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Antimicrobial General Information -Medications used to treat bacterial infections. -Antibacterial is a natural, semi-synthetic or synthetic substance that kills or inhibits bacterial growth. Bacteriocidal – kills the bacteria Bacteriostatic – inhibit growth of bacteria N.B.: Either after arresting the growth of the bacteria by a bacteriostatic or decreasing the number of viable bacteria by a bactericidal ,the body's immune system attacks, immobilizes, and eliminates the pathogens. If the drug is removed before the immune system has scavenged the organisms, enough viable organisms may remain to begin a second cycle of infection. Antimicrobial drugs are effective in the treatment of infections because of their selective toxicity. (i.e): they have the ability to injure or kill an invading microorganism without harming the cells of the host. This term is is relative rather than absolute, requiring that the concentration of the drug be carefully controlled to attack the microorganism while still being tolerated by the host. Factors Controlling Selection of the Antimicrobial Agent: 1) The organism's identity 2) The organism's susceptibility to a particular agent 3) The site of the infection 4) Patient factors 5) Safety of the Agent 6) The cost of therapy. 1-Identification of the infecting organism A-Gram staining A rapid assessment of the nature of the pathogen can sometimes be made on the basis of the Gram stain, which is particularly useful in identifying the presence as well identifying the morphologic features of microorganisms in body fluids that are normally sterile (CSF, pleural fluid, synovial fluid, peritoneal fluid, and urine). B-Culture it is essential to obtain a sample culture of the organism prior to initiating treatment. for definitive identification of the infecting organism to arrive at a conclusive diagnosis Sometimes , for definitive identification of the infecting organism ,other laboratory techniques, such as detection of microbial antigens, microbial DNA it or RNA, or detection of an inflammatory or host immune response to the microorganism is performed. However, some critically ill patients require empiric therapy that is, immediate administration of drug(s) prior to bacterial identification and susceptibility testing. Ex. patient with severe headache, a rigid neck, and sensitivity to bright lights (symptoms characteristic of meningitis)”require immediate treatment. The choice of drug in the absence of susceptibility data is influenced by the site of infection and the patient's history (for example, whether the infection was hospital- or communityacquired, whether the patient is immuno-compromised, as well as the patient's travel record and age). Generally, broadspectrum therapy are needed initially for serious infections when the identity of the organism is unknown 2-Determination of antimicrobial susceptibility of infective organisms After a pathogen is cultured, its susceptibility to specific antibiotics serves as a guide in proper choosing antimicrobial therapy. Even some pathogens, such as Streptococcus usually have predictable susceptibility patterns to certain antibiotics , others as gramnegative bacilli, enterococci, and staphylococcal species often show unpredictable susceptibility patterns to various antibiotics and require susceptibility testing to determine appropriate antimicrobial therapy. 3-Site of infection Adequate levels of an antibiotic must reach the site of infection for the invading microorganisms to be effectively eradicated. This is affected by : 1-Lipid solubility of the drug. 2- Molecular weight of the drug 3-Plasm Protein Binding. 4-Patient factors In selecting an antibiotic, attention must be paid to the condition of the patient. For example, the status of the patient's immune system, kidneys, liver, circulation, And age must be considered. In women, pregnancy or breastfeeding also selection of The antimicrobial agent Immune system: Elimination of infecting organisms from the body depends on an intact immune system. the host defense system must ultimately eliminate the invading organisms. Alcoholism, diabetes, infection with the human immunodeficiency virus, malnutrition, or advanced age can affect a patient's immunocompetence, as can therapy with immunosuppressive drugs. Higher-than-usual doses of bactericidal agents or longer courses of treatment are required to eliminate infective organisms in these individuals. Renal dysfunction: Poor kidney function (10 percent or less of normal) causes accumulation in the body of antibiotics that ordinarily are eliminated by this route. This may lead to serious adverse effects of drugs eliminated by the kidneys. Antibiotics that undergo extensive metabolism or are excreted via the biliary route may be favored in such patients. Hepatic dysfunction: Antibiotics that are concentrated or eliminated by the liver (for example, erythromycin and tetracycline) are contraindicated intreating patients with liver disease. Age: Renal or hepatic elimination processes are often poorly developed in newborns, making neonates particularly vulnerable to the toxic effects of chloramphenicol and sulfonamides. Young children should not be treated with tetracyclines, which affect bone growth. Pregnancy: All antibiotics cross the placenta. Adverse effects to the fetus are rare, except the for tooth dysplasia and inhibition of bone growth encountered with the tetracyclines. Of course, all drugs should be used only during pregnancy under the supervision of a patient's physician. lactation: Drugs administered to a lactating mother may enter the nursing infant via the breast milk. Although the concentration of an antibiotic in breast milk is usually low, the total dose to the infant may be enough to cause problems. 5-Safety of the agent Many of the antibiotics, such as the penicillins, are among the least toxic of all drugs, because they interfere with a site unique to the growth of microorganisms. Other antimicrobial agents (for example, chloramphenicol) are reserved for life-threatening infections because of the drug's potential for serious toxicity to the patient. Note: safety is related not only to the inherent nature of the drug but also to patient factors that can predispose to toxicity 6-Cost of therapy Often, several drugs may show similar efficacy in treating an infection but vary widely in cost. It is more preferable to select suitable agent in its coast for treatment of certain infectious disease. Ideal characteristics of antibiotics -selective toxicity with minimal side effects to host -easy to tolerate without a complex drug regimen -bactericidal rather than bacteriostatic -narrow spectrum rather than broad -low cost of production for consumer -stable (shelf-life) -adequate bioavailability: drug much reach adequate concentrations in relevant tissues or body sites A single agent is unlikely to meet all of these criteria Combinations of Antimicrobial Drugs It is therapeutically advisable to treat patients with the single agent that is most specific for the infecting organism.This strategy reduces the possibility of superinfection, decreases the emergence of resistant organisms,and minimizes toxicity. However, situations in which combinations of drugs are employed do exist. For example, the treatment of tuberculosis benefits from drug combinations. Advantages of drug combinations Certain combinations of antibiotics, such as β-lactams and aminoglycosides, show synergism; that is, the combination is more effective than either of the drugs used separately. B. Disadvantages of drug combinations A number of antibiotics act only when organisms are multiplying. Thus, coadministration of an agent that causes bacteriostasis plus a second agent that is bactericidal may result in the first drug interfering with the action of the second. For example, bacteriostatic tetracycline drugs may interfere with the bactericidal effect of penicillins and cephalosporins Mechanisms of Antibiotic Resistance Many species of bacteria have evolved resistance to certain antibiotics and synthetic agents - Resistance may develop if the target bacterial enzyme changes or if the bacteria evolves an alternate metabolic pathway Antibiotic Assays and Resistance - Bacteria may evolve the ability to enzymatically inactivate an antibiotic e.g. Β-lactamase - Bacteria may evolve the ability to prevent drug entry into the cytoplasm or to pump the drug out of the cytoplasm - Bacteria can evolve changes in drug targets like 30 S ribosomes binding site. Complications of Antibiotic Therapy The drug may produce an allergic response or be toxic in ways unrelated to the drug's antimicrobial activity. A. Hypersensitivity Hypersensitivity reactions to antimicrobial drugs or their metabolic products frequently occur. For example, the penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems, ranging from urticaria (hives) to anaphylactic shock. B. Direct toxicity High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. For example, aminoglycosides can cause ototoxicity by interfering with membrane function in the hair cells of the organ of Corti. C. Superinfections Drug therapy, particularly with broad-spectrum antimicrobials or combinations of agents, can lead to alterations of the normal microbial flora of the upper respiratory, intestinal, and genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. These infections are often difficult to treat Mechanism of antimicrobial Agents 1. Inhibition of cell wall synthesis e.g. Penicillins, cephalosporins & vancomycin Human cells do not have a cell wall, so these drugs are specific only for bacteria. They will kill or stop replication of the bacteria without damaging the host. 2. Inhibition of protein synthesis e.g. Tetracycline, aminoglycosides, chloramphenicol, erythromycin Selective toxicity relies on the fact that the bacterial ribosome differs in size to the human ribosome 3. Inhibition of nucleic acid synthesis Affect microbial specific enzymes, e.g. DNA dependent RNA polymerase. 4. Antimetabolites Affect the metabolism of the organism by having a negative effect on some vital metabolite. Humans are unable to synthesize foliate and so must get it from the food, whereas bacteria must make their own. Hence, inhibition of foliate metabolism can hinder bacterial growth. e.g. Trimethoprim I-Antimetabolites Folate Antagonists Folate-derived cofactors are essential for the synthesis of purines and pyrimidines (precursors of RNA and DNA) and other compounds necessary for cellular growth and replication. Therefore, in the absence of folate, cells cannot grow or divide. To synthesize the critical folate derivative, tetrahydrofolic acid, humans must first obtain preformed folate in the form of folic acid as a vitamin from the diet. In contrast, many bacteria are impermeable to folic acid and other folates and, therefore, must rely on their ability to synthesize folate de novo. The sulfonamides (sulfa drugs) are a family of antibiotics that inhibit this de novo synthesis of folate. Cont; Sulfonamides -One of the first groups of antibiotics -Bacteriostatic in action -Prevent synthesis of folic acid required for synthesis of purines and pyrimidines. -Does not affect human cells or certain bacteria that can use preformed folic acid -Examples: Short acting: sulfadiazine, sulfamethazine Intermediate acting : sulfamethoxazole Long acting : sulfathiazole , sulfasalazine F. Spectrum of Activity -Broad range of Gm+ and Gm-They are also active against some protozoa as toxoplasmosis and chloroquine-resistant malaria. G. Resistance - common due to: 1) an altered dihydropteroate synthetase. 2)decreased cellular permeability to sulfa drugs 3) enhanced production of the natural substrate, PABA. H. Uses 1- Respiratory and urinary tract infection. 2-Ulcerative colitis 3-Skin wounds and skin burns. 4-Toxoplasmosis and malaria. 5-in burn units, they have been effective in reducing burnassociated sepsis, because they prevent colonization of bacteria. I. Side effects -Hypersensitivity reactions (e.g., rashes and drug fever) in a small number of patients. Other cause allergic reactions include photosensitivity. -Stevens-Johnson syndrome is also associated with sulfonamide use; it is characterized by fever, malaise, erythema ,and ulceration of the mucous membranes of the mouth and genitalia. -High concentration of sulfonamides with aqueous solubility which is sufficiently low, the free drug or its metabolites may form crystals and cause bleeding or complete obstruction of the kidneys. i-Combinations of sulfa (for lowering the dosage of individual agents) ii- A lot of fluids intake iii-Alkalinization of the urine (to increase excretion) to reduce the chance of crystalluria -Sulfonamides compete for sites on plasma proteins that are responsible for the binding of bilirubin. As a result, less bilirubin is bound, and in the newborn, the unbound bilirubin can be deposited in the basal ganglia, causing kernicterus, a toxic encephalopathy. For this reason, sulfonamides should not be administered to newborns or to women during the last 2 months of pregnancy or lactating females. D. Antibacterial spectrum -The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole. It is active against most gram- positive and gram negative organisms. There is little activity against anaerobic bacteria.However, trimethoprim is 20-to 50-fold more potent than the sulfonamide. E. Uses Trimethoprim may be used alone in the treatment of acute UTIs and in the treatment of bacterial prostatitis and vaginitis is used in the treatment of genitourinary, GI, and respiratory tract infections. F. Resistance Resistance in bacteria is due to the presence of an altered dihydrofolate reductase that has a lower affinity for trimethoprim. Overproduction of the enzyme may also lead to resistance, because this can decrease drug permeability. G. Adverse effects Trimethoprim can produce the effects of folic acid deficiency. These effects include megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant patients and those having very poor diets. These blood disorders can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria. III-Cotrimoxazole The combination of trimethoprim with sulfamethoxazole, called cotrimoxazole shows greater antimicrobial activity than equivalent quantities of either drug used alone .The combination was selected because of the similarity in the half-lives of the two drugs. Rationally, by blocking the first stepin folic acid synthesis, there is no real reason to block further steps. However, there are some bacteria which can inhibits the initial blockage, and so this may be the rationale for the use of such combination. -There is synergy between the two drugs - the combined effect is greater that the expected sum of their activities -Individually the drugs are bacteriostatic; however, in combination they are bactericidal -The use of two drugs will delay the emergence of resistance. Mechanism of action Resistance -The bacteria by gentic mutation they do not need to make folic acid they utilize already formed folic acid. --Overproduce the target e.g. To overcome trimethoprim, bacteria can overproduce DHFR to overcome the inhibition of trimethoprim. -Bacteria produce mutated DHFR Side effects TMP-SMX can cause the same adverse effects as those associated with sulfonamide administration. Most of the adverse effects of this combination are due to the sulfamethoxazole component. Uses TMP-SMX is used in the treatment of infection caused by ampicillin-resistant Shigella and for antibiotic-resistant Salmonella. -Successful in treatment of traveler’s diarrhea due to susceptible E. coli. -Because trimethoprim accumulates in the prostate, TMP-SMX is used to treat prostatitis caused by sensitive organisms. - Used n Pneumocystis jiroveci pneumonia occur in HIV patients. Uses of Cotrimoxazol II-Protein Synthesis Inhibitors Reason For Selective Toxicity A number of antibiotics exert their antimicrobial effects by targeting the bacterial ribosome, which has components that differ structurally from those of the mammalian cytoplasmic ribosome. In general, the bacterial ribosome is smaller (70S) than the mammalian ribosome (80S) and is composed of 50S and 30S subunits (as compared to 60S and 40S subunits in human). 1-Aminoglycosides They are highly polar, polycationic structure that prevents adequate absorption after oral administration. Therefore, all aminoglycosides (except neomycin )must be given parenterally to achieve adequate serum levels. Note: The severe nephrotoxicity associated with neomycin precludes parenteral administration, and its current use is limited to topical application for skin infections or oral administration to prepare the bowel prior to surgery. The bactericidal effect of aminoglycosides is concentration and time dependent; that is, the greater the concentration of drug, the greater the rate at which the organisms die. They also have a postantibiotic effect. Because of these properties: once-daily dosing with the aminoglycosides can be employed. Mechanism of action -They passively diffuse via porin channels across the cell wall of the bacteria. The drug is then transported across the cell membrane into the cytoplasm by active transport which require energy and O2 - It bind irreversibly to the 30s unit of the ribosome and distorts the reading frame. Protein synthesis can still continue, but distortion results in either misense or nonsense codons leading to the wrong amino acid being used and premature termination· The proteins produced by the bacteria which are required in maintaining cell integrity and functions are going to be non-functional ones. - Under anaerobic conditions, aminoglycosides are highly charged, and therefore will be unable to work. Hence, anaerobic bacteria tend to be more resistant to them. -Note: The aminoglycosides synergize with β-lactam antibiotics because of the latter's action on cell wall synthesis, which enhances diffusion of the aminoglycosides into the bacterium. Resistance 1-Resistance can occur by altering the 30s ribosome binding site of the drug / low affinity of the drug. 2- Impaired intracellular transport: Decrease the active transport of the AB. 3- Inactivation by microbial enzymes :Bacteria can produce deactivating enzymes as phosphotransferases, adenyltransferases and acetyltransferases Each of these enzymes has its own aminoglycoside specificity; therefore, cross-resistance is not an invariable rule. Note: 1- Amikacin is less vulnerable to these enzymes than are the other antibiotics of this group 2-Any organism resistant to one aminoglycoside is not resistant to all Spectrum and Uses Aminoglycosides act bactericidal on dividing and no dividing microorganisms.They are in general active against aerobic Gram-negative including Pseudomonas aeruginosa. The exact mechanism of their lethality is unknown because other antibiotics that affect protein synthesis are generally bacteriostatic -Respiratory tract infection -Their oral use are restricted to their action against GIT infections as amebiasis (mostly neomycin). Adverse effects All aminoglycosides are ototoxic and nephrotoxic. -Ototoxicity and nephrotoxicity are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency. -Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (vancomycin, amphotericin) can potentiate nephrotoxicity and should be avoided. -Ototoxicity can manifest itself either as auditory damage, resulting in tinnitus and high-frequency hearing loss initially, or as vestibular damage, evident by vertigo, ataxia, and loss of balance. Copnt.: Adverse effects -Also they produce a curare-like effect with neuromuscular blocking effect that results in respiratory paralysis. The mechanism responsible is a decrease in both the release of acetylcholine from prejunctional nerve endings and the sensitivity of the postsynaptic site. Patients with myasthenia gravis are particularly at risk.This paralysis is usually reversible by calcium gluconate or neostigmine. -Hypersensitivity occurs infrequently. 2- TETRACYCLINES They are safe, inexpensive ,broad-spectrum, bacteriostatic . antibiotics, that are effective against aerobic and anaerobic grampositive and gram-negative bacteria as well as against organisms other than bacteria (ex. Protozoa). 7 6 5 4 The basic tetracycline structure consists of four benzene rings with various substituent on each ring. - Tetracyclines are classified as: (1) short-acting :chlortetracycline, tetracycline, oxytetracycline (2) intermediate acting :demeclocycline and methacycline (3) long-acting :doxycycline and minocycline The almost complete absorption and slow excretion of doxycycline and minocycline allow for once-daily dosing. A newly approved tetracycline analog, tigecycline, Is a semisynthetic derivative of minocycline. Many tetracycline-resistant strains are susceptible to tigecycline. It has broad spectrum. Tigecycline was developed to overcome the recent emergence of tetracycline “resistant organisms that utilize efflux and ribosomal protection to infer resistance WHY???. Mechanism of action -Tetracyclines enter microorganisms in part by passive diffusion (through cell wall) and in part by an energydependent process (active transport through cell membrane). Susceptible cells concentrate the drug intracellularly. -Once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. This prevents addition of amino acids to the growing peptide. -Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. Mechanisms of resistance (1) impaired influx or increased efflux by an active transport protein pump (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome Any organism resistant to one tetracycline is resistant to all. Pharmacokinetics -Substitutions on these rings are responsible for variation in the drugs'individual pharmacokinetics, which cause small differences in their clinical efficacy. -Absorption after oral administration is approximately 60–70% for tetracycline, oxytetracycline, and methacycline; and 95–100% for doxycycline and minocycline. -Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain multivalent cations. -Tetracyclines are 40–80% bound by plasma proteins.Tetracyclines are distributed widely to tissues and body fluids except for CSF, where concentrations are 10–25% of those in serum. (Minocycline reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcalcarrier state). -Tetracyclines cross the placenta to reachthe fetus and are also excreted in milk. As a result of chelation with calcium, tetracyclines are bound to and damage growing bones and teeth. -Tetracyclines are excreted mainly in bile and urine. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and may contribute to maintenance of serum levels . Excretion into the urine, mainly by glomerular Filtration . Small % of the these drugs are excreted in feces. -Minocycline and mostly Doxycycline, in contrast to other tetracyclines, is eliminated nonrenaly , do not require dosage adjustment in renal failure. Thus it is one of the safest TET for the treatment of extrarenal infections Spectrum & Clinical Uses -Tetracyclines are active against many Gram-positive and Gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and against some protozoa, as amebas. -Minocycline is usually the most active followed by doxycycline. -Tetracyclines remain effective in most chlamydial infections, including sexually transmitted diseases. -Tetracyclines are effective in treatment of Rocky Mountain spotted fever by rickettsia rickettsii. -Other uses include treatment of acne, exacerbations of bronchitis & communityacquired pneumonia -They are used in combination regimens to treat gastric and duodenal ulcer disease caused by H. pylori. - Although all tetracyclines enter the (CSF), levels are insufficient for therapeutic efficacy, except for minocycline enters the brain in the absence of inflammation and also appears in tears and saliva so it is useful in eradicating the meningococcal carrier state, but not effective for central nervous system infections. Adverse Reactions TET can produce a variety of adverse effects ranging from minor inconvenience to life-threatening. -Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are not very common. -Nausea, vomiting, and diarrhea are the most common reasons for discontinuing tetracycline medication. These effects are attributable to direct local irritation of the intestinal tract. These effects can usually be controlled by administering the drug with carboxymethylcellulose, reducing drug dosage, or discontinuing the drug. -TET like other antimicrobial agents administered orally may lead to development superinfections, as Tetracyclines modify the normal flora, with suppression of susceptible organisms and overgrowth of pseudomonas, proteus, staphylococci, , clostridia (causing Pseudo membranous colitis ), and candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis Diarrhea must be distinguished either: A. Normal -loose stools do not contain blood or leukocytes B. Pseudo membranous colitis -severe diarrhea, fever, stools containing shreds of mucous membrane and large number of neutrophils. As CI. difficile produces a toxin which is cytotoxic to mucosal cells. --Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it can also be deposited in bone, where it may cause deformity or growth inhibition. If the drug is given for long periods to children under 8 years of age, similar changes can result. 3-Macrolides -The macrolides are a group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached. Erythromycin was the first of these drugs to find clinical application, both as a drug of first choice and as an alternative to penicillin in individuals who are allergic to penicillin . -The newer members of this family include clarithromycin and azithromycin . Telithromycin is a semisynthetic derivative of erythromycin, is the first ketolide antimicrobial agent that has been approved and is now in clinical use. -Ketolides and macrolides have very similar antimicrobial coverage. However, the ketolides are active against many macrolide resistant grampositive strains . Mechanism of action The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting the translocation steps of protein synthesis. They may also interfere at other steps, such as transpeptidation. Generally considered to be bacteriostatic, they may be bactericidal at higher doses. Their binding site is either identical or in close proximity to that for clindamycin and chloramphenicol Resistance 1)The inability of the organism to take up the antibiotic or the presence of an efflux pump, both of which limit the amount of intracellular drug 2) Decreased affinity of the 50S ribosomal subunit for the antibiotic, resulting from the methylation of bacterial ribosomal RNA . Pharmacokinetics -The erythromycin base is destroyed by gastric acid. Thus, either enteric-coated tablets or esterified forms of the antibiotic are administered. All are adequately absorbed upon oral administration Clarithromycin, azithromycin, and telithromycin are stable to stomach acid and are readily absorbed. -Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin. -Erythromycin and telithromycin are extensively metabolized and are known to inhibit the oxidation of a number of drugs through their interaction with the cytochrome P450 system Interference with the metabolism of drugs such as theophylline and carbamazepine has been reported . Erythromycin and azithromycin are primarily excreted in the bile Partial reabsorption occurs through the enterohepatic circulation. In contrast, clarithromycin and its metabolites are eliminated by the kidney as well as the liver, , and it is recommended that the dosage of this drug be adjusted in patients with compromised renal Adverse effects Epigastric distress: This side effect is common for erythromycin. Clarithromycin and azithromycin seem to be better tolerated by the patient Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages. Contraindications: Patients with hepatic dysfunction should be treated cautiously with erythromycin, telithromycin, or azithromycin, because these drugs accumulate in the liver. Similar situation with patients who are renally compermized. Telithromycin has the potential to prolongate the QTc interval in some patients. Therefore, it should be avoided in patients with congenital prolongation of the QTc interval and in those patients with proarrhythmic conditions Interactions: Erythromycin, telithromycin, and clarithromycin inhibit the hepatic metabolism of a number of drugs, which can lead to toxic accumulations of these compounds . 4-Chloramphenicol An antibiotic produced by Streptomyces venezuelae, an organism first isolated from a soil sample in Venezuela. Chloramphenicol inhibits protein synthesis in bacteria and, to a lesser extent, in eukaryotic cells The drug is either bacteriostatic, or bactericidal depending on the organism. Mechanism of Action -It readily penetrates bacterial cells, by facilitated diffusion. -It acts primarily by binding reversibly to the 50S ribosomal subunit. The drug prevent the interaction between peptidyltransferase and its amino acid substrate, and peptide bond formation is inhibited . Because of the similarity of mammalian mitochondrial ribosomes to those of bacteria,protein synthesis in these organelles may be inhibited at high circulating chloramphenicol levels, producing bone marrow toxicity. Resistance Resistance is conferred by the presence of an acetyl coenzyme A transferase. This enzyme inactivates chloramphenicol . Adverse effects 1-Nausea, vomiting, unpleasant taste, and diarrhea may follow the oral administration of chloramphenicol. Among the rare toxic effects produced by this antibiotic are blurring of vision and paresthesias. 2-Hematologic Toxicity The most important adverse effect of chloramphenicol is on the bone marrow cells. Chloramphenicol affects the hematopoietic system in two ways: by an non-dose-related idiosyncratic response manifested by aplastic anemia, leading in many cases to death of the patient. -by a dose-related toxic effect that presents as anemia, It seems to occur more commonly in individuals who undergo prolonged therapy. 3-Gray baby syndrome Fatal chloramphenicol toxicity may develop in neonates, especially premature babies, when they are exposed to excessive doses of the drug. The gray baby syndrome, usually begins 2 to 9 days after treatment is started. The manifestations in the first 24 hours are vomiting, refusal to suck, irregular and rapid respiration, abdominal distention, periods of cyanosis, and passage of loose, green stools. Soon they become flaccid, turn an ashen-gray color, and become hypothermic Two mechanisms are apparently responsible for chloramphenicol toxicity in neonates (1) failure of the drug to be conjugated with glucuronic acid, owing to inadequate activity of glucuronyl transferase in the liver of the infant , which is characteristic of the first 3 to 4 weeks of life. (2) inadequate renal excretion of unconjugated drug in the newborn. -Exchange transfusion and charcoal hemoperfusion have been used to treat overdose with chloramphenicol in infants 4-Although relatively uncommon skin rashes occur as a result of hypersensitivity to chloramphenicol. Therapeutic Uses Chloramphenicol has a wide range activity that includes gram+, gram-, aerobic and anaerobic bacteria But because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used. -It may be considered for treatment of : -Typhoid Fever -Bacterial Meningitis (alternative to a beta-lactams for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci) -Rickettsial Diseases (alternative to tetracycline especially in children <8 years old ) III-Drugs Inhibit nucleic acid synthesis Fluoroquinolones Fluoroquinolones were first introduced in 1986, they are modified quinolones, a class of antibiotics, whose accidental discovery occurred in the early 1960. The fluoroquinolones are a family of synthetic, broad-spectrum antibacterial agents with bactericidal activity. The parent of the group is nalidixic acid, discovered in 1962 by Lescher and colleagues. It was used orally for the treatment of infections caused by gram-negative organisms. The newer fluoroquinolones have a wider clinical use and a broader spectrum of antibacterial activity including grampositive and gram-negative aerobic and anaerobic organisms Mechanism of Action The fluoroquinolones enter the bacterium by passive diffusion through water-filled protein channels (porins) in the outer membrane. Once inside the cell, they inhibit the replication of bacterial DNA by interfering with the action of DNA gyrase (topoisomerase II) and topoisomerase IV during bacterial growth Binding of the quinolone to both the enzyme and the DNA forms a ternary complex that inhibits the resealing step, and can cause cell death. In gram-negative organisms ,the inhibition of DNA gyrase is more significant than that of topoisomerase IV, whereas in gram-positive organisms the opposite is true. •Basis for Selective Toxicity - Quinolones have a relatively low affinity for mammalian DNA topoisomerase Mechanisms of bacterial resistance – change in target enzyme (DNA gyrase or topoisomerase IV) – change in permeability of organism (decrease in number of porin channles). -Increase in efflux of the AB. Classification of Fluoroquinolones First Generation The first-generation agents include cinoxacin, pipdemic acid and nalidixic acid, which are the oldest and least often used quinolones. These drugs had poor systemic distribution , limited activity (against gramnegative bacteria not including psudomionas sp),and were used primarily simple urinary tract infections. - Cinoxacin and nalidixic acid require more frequent dosing (4 times daily) than the newer quinolones, and they are more susceptible to the development of bacterial resistance. Nalidixic acid Second Generation. -The second-generation fluoroquinolones have increased gram-negative activity, as well as some gram-positive and atypical respiratory pathogen coverage. This is mainly due to inserion of F atom in position 6 in the naphthyridine core. -Compared with first-generation quinolones, these drugs have broader clinical applications in the treatment of :complicated urinary tract infections ,pyelonephritis, sexually transmitted diseases , and skin infections. -Agents of Second-generation include norfloxacin ,ciprofloxacin, enoxacin, lomefloxacin, and ofloxacin. -Ciprofloxacin and ofloxacin are the most widely used second-generation quinolones because of their availability in oral and intravenous formulations and their broad set of FDA-labeled indications. N-cyclopropyle moity increased bioavilibility Ciprofloxacin *Secound generation Fluoroquinolones advantages: -Active against gram-negative including Pseudomonas species and some gram- positive aerobic organism -Twice daily dosing. -Excellent oral absorption reached in some members to 99% -Excellent tissue penetration with prolonged half-lives -Overall safety Third Generation. The third-generation fluoroquinolones are separated into a third class because of their expanded activity against gram-positive organisms (particularly penicillin-sensitive and penicillinresistant S. pneumoniae) and atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae. -Although the third-generation agents retain broad gram-negative coverage, they are less active than ciprofloxacin against Pseudomonas species. -Because of their expanded antimicrobial spectrum, thirdgeneration fluoroquinolones are useful in the treatment of community-acquired pneumonia -The third-generation fluoroquinolones include levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin (maine adverse effect is rash in females under 40 years old). Levofloxacin (Levo- enantiomer of ofloxacin) Fourth Generation. The fourth-generation fluoroquinolones add significant antimicrobial activity against anaerobes while maintaining the gram-positive and gram-negative activity of the third-generation drugs. They also retain activity against Pseudomonas species comparable to that of ciprofloxacin. The fourth-generation fluoroquinolones include trovafloxacin (Trovan). -Because of concern about hepatotoxicity, trovafloxacin therapy should be reserved for life-threatening infections requiring in patient treatment (hospital or long-term care facility), and the drug should be taken for no longer than 14 days. Side effects The fluoroquinolones as a class are generally well tolerated. Most adverse effects are mild in severity, self-limited, and rarely result in treatment discontinuation. However, they can have some serious adverse effects. -Fluoroquinolones are approved for use only in people older than 18. They can affect the growth of cartilage in a child or fetus. The FDA has assigned fluoroquinolones to pregnancy risk category C, indicating that these drugs have the potential to cause teratogenic or embryocidal effects. -These agents are also excreted in breast milk and should be avoided during breast-feeding if at all possible Gastrointestinal effects. The most common adverse events experienced with fluoroquinolone administration are gastrointestinal (nausea, vomiting, diarrhea, constipation, and abdominal pain), which occur in 1 to 5% of patients. CNS effects. -Headache, dizziness, and drowsiness have been reported with all fluoroquinolones. -Insomnia was reported in 3-7% of patients with ofloxacin. -Severe CNS effects, including seizures, have been reported in patients receiving some members of fluoroquinolones. Seizures may develop within 3 to 4 days of therapy but resolve with drug discontinuation. Although seizures are infrequent, fluoroquinolones should be avoided in patients with a history of convulsion, cerebral trauma, or anoxia. Phototoxicity. Exposure to ultraviolet rays from direct or indirect sunlight should be avoided during treatment and several days (5 days) after the use of the drug. The degree of phototoxic potential of fluoroquinolones is as follows: lomefloxacin > sparfloxacin > ciprofloxacin Tendon damage (tendon rupture). Although fluoroquinolone-related tendinitis generally resolves within one week of discontinuation of therapy, spontaneous ruptures have been reported as long as nine months after cessation of fluoroquinolone use. Potential risk factors for tendinopathy include age >60 years, male gender, and concomitant use of corticosteroids. Hepatoxicity. Trovafloxacin use has been associated with rare liver damage, which prompted the withdrawal of the oral preparations from the U.S. market. Cardiovascular effects. The newer quinolones have been found to produce additional toxicities to the heart that were not found with the older compounds. Evidence suggests that grapifloxacin may have the most cardiotoxic potential. Glucose homostasis abnormalities (Hypoglycemia or hyperglycemia). Recently, rare cases of hypoglycemia have been reported with ciprofloxacin in patients also receiving oral diabetic medications, primarily sulfonylureas. Although hypoglycemia has been reported with other fluoroquinolones (levofloxacin and moxifloxacin), the effects have been mild. On the other hand, hyperglycemia can occur in other patients receiving fluoroquinolones . Indications and uses The newer fluoroquinolones have a wider clinical use and a broader spectrum of antibacterial activity including gram-positive and gram-negative aerobic and anaerobic organisms. All of the fluoroquinolones are effective in treating urinary tract infections caused by susceptible organisms. They are the first-line treatment of acute uncomplicated cystitis in patients who cannot tolerate sulfonamides or TMP. -Urinary tract infections -Lower respiratory tract infections -Skin and skin-structure infections -Urethral and cervical gonococcal infections -Prostatitis -Acute exacerbations of chronic bronchitis -Inhalation anthrax -Community-acquired pneumonia IV-Cell Wall Synthesis Inhibitors 1-Penicillins -The penicillins constitute one of the most important groups of antibiotics. Although numerous other antimicrobial agents have been produced since the first penicillin became available, these still are widely used, major antibiotics, and new derivatives of the basic penicillin nucleus still are being produced. -The penicillins were the first antibiotics discovered as natural products from the mold Penicillium. In 1928, Sir Alexander Fleming, professor of bacteriology at St. Mary's Hospital in London, was culturing Staphylococcus aureus. He noticed zones of inhibition where mold spores were growing. He named the mold Penicillium rubrum. It was determined that a secretion of the mold was effective against Gram-positive bacteria. Penicillins as well as cephalosporins are called beta-lactam antibiotics, as their beta-lactam nucleus is the chief structural requirement for biological activity. Classification 1. Natural penicillins: Ex. penicillin G and penicillin V. They are highly active against sensitive strains of gram-positive cocci, but they are readily hydrolyzed by penicillinase. Thus, they are ineffective against most strains of Staphylococcus aureus. Penicillin V has a spectrum similar to that of penicillin G, but it more acid-stable than penicillin G. 2-Antistaphylococcal penicillins The penicillinase-resistant penicillins (methicillin, nafcillin, oxacillin, cloxacillin, and dicloxacillin) have less potent antimicrobial activity against microorganisms that are sensitive to penicillin G, but they are effective against penicillinase-producing bacteria .Their use is restricted to the treatment of infections caused by penicillinaseproducing staphylococci. [Note: Because of its toxicity, methicillin is not used clinically except to identify resistant strains of S. aureus] . 3-Extended-spectrum penicillins Ampicillin and amoxicillin have an antibacterial spectrum similar to that of penicillin G but are more effective against gram-negative bacilli but are destroyed by betalactamases. They are therefore referred to as extended-spectrum penicillins. Formulation with a beta-lactamase inhibitor, such as clavulanic acid or sulbactam, protects amoxicillin or ampicillin, respectively, from enzymatic hydrolysis and extends their antimicrobial spectrum. 4-Antipseudomonal penicillins Carbenicillin ,ticarcillin ,and piperacillin are called antipseudomonal penicillins because of their activity against P. aeruginosa. They are effective against many gram-negative bacilli, but not against klebsiella, because of its constitutive penicillinase. Formulation of ticarcillin or piperacillin with clavulanic acid extends the antimicrobial spectrum of these antibiotics to include penicillinase-producing organisms Mechanisms of Action The cell wall is uniqe to bacteria , it is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. All penicillin produce their bacteriocidal effects by inhibition of bacterial cell wall synthesis. The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently, they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses; and they have little or no effect on bacteria that are not growing and Targets for the actions of penicillins and cephalosporins are collectively termed penicillin-binding proteins (PBPs). They are numerous proteins on the bacterial cell membrane. There functions are diverse: catalyze the transpeptidase reaction, maintam shape, forms septums during division, Inhibit autolytic enzymes Binding to PBPs results in: 1. Inhibition of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains . Penicillins inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of cross-links essential for cell wall integrity. As a result of this blockade of cell wall synthesis. 2.Structural irregularities: binding to PBPs may result in abnormal elongation, abnormal shape, cell wall defects. 3. Production of autolysins: Many bacteria, particularly the gram-positive cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall. In the presence of a penicillin,the degradative action of the autolysins proceeds in the absence of cell wall synthesis. [Note: The exact autolytic mechanism is unknown, but it may be due to a disinhibition of the autolysins.] Thus, the antibacterial effect of a penicillin is the result of both inhibition of cell wall synthesis and destruction of existing cell wall by autolysins Therapeutic Uses Pneumococcal Infections Pneumococcal Meningitis Pneumococcal Pneumonia Streptococcal Infections Staphylococcal Infections Meningococcal Infections Gonococcal Infections Syphilis Diphtheria Anthrax Listeria Infections Surgical Procedures in Patients with Valvular Heart Disease Mechanisms of Bacterial Resistance to Penicillins Resistance to penicillins and other beta lactams is due to one of four general mechanisms: 1-Inactivation of the antibiotic by beta lactamase 2-Modification of target PBPs 3-Imparied penetration of drug to target PBPs 4-The presence of an efflux pump The occurrence of modified penicillin binding sites is responsible for methicillin resistance in Pneumococci. Adverse effects 1-Hypersensitivity Reactions The basis of which is the fact that degradation products of penicillin combine with host protein and become antigenic . Manifestations of allergy to penicillins include urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome(Painful Blistering of the skin and mucous membrane involvment. In many cases preceded with flu like symptoms and high fever, and as it evolves the skin literally sloughs off) ,and anaphylaxis. Convulsions and encephalopathy can occur, especially at higher doses and especially if administered intrathecally (NOT advised). Interstitial nephritis (Methicillin) Neutropenia (especially the b-lactamase -resistant penicillins) Decreased platelet aggregation (carbenicillin and ticarcillin) Hypernatremia and hypokalemia 2-Cephalosporins Mechanism of Action: The mechanism of action is identical to penicillins. Mechanism of Resistance Same as penicillins. N.B. Cephalosporins are less susceptible to Staphylococcus beta lactamase; therefore have a broader spectrum of activity. Other bacteria are resistant, because they produce distinct betalactamases. Methicillin-resistant Staphylococcus is resistant to most cephalosporins. Classification The cephalosporins are classified as first, second, third generation or forth generation cephalosporins. This classification is dependent on the antimicrobial activity. Cephalosporins First Generation Second Generation Third Generation Cefadroxil * Cefaclor * Cefdinir Cefazolin Cefamandole Cefoperaxone Cefelixin * Cefonicid Cefotaxime Cephalothin Ceforanide Ceftazidime Cephaprin Cefotetan Ceftibuten Cephradine * Cefoxitin Ceftizoxime Fourth Generation Cefepime Cefuroxime Ceftriaxone moxalactam * Oral Agent Adverse effects 1-Hypersensitivity reactions very similar to those that occur with penicillins. 2-Nephrotoxicity and intolerance to alcohol (disulfiram like reaction) 3-Diarrhea may occur with oral forms as well as superinfection. 4-Hyperprothrombinemia, Thrombocytopenia, Platelet dysfunction. Administration of vitamin K (10mg) twice a week can prevent this. Uses 1-A cephalosporin with or without an aminoglycoside is firstline treatment of Klebsiella. 2-First generation cephalosporins are used for surgical prophylaxis of wound infection. 3-Third generation cephalosporins are used to treat meningitis due to pneumococci, meningococci, and Haemophillus influenza. 4-Ceftriaxone is the drug of choice for treating beta-lactamase producing Neisseria gonorrhea.