
Only minimal amounts of a topically applied dose are absorbed through normal stratum corneum. Percutaneously absorbed propylene glycol is oxidized by the liver to lactic acid and pyruvic acid, with subsequent utilization in general body metabolism. Approximately 12-45% of the absorbed agent is excreted unchanged in the urine.
Propylene glycol is an effective keratolytic agent for the removal of hyperkeratotic debris. It is also an effective humectant and increases the water content of the stratum corneum. The hygroscopic characteristics of propylene glycol may help it to develop an osmotic gradient through the stratum corneum, thereby increasing hydration of the outermost layers by drawing water out from the inner layers of the skin.
Propylene glycol is used under polyethylene occlusion or with 6% salicylic acid for the treatment of ichthyosis, palmar and plantar keratodermas, psoriasis, pityriasis rubra pilaris, keratosis pilaris, and hypertrophic lichen planus.
In concentrations greater than 10%, propylene glycol may act as an irritant in some patients; those with eczematous dermatitis may be more sensitive. Allergic contact dermatitis occurs with propylene glycol, and a 4% aqueous propylene glycol solution is recommended for the purpose of patch testing.
Urea in a compatible cream vehicle or ointment base has a softening and moisturizing effect on the stratum corneum. It has the ability to make creams and lotions feel less greasy, and this has been utilized in dermatologic preparations to decrease the oily feel of a preparation that otherwise might feel unpleasant. It is a white crystalline powder with a slight ammonia odor when moist.
Urea is absorbed percutaneously, although the precise amount absorbed is not well documented. It is distributed predominantly in the extracellular space and excreted in urine. Urea is a natural product of metabolism, and systemic toxicities with topical application do not occur.
Urea allegedly increases the water content of the stratum corneum, presumably as a result of the hygroscopic characteristics of this naturally occurring molecule. Urea is also keratolytic. The mechanism of action appears to involve alterations in prekeratin and keratin, leading to increased solubilization. In addition, urea may break hydrogen bonds that keep the stratum corneum intact.
As a humectant, urea is used in concentrations of 2-20% in creams and lotions. As a keratolytic agent, it is used in 20% concentration in diseases such as ichthyosis vulgaris, hyperkeratosis of palms and soles, xerosis, and keratosis pilaris. Concentrations of 30-50% applied to the nail plate have been useful in softening the nail prior to avulsion.
Podophyllum resin, an alcoholic extract of Podophyllum peltatum, commonly known as mandrake root or May apple, is used in the treatment of condyloma acuminatum and other verrucae. It is a mixture of podophyllotoxin, and peltatin, desoxypodophyllotoxin, dehydropodophyllotoxin, and other compounds. It is soluble in alcohol, ether, chloroform, and compound tincture of benzoin.
Percutaneous absorption of podophyllum resin occurs, particularly in intertriginous areas and from applications to large moist condylomas. It is soluble in lipids and therefore is distributed widely throughout the body, including the central nervous system.
The major use of podophyllum resin is in the treatment of condyloma acuminatum. Podophyllotoxin and its derivatives are active cytotoxic agents with specific affinity for the microtubule protein of the mitotic spindle. Normal assembly of the spindle is prevented, and epidermal mitoses are arrested in metaphase. A 25% concentration of podophyllum resin in compound tincture of benzoin is recommended for the treatment of condyloma acuminatum. Application should be restricted to wart tissue only, to limit the total amount of medication used and to prevent severe erosive changes in adjacent tissue. In treating cases of large condylomas, it is advisable to limit application to sections of the affected area to minimize systemic absorption. The patient is instructed to wash off the preparation 2-3 hours after the initial application, because the irritant reaction is variable. Depending on the individual patient’s reaction, this period can be extended to 6-8 hours on subsequent applications. If three to five applications have not resulted in significant resolution, other methods of treatment should be considered.
Toxic symptoms associated with excessively large applications include nausea, vomiting, alterations in sensorium, muscle weakness, neuropathy with diminished tendon reflexes, coma, and even death. Local irritation is common, and inadvertent contact with the eye may cause severe conjunctivitis. Use during pregnancy is contraindicated in view of possible cytotoxic effects on the fetus.
Pure podophyllotoxin (podofilox) is approved for use as a 0.5% podophyllotoxin preparation (Condylox) for application by the patient in the treatment of genital condylomas. The low concentration of podofilox significantly reduces the potential for systemic toxicity. Most men with penile warts may be treated with less than 70 uL per application. At this dose, podofilox is not routinely detected in the serum. Treatment is self administered in treatment cycles of twice-daily application for 3 consecutive days followed by a 4-day drug-free period. Local adverse effects include inflammation, erosions, burning pain, and itching.
Fluorouracil is a fluorinated pyrimidine antimetabolite that resembles uracil, with a fluorine atom substituted for the 5-methyl group. Fluorouracil is used topically for the treatment of multiple actinic keratoses.
Approximately 6% of a topically applied dose is absorbedan amount insufficient to produce adverse systemic effects. Most of the absorbed drug is metabolized and excreted as carbon dioxide, urea, and -fluoro--alanine. A small percentage is eliminated unchanged in the urine. Fluorouracil inhibits thymidylate synthetase activity, interfering with the synthesis of DNA and, to a lesser extent, RNA. These effects are most marked in atypical, rapidly proliferating cells.
Fluorouracil is available in multiple formulations containing 0.5%, 1%, 2%, and 5% concentrations. The response to treatment begins with erythema and progresses through vesiculation, erosion, superficial ulceration, necrosis, and finally reepithelialization. Fluorouracil should be continued until the inflammatory reaction reaches the stage of ulceration and necrosis, usually in 3-4 weeks, at which time treatment should be terminated. The healing process may continue for 1-2 months after therapy is discontinued. Local adverse reactions may include pain, pruritus, a burning sensation, tenderness, and residual postinflammatory hyperpigmentation. Excessive exposure to sunlight during treatment may increase the intensity of the reaction and should be avoided. Allergic contact dermatitis to fluorouracil has been reported, and its use is contraindicated in patients with known hypersensitivity.
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Scheld WM: Maintaining fluoroquinolone class efficacy: Review of influencing factors. Emerg Infect Dis 2003;9:1.
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