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 bacteriaBacteriostatic – 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 hasscavenged 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 organismA-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-Cultureit 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 community-acquired, whether the patient is immuno-compromised, as well as the patient's travel record and age). Generally, broad-spectrum 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 gram-negative 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 factorsIn 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 therapyOften, 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 DrugsIt 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 combinationsCertain 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 combinationsA 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

Antibiotic Assays and Resistance

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

- 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 TherapyThe drug may produce an allergic response or be toxic in ways unrelated to

the drug's antimicrobial activity.A. HypersensitivityHypersensitivity reactions to antimicrobial drugs or their metabolic products

frequently occur. For example, thepenicillins, despite their almost absolute selective microbial toxicity, can

cause serious hypersensitivity problems,ranging from urticaria (hives) to anaphylactic shock.B. Direct toxicityHigh serum levels of certain antibiotics may cause toxicity by directly

affecting cellular processes in the host. Forexample, aminoglycosides can cause ototoxicity by interfering with

membrane function in the hair cells of the organof Corti.

C. SuperinfectionsDrug 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 synthesise.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-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.

Folate Antagonists

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, sulfamethazineIntermediate acting : sulfamethoxazoleLong 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. Uses1- Respiratory and urinary tract infection. 2-Ulcerative colitis3-Skin wounds and skin burns. 4-Toxoplasmosis and malaria.5-in burn units, creams of silver sulfadiazine or mafenide acetate

have been effective in reducing burn-associated sepsis, becausethey prevent colonization of bacteria. However,Silver sulfadiazine is

preferred, because mafenide produces pain on application. 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.

-Hemolytic anemia may develop in persons with a genetic deficiency of red blood cell glucose-6-phosphate dehydrogenase (G6PD).

-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.

-Significant drug–drug interactions are those that potentiate the effects of other agents and require dosage reduction. These include certain anticoagulants, and hypoglycemic

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. UsesTrimethoprim 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. ResistanceResistance in gram-negative 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 effectsTrimethoprim can produce the effects of folic acid deficiency.6 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-CotrimoxazoleThe 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.

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

Mechanism of action

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-Drugs Inhibit nucleic acid synthesis

FluoroquinolonesFluoroquinolones 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 gram-positive and gram-negative aerobic and anaerobic organisms

Mechanism of ActionThe 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 ofDNA 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 FluoroquinolonesFirst GenerationThe 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 gram-negative 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.

Ciprofloxacin

N-cyclopropyle moity increased bioavilibility

*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 penicillin-resistant 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, third-generation 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 effectsThe 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 usesThe 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

III-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-AminoglycosidesThey 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.Aminoglycosides that are derived from Streptomyces have -mycin suffixes,

whereas those derived from Micromonospora end in –micin ex. gentamicin

Mechanism of action -The initial event is passive diffusion via porin channels across the cell wall. Drug is

then transported across the cell membrane into the cytoplasm. They are concenterated in the bacteria by this active transport which require energy and O2

- 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.

Resistance1-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: Amikacin is less vulnerable to these enzymes than are the other antibiotics of this group

(mostly neomycin).

Spectrum and UsesAminoglycosides 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 effectsAll 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 gram-positive and gram-negative bacteria as well as against organisms other than bacteria.

-The basic tetracycline structure consists of four benzene rings with various substituent on each ring.

-They are faintly yellow, odorless, slightly bitter compounds.  

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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 thatutilize efflux and ribosomal protection to infer resistance WHY???.

Mechanism of action

-Tetracyclines enter microorganisms in part by passivediffusion (through cell wall) and in part by an energy-dependent 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 bacteriostaticantibiotics 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 intestineand 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 & community-acquired 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 ineradicating the meningococcal carrier state, but not effective for central nervous system infections.

Adverse ReactionsTET 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 con-trolled by administering the drug with carboxy-methylcellulose, reducing drug dosage, or discont-inuing 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 depositedin newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it canbe 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.

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 cellsThe 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.

ResistanceResistance 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 ToxicityThe 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 syndromeFatal 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 UsesChloramphenicol has a wide range activity that includes gram+,

gram-, aerobic and anaerobic bacteriaBut 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 )

5-Clindamycin

Clindamycin has a mechanism of action that is the same as that of erythromycin. (i.e) Inhibiting the translocation steps of protein synthesis. They may also interfere at other steps, such as transpeptidation

Clindamycin is employed primarily in the treatment of infections caused by anaerobic bacteria, such that causes abdominal infections associated with trauma. However, it is also significantly active against gram-positive cocci. Resistance1)The inability of the organism to take up the antibiotic or the presence of an efflux pump.

2) Decreased affinity of the 50S ribosomal subunit for the antibiotic, resulting from the methylation of bacterial ribosomal RNA

..

Adverse effect-Skin rashes.

-The most serious adverse effect is potentially fat

pseudomembranous colitis caused by overgrowth of

Clostridium. difficile, which elaborates necrotizing

toxins. Oraladministration of either metronidazole or

vancomycin is usually effective in controlling this

serious problem. [Note: Vancomycin should be reserved for a condition that does not respond to metronidazole.]