DRUG THERAPY OF INFECTIOUS DISEASES. Classification of infectious diseases According to onset and duration According to location According to item.

DRUG THERAPY OF INFECTIOUS DISEASES

Classification of infectious diseases

•According to onset and duration •According to location •According to item present •According to sequence of appearance •According to epidemiological factors

Classifications according to onset and duration Acute disease -- Rapid onset and short

duration. E.g. common cold, measles Chronic disease -- Slower onset and

longer duration. eg TB, leprosy Subchronic disease -- ermediate to

acute and chronic both in onset and duration. eg gingivitis

Latent disease -- One characterized by periods of activity erspersed with periods of inactivity. E.g.: malaria, herpes simplex.

Classification according to location

Local infection -- Confined to a specific area of the body. E.g.: cystitis, vaginitis, myocarditis.

Focal infection -- Infection that started in one place and later on spread to other areas. E.g. tuberculosis, sinus infection, infected tooth.

Systemic (generalized) infection - Occurring throughout the body

Classifications according to item present Septicemia -- A microbe is present in the blood,

is continuously being delivered from tissues to blood and is actively multiplying in the blood. Typical of systemic diseases. Often fatal.

Bacteremia -- Presence of bacteria in the blood Viremia -- Presence of virus in the blood of the

body Pyemia -- Poisoning of the blood by pus-

producing bacteria released from an abscess Toxaemia -- Presence of bacterial toxins in the

blood. Can result in fever, diarrhea and vomiting.

Classification according to sequence of appearance Primary infection - Initial infection in a healthy

person Secondary infection - Occurs after primary

infection Superinfection - A secondary infection due to

the destruction of the protective normal flora of the body by the use of a broad spectrum antibiotic

Also defined as a secondary infection facilitated by a primary infection e.g. HIV and AIDS

Epidemiological factors - mode of appearance, number of cases, trends of diseases in populationsClassifications according to epidemiological

factors Endemic disease (endemia) - Present regularly in particular

area of the world, and total number and severity are low Ecdemic disease (ecdemia) - A foreign disease brought to a

new area by travelers or immigrants from a foreign country Pandemic disease (pandemia) - A disease that affects many

people and which occurs across neighboring cities, countries or continents. Affects many people.

Epidemic disease (epidemia) - Appears suddenly, affects many people and is confined to a particular, often the same, area. Morbidity rate and mortality rate above what is normal.

Sporadic disease (epidemia) - Appears suddenly, in a random and unpre-dictable manner, affects only a few people, and limited to a few, usually unrelated, places.

Outbreak - Few cases, often related in time and location, and sharing same manifestations

Threat of emerging infectious diseases

Due to constant changes in our lifestyles and environments,

there are constantly new diseases that peopleare susceptible to, making protection from the

threat ofinfectious disease urgent. Many new

contagious diseaseshave been identified in the past 30 years, such

asAIDS, Ebola, and hantavirus. Increased travel

betweencontinents makes the worldwide spread of

disease a biggerconcern than it once was. Additionally, many

commoninfectious diseases have become resistant to

knowntreatments.

Problems of antibiotic resistanceBecause of the overuse of antibiotics, many bacteria

have developed a resistance to common antibiotics. Thismeans that newer antibiotics must continually be developedin order to treat an infection. However, furtherresistance seems to come about almost simultaneously.This indicates to many scientists that it might becomemore and more difficult to treat infectious diseases. Theuse of antibiotics outside of medicine also contributes toincreased antibiotic resistance. One example of this is theuse of antibiotics in animal husbandry. These negativetrends can only be reversed by establishing a more rationaluse of antibiotics through treatment guidelines.

Beta-Lactam Antibiotics

A penicillin culture

Cephalosporins and cephamycins are similar to penicillins chemically, in mechanism of action, and in toxicity. Cephalosporins are more stable than penicillins to many bacterial -lactamases and therefore usually have a broader spectrum of activity. Cephalosporins are not active against enterococci and Listeria monocytogenes.

These are drugs with a monocyclic -lactam ring . They are relatively resistant to

lactamases and active against gram-negative rods (including pseudomonas and serratia). They have

no activity against gram-positive bacteria or anaerobes. Aztreonam is the only monobactam

available in the USA. It resembles aminoglycosides in its spectrum of activity. Aztreonam is given

intravenously every 8 hours in a dose of 1–2 g, providing peak serum levels of 100 g/mL. The

half-life is 1–2 hours and is greatly prolonged in renal failure.

Penicillin-allergic patients tolerate aztreonam without reaction. Occasional skin rashes and

elevations of serum aminotransferases occur during administration of aztreonam, but major toxicity

has not yet been reported. The clinical usefulness of aztreonam has not been fully defined.

These substances resemble -lactam molecules (Figure 43–7) but themselves have very weak

antibacterial action. They are potent inhibitors of many but not all bacterial lactamases and can

protect hydrolyzable penicillins from inactivation by these enzymes. -Lactamase inhibitors are

most active against Ambler class A lactamases (plasmid-encoded transposable element [TEM] -

lactamases in particular) such as those produced by staphylococci, H influenzae, N gonorrhoeae,

salmonella, shigella, E coli, and K pneumoniae. They are not good inhibitors of class C -

lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter,

citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal lactamases of legionella,

bacteroides, and branhamella.

The indications for penicillin- -lactamase inhibitor combinations are empirical therapy for

infections caused by a wide range of potential pathogens in both immunocompromised and

immunocompetent patients and treatment of mixed aerobic and anaerobic infections, such as intraabdominal

infections. Doses are the same as those used for the single agents except that the

recommended dosage of piperacillin in the piperacillin-tazobactam combination is 3 g every 6

hours. This is less than the recommended 3–4 g every 4–6 hours for piperacillin alone, raising

concerns about the use of the combination for treatment of suspected pseudomonal infection.

Adjustments for renal insufficiency are made based on the penicillin component.

The carbapenems are structurally related to beta-lactam antibiotics. Ertapenem, imipenem, and meropenem are licensed for use in the USA. Imipenem has a wide spectrum with good activity against many gram-negative rods, including Pseudomonas aeruginosa, gram-positive organisms, and anaerobes. It is resistant to most lactamases but not metallo- lactamases. Enterococcus faecium, methicillin-resistant strains of staphylococci, Clostridium difficile,

Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Consequently, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use. Meropenem is similar to imipenem but has slightly greater activity against gram-negative aerobes and slightly less activity against gram-positives. It is not significantly degraded by renal

dehydropeptidase and does not require an inhibitor. Ertapenem is less active than meropenem or imipenem

against Pseudomonas aeruginosa and acinetobacter species. It is not degraded by renal dehydropeptidase.

The usual dose of imipenem is 0.25–0.5 g given intravenously every 6–8 hours (half-life 1 hour). The usual adult dose of meropenem is 1 g intravenously every 8 hours. Ertapenem has the longest half-life (4 hours) and is administered as a once-daily dose of 1 g intravenously or intramuscularly. Intramuscular ertapenem is irritating, and for that reason the drug is formulated with 1% lidocaine for

administration by this route. A carbapenem is indicated for infections caused by susceptible organisms that are resistant to other available drugs and for treatment of mixed aerobic and anaerobic infections. Carbapenems are active against many highly penicillin-resistant strains of pneumococci. A carbapenem is the beta- lactam antibiotic of choice for treatment of enterobacter infections, since it is resistant to destruction by the lactamase produced by these organisms. Strains of Pseudomonas aeruginosa may rapidly develop resistance to imipenem or meropenem, so simultaneous use of an aminoglycoside is recommended for infections caused by those organisms. Ertapenem is insufficiently active against P aeruginosa and should not be used to treat infections caused by that organism. Imipenem or meropenem with or without an aminoglycoside may be effective treatment for febrile neutropenic patients.

Chloramphenicol is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome.

Because of potential toxicity, bacterial resistance, and the availability of other effective drugs (eg, cephalosporins), chloramphenicol is all but obsolete as a systemic drug. It may be considered for treatment of serious rickettsial infections, such as typhus or Rocky Mountain spotted fever, in children for whom tetracyclines are contraindicated, ie, those under 8 years of age. It is an alternative to a -lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillinresistant strains of neumococci. The dosage is 50–100 mg/kg/d in four divided doses.Chloramphenicol is occasionally used topically in the treatment of eye infections because of its wide antibacterial spectrum and its penetration of ocular tissues and the aqueous humor. It is ineffective for chlamydial infections.

Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and

detoxification of chloramphenicol. Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. To avoid this toxic effect, chloramphenicol should be

used with caution in infants and the dosage limited to 50 mg/kg/d or less (during the first week of

life) in full-term infants and 25 mg/kg/d in remature infants.

Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. They are active against many gram-positive and gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and L forms; and against some protozoa, eg, amebas. The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may remain susceptible to doxycycline or minocycline, drugs that are less rapidly transported by the pump that is responsible for resistance

A tetracycline is the drug of choice in infections with Mycoplasma pneumoniae, chlamydiae, rickettsiae, and some spirochetes. They are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori. In cholera, tetracyclines rapidly stop the shedding of vibrios, but tetracycline resistance has appeared during epidemics. Tetracyclines remain effective in most chlamydial infections, including sexually transmitted diseases. Tetracyclines are no longer recommended for treatment of gonococcal disease because of resistance. A tetracycline—usually in combination with an aminoglycoside—is indicated for plague, tularemia, and brucellosis. Tetracyclines are sometimes employed in the treatment of protozoal infections, eg, those due to Entamoeba histolytica or Plasmodium falciparum. Other uses include treatment of acne, exacerbations of bronchitis, community-acquired pneumonia, Lyme disease, relapsing fever, leptospirosis, and some nontuberculous mycobacterial infections (eg, Mycobacterium marinum). Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis, pneumonia (other than mycoplasmal or chlamydial pneumonia), and urinary tract infections. However, many strains of bacteria causing these infections now are resistant, and other agents have largely supplanted Tetracyclines.

ErythromycinClarithromycin (is derived from erythromycin)Azithromycin (differs from erythromycin and

clarithromycin mainly in pharmacokinetic properties). The drug is slowly released from tissues (tissue half-life of 2–4 days) to produce an elimination half-life approaching 3 days. These unique properties permit once-daily dosing and shortening of the duration of treatment in many cases. For example, a single 1 g dose of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Community-acquired pneumonia can be treated with zithromycin given as a 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days.

Ketolides (Telithromycin)

Aminoglycosides

Streptomycin, neomycin, kanamycin, amikacin,

gentamicin, tobramycin, sisomicin, netilmicin

Sulfonamides are infrequently used as single agents. Formerly drugs of choice for infections such as Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections, they have been largely supplanted by the fixed drug combination of trimethoprim-sulfamethoxazole. Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant. Nevertheless, sulfonamides can be useful for treatment of urinary tr

Sulfisoxazole and sulfamethoxazole are short- to medium-acting agents that are used almostexclusively to treat urinary tract infections. The usual adult dosage is 1 g of sulfisoxazole four times daily or 1 g of sulfamethoxazole two or three times daily.Sulfadiazine achieves therapeutic concentrations in cerebrospinal fluid and in combination withpyrimethamine is first-line therapy for treatment of acute toxoplasmosis. Pyrimethamine, an antiprotozoal agent, is a potent inhibitor of dihydrofolate reductase.Sulfadoxine is available only as Fansidar, a combination formulation with pyrimethamine, which is used as a second-line agent in treatment for malaria

Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease

Topical AgentsSodium sulfacetamide ophthalmic solution or ointment is effective treatment for bacterialconjunctivitis and as adjunctive therapy for trachoma. Mafenide acetate is used topically to prevent bacterial colonization and infection of burn wounds.

FluoroquinolonesThe important quinolones are synthetic

fluorinated analogs of nalidixic acid. They are active against a variety of gram-positive and gram-negative bacteria. Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV.Earlier quinolones (nalidixic acid, oxolinic acid, cinoxacin) did not achieve systemic antibacteriallevels. These agents were useful only for treatment of lower urinary tract infections.Fluorinated derivatives (ciprofloxacin, levofloxacin,and others) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues.

Ciprofloxacin, enoxacin, lomefloxacin, evofloxacin, ofloxacin, and pefloxacin comprise a second group of similar agents possessing excellent gram-negative activity and moderate to good activity against grampositive bacteria.Gatifloxacin, moxifloxacin, sparfloxacin, and rovafloxacin comprise a third group of fluoroquinolones with improved activity against gram-positive organisms, particularly Spneumoniae and to some extent staphylococci.

Antifungal AgentsAntifungal Agents

The antifungal drugs presently available fall into several categories: systemic drugs (oral or parenteral) for systemic infections, oral drugs for mucocutaneous infections, and topical drugs for mucocutaneous infections.

Immunologic therapiesImmunologic therapies

Immunologic therapy is the treatment of diseaseImmunologic therapy is the treatment of diseaseusing medicines that boost the body’s natural using medicines that boost the body’s natural

immuneimmuneresponse.response.

PurposePurposeImmunologic therapy is used to improve theImmunologic therapy is used to improve the

immune system’s natural ability to fight such immune system’s natural ability to fight such diseases asdiseases as

cancercancer, hepatitis and , hepatitis and AIDSAIDS. These drugs may also . These drugs may also bebe

used to help the body recover from used to help the body recover from immunosuppressionimmunosuppression

resulting from such treatments as resulting from such treatments as chemotherapy chemotherapy ororradiation therapyradiation therapy..DescriptionDescription

Immunologic therapiesImmunologic therapiesMost drugs in this category are synthetic versions ofMost drugs in this category are synthetic versions of

substances produced naturally in the body. In their substances produced naturally in the body. In their naturalnatural

forms, these substances help defend the body againstforms, these substances help defend the body againstdisease. For example, aldesleukin (Proleukin) is an disease. For example, aldesleukin (Proleukin) is an

artificiallyartificiallymade form of interleukin-2, which helps whitemade form of interleukin-2, which helps whiteblood cells work. Aldesleukin is administered to patientsblood cells work. Aldesleukin is administered to patientswith kidney cancers and skin cancers that have spread with kidney cancers and skin cancers that have spread

totoother parts of the body. Filgrastim (Neupogen) and other parts of the body. Filgrastim (Neupogen) and

sargramostimsargramostim (Leukine) are versions of natural (Leukine) are versions of natural substancessubstances called called colony stimulating factorscolony stimulating factors, , which drive the bonewhich drive the bone marrow to make new white marrow to make new white blood cells. Another type ofblood cells. Another type of drug, epoetin (Epogen, drug, epoetin (Epogen, Procrit), is a synthetic version ofProcrit), is a synthetic version of human human erythropoietin that stimulates the bone marrow toerythropoietin that stimulates the bone marrow to make new red blood cells. Thrombopoietin stimulates make new red blood cells. Thrombopoietin stimulates thethe production of platelets, disk-shaped bodies in the production of platelets, disk-shaped bodies in the bloodblood that are important in clotting.that are important in clotting.

Immunologic therapiesImmunologic therapies cont’dcont’dInterferonsInterferons are substances are substances the body the body produces naturally using immune cells to fightproduces naturally using immune cells to fight infections and tumors. The synthetic infections and tumors. The synthetic interferons carryinterferons carry such brand names as Alferon, such brand names as Alferon, Roferon or Intron A. SomeRoferon or Intron A. Someof the interferons that are currently in use as of the interferons that are currently in use as drugs aredrugs are Recombinant Interferon Alfa-2a, Recombinant Interferon Alfa-2a, Recombinant InterferonRecombinant Interferon Alfa-2b, interferon Alfa-2b, interferon alfa-n1 and Interferon Alfa-n3. Alfaalfa-n1 and Interferon Alfa-n3. Alfa interferons interferons are used to treat are used to treat hairy cell leukemiahairy cell leukemia, , malignantmalignant melanoma melanoma and AIDS-related and AIDS-related Kaposi’s sarcoma,Kaposi’s sarcoma, which is a form of cancer. which is a form of cancer. In addition interferons are alsoIn addition interferons are also used for such used for such other conditions as laryngeal papillomatosis,other conditions as laryngeal papillomatosis,genital warts genital warts and certain types of hepatitis.and certain types of hepatitis.

General precautions for all types of General precautions for all types of immunologicimmunologic

therapytherapy

Regular physician visits are necessary duringRegular physician visits are necessary duringimmunologic therapy treatment. This gives immunologic therapy treatment. This gives the the physicianphysician a chance to make sure the a chance to make sure the medicine is working and tomedicine is working and to check for check for unwanted side effects.unwanted side effects.Anyone who has had unusual reactions to Anyone who has had unusual reactions to drugs useddrugs used in immunologic therapy should let in immunologic therapy should let the physician knowthe physician know before resuming the before resuming the drugs. Any drugs. Any allergies allergies to foods, dyes,to foods, dyes, preservatives, or other substances should preservatives, or other substances should also be reported.also be reported.