Pharmacology of Antibiotics

Pharmacology of the Antibiotics

Pharma. Amr RafatNeuropsychiatry hospital

Tanta university

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The anti-infective drugsAnti-infective agents are drugs that are designed to act selectively on foreign organisms that have invaded and infected the body

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Infectious bacteria

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Microbial Sources of Antibiotics

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General Mechanisms of Action of anti-infective agents

The mechanisms are: 1.Inhibition the biosynthesis of bacterial

cell WALL2.Inhibition of protein synthesis 3.Some change the cell membrane

permeability4.Some inhibit DNA synthesis

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The Action of Antimicrobial Drugs

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Modes of Antimicrobial Action

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Inhibition of Protein Synthesis by Antibiotics

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Examples

CELL WALL CELL WALL INHIBITORSINHIBITORS

penicillin, penicillin, cephalosporin, cephalosporin, vancomycinvancomycin

PROTEIN PROTEIN SYNTHESIS SYNTHESIS INHIBITORSINHIBITORS

Macrolides, Macrolides, aminogylcosidesaminogylcosides

CELL WALL CELL WALL PermeabilityPermeability

KetoconazoleKetoconazole

DNA SYNTHESIS DNA SYNTHESIS INHIBITORSINHIBITORS

QuinolonesQuinolones9

Features of Antimicrobial Drugs

• Selective toxicity: Drug kills pathogens without damaging the host.

• Therapeutic index: ratio between toxic dose and therapeutic dose – or ratio of LD50 to ED50

High therapeutic index less toxic• Antimicrobial action – Bacteriostatic vs. bactericidal• Activity Spectrum – Broad-spectrum vs. narrow- spectrum• Tissue distribution, metabolism, and excretion – BBB;

Unstable in acid; half-life duration

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Antibiotic Spectrum of Activity

No antibiotic is effective against all microbes

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Spectrum of Activity of Anti-infectives

Antibiotics agents can also be:

• Bacteriostatic Erythromycin, tetracyclines,clindamycin,

chloramphenicol, spectinomycin, sulfonamides

• Bactericidal Penicillins, Cephalosphorins, Metronidazole, Aminoglycosides, Vancomycin, Polymyxin

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• Anti-infectives that interfere with the ability of the cell to reproduce/replicate without killing them are called BACTERIOSTATIC drugs.

• Tetracycline is an example.

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• Antibiotics that can aggressively cause bacterial death are called BACTERICIDAL.

• These properties (-cidal and –static) can also depend on the antibiotic concentration in the blood.

• (e.g. Erythromycin and Clindamycin may be bactericidal at higher blood levels)

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Factors That Determine the Likehood Of a microorganism Causing an Infection:

1. Virulence of the microorganism

2. Number of the microorganism present

3. Resistance of the host

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Antimicrobial activityD

rug

Con

cent

ratio

n

Time

Peak (Peak/MIC)

Area Under the Curve (AUC/MIC)

Time above MIC

MIC

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Pharmacodynamic properties of antibiotics

Type of bactericidal profile

Important parameter Dosage optimization

Dose-dependent Aminoglycosides, quinolones

Cmax / MIC Prolonged PAE Single daily dose

Time-dependent Penicillin, cephalosporins T > MIC No PAE Multiple DD or

continuous infusion

Cumulative-dose dependent Clarithromycin, clindamycin

AUC / MIC Prolonged PAE

Total dose and duration

PAE: Post-Antibiotic Activity17

S. aureus

Penicillin

[1950s]

Penicillin-resistantS. aureus

Evolution of Drug Resistance in Evolution of Drug Resistance in S. S. aureusaureus

Methicillin

[1970s]Methicillin-resistant S. aureus (MRSA)

Vancomycin-resistantenterococci (VRE)

Vancomycin

[1990s]

[1997]

Vancomycinintermediate-

resistantS. aureus (VISA)

[ 2002 ]Vancomycin-

resistantS. aureus

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Antibiotic Resistance

• A variety of mutations can lead to antibiotic resistance• Mechanisms of antibiotic resistance

1. Enzymatic destruction of drug

2. Prevention of penetration of drug

3. Alteration of drug's target site

4. Rapid ejection of the drug• Resistance genes are often on plasmids or transposons

that can be transferred between bacteria.

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Resistance to Antibiotics

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Antibiotic Resistance

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Only three of the approved antibiotics in the last 10 years (25% of total) have of new mode of action

Superbugs, is the situation really that bad?

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Lots of drugs Not so many

Superbugs, is the situation really that bad?

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Common Adverse Reactions to Anti-infective Therapy

The most common adverse effects are due to the direct action of the drugs in the following organ system- Neuro, nephro and GI system

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1. Nephrotoxicity• Antibiotics that are metabolized and

excreted in the kidney most frequently cause kidney damage..

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2. Gastro-intestinal toxicity• Direct toxic effect to the cells of the GI tract

can cause nausea, vomiting, stomach pain and diarrhea.

• Some drugs are toxic to liver cells and can cause hepatitis or liver failure.

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3. CNS toxicity• When drugs can pass through the brain

barrier and accumulate in the nervous tissues, they can interfere with neuronal function.

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4. Hypersensitivity• Most protein antibiotics can induce the

body’s immune system to produce allergic responses.

• Drugs are considered foreign substances and when taken by the individual, it encounters the body’s immune cells.

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5. Super-infections• Opportunistic infections that develop during

the course of antibiotic therapy are called SUPERINFECTIONS.

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The PENICILLINS

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PenicillinPenicillin is a beta-lactam drug, with a

beta-lactam ring.

The group of penicillins is called beta lactam antibiotics.

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PenicillinThe action of Penicillins

The penicillin and penicillinase-resistant penicillins produce BACTERICIDAL effects by interfering with the ability of susceptible bacteria from biosynthesizing the framework of the cell wall.

The bacterium will have weakened cell wall, will swell and then burst from the osmotic pressure within the cell.

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Typical therapeutic applications of penicillin

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Penicillin cont.

Penicillinase (β-lactamase): bacterial enzyme that destroys natural penicillinsPenicillinase resistant penicillins: methicilin replaced by oxacilin and nafcilin due to MRSAExtended-spectrum penicilins: Ampicilin, amoxicilin; new: carboxypenicilins and ureidopenicillins (also good against P. aeruginosa)

Fig 20.838

Penicillin Pharmacokinetics:

Amoxicillin is well absorbed in the GIT. This in NOT affected by food intake!!

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Retention of Penicillin G

Figure 20.740

Penicillin

Therapeutic Indications of penicillin:-

No other class of antibacterial drugs provides as wide a spectrum of antimicrobial activity as the penicillins.

As a class, they cover gram-positive, gram-negative, and anaerobic organisms, although specific penicillins are more effective against specific organisms.

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Adverse Effects of Penicillins

• GI system effects- the major adverse effects of penicillin therapy involve the GIT.

• Nausea, vomiting, diarrhea, abdominal pain, glossitis, stomatitis, gastritis, sore mouth and furry tongue.

• The reason for some of these effects (superinfection) is associated with the loss of bacterial flora.

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Summary of the adverse effects of

penicillin

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Adverse Effects of Penicillins

• Hypersensitivity reactions- rashes, pruritus, fever and urticaria

• Anaphylaxis can also happen leading to shock or death. It occurs in 5-10% of those receiving penicillins.

• Pain and inflammation on injection sites

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Cephalosporins

Fungi of genus Cephalosporium 4 Generations of cephalosporins

1. First-generation: Narrow spectrum, gram-positive2. Second-generation: Extended spectrum includes gram-

negative3. Third-generation: Includes pseudomonads; mostly

injected, some oral.4. Fourth-generation: Most extended spectrum

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Cephalosporins cont.

Structure and mode of action resembles penicilins

1. More stable to bacterial -lactamases than penicilins

2. Broader spectrum used against penicillin-resistant strains

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THE CEPHALOSPORINS

• First Generation cephalosporins- are largely effective against the same gram-positive organisms affected by penicillin.

• Second generation cephalosporins- are effective against those strains as well as Haemophilus influenza, Entreobacter aerogenes and Nesseria sp. These drugs are less effective against gram positive bacteria

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THE CEPHALOSPORINS

• Third Generation cephlosporins- are relatively weak against gram-positive bacteria but more potent against gram-negative bacteria, to include Serratia marcescens.

• Fourth generation cephalosporins- are developed to fight against the resistant gram-negative bacteria. The first drug is cefepime.

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CephalosporinThe mechanism of action:-

• The cephalosporins are primarily bactericidal .

• They interfere with the cell-wall building ability of bacteria when they divide.

• They prevent the bacteria from biosynthesizing the framework of their cell wall.

• The weakened cell wall will swell and burst causing cell death.

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Administration and fate of the cephalosporins

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Cephalosporin• Pharmacokinetics

– Only a few cephalosporins are administered orally, most are administered parenterally.

– Their half-lives are short and they are excreted mainly in the urine.

• Contraindications and Precautions– The drugs are contraindicated in patients

with known allergies to cephalosporins and penicillins.

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Cephalosporin

Adverse Effects• GI system- Nausea, vomiting, diarrhea,

anorexia, abdominal pain and flatulence are common effects.

• CNS – headache, dizziness, lethargy and paresthesias have been reported.

• Renal system- nephrotoxicity in individuals with pre-existing renal disease

• Hypersensitivity

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CephalosporinDrug-Drug interactions• ALCOHOL- many patients experience a

disulfiram-like reactions when taken with some specific cephlosporins ( cefamandole, cefoperazone or moxalactam).

• The patient may experience flushing, headache, nausea, vomiting and muscular cramps. This may occur even up to 72 hours of cephalosporin discontinuance.

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Carbapenems are a class of beta-lactam antibacterials that includes:

1.ertapenem2.imipenem-cilastatin sodium (a combination drug)3.meropenem.

Carbapenems

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The antibacterial spectrum of activity for imipenem-cilastatin is broader than that of any other antibacterial studied to date.

Because of this broad spectrum of activity, it’s used for serious or life-threatening infection, especially gram-positive and gram-negative health-care acquired infections

Pharmacodynamics• Imipenem-cilastatin, ertapenem, and meropenem are

bactericidal. • They exert antibacterial activity by inhibiting bacterial cell-wall

synthesis.

PharmacotherapeuticsImipenem has the broadest spectrum of activity of currently

available beta-lactam antibiotics:-1. It’s effective against aerobic gram-positive species, such as

Streptococcus, S. aureus, and S. epidermidis.2. It inhibits most Enterobacter species.3. It also inhibits P. aeruginosa (including strains resistant to

piperacillin and ceftazidime) and most anaerobic ( B. fragilis).

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Common adverse reactions to ertapenem, imipenem-cilastatin, and meropenem include:

nausea and vomitingdiarrhea.Hypersensitivity reactions, such as rashes, may occur, particularly in the patient with a known hypersensitivity to penicillins.Kidney conditions (In the patient with decreased or impaired renal function, the dosage may need to be adjusted).

Adverse reactions to carbapenems

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Aztreonam is the first member in the class of monobactam antibiotics and the only one currently available.

It’s a synthetic monobactam with a narrow spectrum of activity that includes many gram-negative aerobic bacteria.

Pharmacokinetics• After parenteral administration, aztreonam is rapidly

and completely absorbed and widely distributed throughout the body.

• It’s metabolized partially and excreted primarily in urine as unchanged drug.

Monobactams

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PharmacodynamicsAztreonam’s bactericidal activity results from inhibition of bacterial cell-wall synthesis.

It binds to the PBP-3 of susceptible gram-negative bacterial cells, inhibiting cell-wall division and resulting in lysis.

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PharmacotherapeuticsAztreonam is indicated in a range of therapeutic situations:-

1)It’s effective against a wide variety of gram-negative aerobic organisms, including P. aeruginosa.2)It’s effective against most strains of the following organisms: E. coli, Enterobacter, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Serratia marcescens, H. influenzae, and Citrobacter.3)It’s also used to treat complicated and uncomplicated UTIs, septicemia, and lower respiratory tract, skin and skin-structure, intra-abdominal, and gynecologic infections caused by susceptible gram-negative aerobic bacteria.4)It’s usually active against gram-negative aerobic organisms that are resistant to antibiotics hydrolyzed by beta-lactamases.

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Aztreonam can cause some adverse reactions including:-diarrheahypersensitivity and skin reactionshypotensionnausea and vomitingtransient electrocardiogram changes (including ventricular arrhythmias)transient increases in serum liver enzyme levels.

Adverse reactions to aztreonam

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Vancomycin– Glycopeptide from Streptomyces– Inhibition of cell wall synthesis– Used to kill MRSA– Emerging Vancomycin

resistance: VRE and VRSA

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PharmacodynamicsVancomycin inhibits bacterial cell-wall synthesis, damaging the bacterial plasma membrane. When the bacterial cell wall is damaged, the body’s natural defenses can attack the organism.

PharmacotherapeuticsVancomycin is active against gram-positive organisms, such as S. aureus, S. epidermidis, S. pyogenes, Enterococcus, and S. pneumoniae.

In the I.V. leagueI.V. vancomycin is the therapy of choice for the patient with a serious resistant staphylococcal infection who’s hypersensitive to penicillins.

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PharmacokineticsBecause vancomycin is not absorbed from the GI tract, it must be given I.V. to treat systemic infections.an oral form of vancomycin is used to treat pseudomembranous colitis. Vancomycin diffuses well into pleural, pericardial, synovial joint ascitic fluids.Normal T ½ of vancomycin is 6 to 10 hr , compared to over 200 hr in end-stage renal disease.

No switching!Remember that I.V. vancomycin can’t be used in place of oral vancomycin and vice versa. The two forms aren’t interchangeable.

Metabolism and excretionThe metabolism of vancomycin is minimal . About 90% of the dose is excreted unchanged in urine within 24 hours. 67

Antimicrobial spectrum of vancomycin

Some adverse effects of vancomycin

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Oral historyOral vancomycin is used for the patient with antibiotic-associated Clostridium difficile colitis who can’t take or has responded poorly to metronidazole.

The 1 in the 1-2 punchVancomycin, when used with an aminoglycoside, is also the treatment of choice for E. faecalis endocarditis in the patient who’s allergic to penicillin.

Drug interactionsVancomycin may increase the risk of toxicity when administered with other drugs toxic to the kidneys and organs of hearing, such as aminoglycosides, amphotericin B, bacitracin, cisplatin, colistin, and polymyxin B.

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Adverse reactions to vancomycin, although rare, include:1)hypersensitivity and anaphylactic reactions2)drug fever3)eosinophilia (an increased number of eosinophils)4)neutropenia5)hearing loss (transient or permanent), dose dependent ototoxicty s (as when it’s given with other ototoxic drugs).

Rash behavior(red man’s syndrome):-Severe hypotension may occur with rapid I.V. administration of vancomycin and may be accompanied by a red rash with flat and raised lesions on the face, neck, chest, and armsInfusion of 1 g or less should be given over 1 hour.

Adverse reactions to vancomycin

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Daptomycin is a cyclic lipopeptide antibiotic that is an alternative to other agents, such as linezolid and quinupristin/dalfopristin, for treating infections caused by resistant gram-positive organisms, including MRSA and vancomycin-resistant enterococci (VRE).

Mode of actionUpon binding to the bacterial cytoplasmic membrane, daptomycin induces rapid depolarization of the membrane, thus disrupting multiple aspects of membrane function and inhibiting intracellular synthesis of DNA, RNA, and protein.

Daptomycin is bactericidal, and bacterial killing is concentration dependent.

Daptomycin

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Antibacterial spectrumDaptomycin has a spectrum of activity limited to gram-positive organisms, which includes:- methicillin-susceptible methicillin-resistant S. aureuspenicillin resistant Strept.pneumoniaeStreptococcus pyogenesCorynebacterium jeikeiumE. faecalis E. faecium (including VRE)

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Adverse effects•The most common adverse effects reported in clinical trials included:- constipation, nausea, headacheinsomnia.Increased hepatic transaminases elevations in creatin phosphokinases

•Although no clinically significant interactions have been identified, it is recommended to temporarily discontinue 3-hydroxy-3-methylglutary coenzyme A reductase inhibitors (statins) while receiving daptomycin due to the potential for additive muscle toxicity.

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Quinupristin/dalfopristin is a mixture of two streptogramins in a ratio of 30 to70, respectively.

They are derived from a streptomycete and then chemically modified.

The drug is normally reserved for the treatment of vancomycin-resistant Enterococcus faecium (VRE).

Mechanism of action Each component of this combination drug binds to a

separate site on the 50S bacterial ribosome, forming a stable ternary complex.

Thus, they synergistically interrupt protein synthesis. The combination drug is bactericidal and has a long

postantibiotic effect.

Quinupristin/Dalfopristin

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Administration and fate of quinupristin/dalfopristin

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Antibacterial spectrumThe combination drug is active primarily against gram-positive cocci, including those resistant to other antibiotics (for example, methicillin-resistant staphylococci). Its primary use is in the treatment of E. faecium infections, including VRE strains. The drug is not effective against Enterococcus faecalis.

PharmacokineticsQuinupristin/dalfopristin is injected intravenously in a 5 percent dextrose solution (the drug is incompatible with saline medium). The combination drug penetrates macrophages and polymorphonucleocytes, a property that is important, because VRE are intracellular.

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Adverse effects1.Venous irritation: This commonly occurs when quinupristin/dalfopristin is administered through a peripheral rather than a central line.2.Arthralgia and myalgia: These have been reported when higher levels 2. of the drugs are employed.3.Hyperbilirubinemia: Total bilirubin is elevated in about 25 percent of patients, resulting from a competition with the antibiotic for excretion.Interactions: 1.Because of the ability of quinupristin/dalfopristin to inhibit the cytochrome P450 (CYP3A4)isozyme, 2.drug interaction with digoxin appears to occur by the same mechanism as that caused by erythromycin (lead to toxicities ).

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Linezolid is a totally synthetic oxazolidinoneIt was introduced recently to combat resistant gram-positive organisms, such as :-methicillin and vancomycin-resistant Staphylococcus aureus, vancomycin-resistant E. faecium and E. faecalis, Penicillin-resistant streptococci.

Mechanism of action•The drug inhibits bacterial protein synthesis by inhibiting the formation of the 70S initiation complex. •Linezolid binds to a site on the 50S subunit near the interface with the 30S subunit.

Linezolid

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Antimicrobial spectrum of linezolid.

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Adverse effectsLinezolid is well-tolerated, with some reports of gastrointestinal upset NauseaDiarrheaheadachesrashThrombocytopenia was found to occur in longer than 2 weeks use .

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The Aminoglycosides

The following are the aminoglycosides:-1) Amikacin sulfate2) Gentamicin sulfate3) Kanamycin sulfate4) Neomycin sulfate5) Paromomycin sulfate6) Streptomycin sulfate7) Tobramycin sulfate

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The Aminoglycosides

Mechanism of action • These are BACTERICIDAL.

• They inhibit protein synthesis in susceptible strains of gram-negative bacteria, leading to loss of functional integrity of the bacterial cell membrane, which causes cell death.

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Typical therapeutic applications of aminoglycosides

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The Aminoglycosides

Therapeutic Use of the Aminoglycosides:- infections caused by gram-negative bacilliserious nosocomial (hospital-acquired) infections,

such as gram-negative bacteremia, peritonitis, and pneumonia, in critically ill patients

urinary tract infections (UTIs) caused by enteric bacilli that are resistant to less toxic antibiotics, such as penicillins and cephalosporins

infections of the central nervous system (CNS) and the eye (treated with local instillation).

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The Aminoglycosides Serious adverse reactions limit the use of aminoglycosides include:1.neuromuscular reactions, ranging from peripheral nerve toxicity to neuromuscular blockade2.ototoxicity3.renal toxicity.Oral historyAdverse reactions to oral aminoglycosides include:1.nausea and vomiting2.diarrhea.

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The Aminoglycosides Drug to drug interactions• Diuretics- increased incidence of ototoxicity,

nephrotoxicity and neurotoxicity. • Anesthetics and Neuromusular blockers-

increased neuromuscular blockage and paralysis may be possible

• Penicillin- synergistic action• These drugs are contraindicated in known

allergies to aminoglycosides, in patients with renal failure, hepatic disease, pre-existing hearing loss, myasthenia gravis, Parkinson’s, pregnancy and lactation.

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The Macrolides

The macrolides are Azithromycin Clarithromycin Erythromycin Telithromycin

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The Macrolides

Mechanism of Action of the Macrolides

– They exert their effect by binding to the bacterial cell ribosomes and changing or altering protein production/function

– This will lead to impaired cell metabolism and division.

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The Macrolides

• Pharmacokinetics–Erythromycin is destroyed by the

gastric juice, which is why slats are added to stabilize the drug.

–Food does not interfere with the absorption of the macrolides.

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Administration and fate of the macrolide antibiotics properties of the macrolide antibiotics

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Typical therapeutic applications of macrolides

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The MacrolidesTherapeutic Use of Macrolides:-• It provides a broad spectrum of antimicrobial activity

against gram-positive and gram-negative bacteria, including Mycobacterium, Treponema, Mycoplasma, and Chlamydia.

• It’s also effective against pneumococci and group A streptococci. Staphylococcus aureus is sensitive to erythromycin; however, resistant strains may appear during therapy.

• Erythromycin is the drug of choice for treating Mycoplasma pneumoniae infections as well as pneumonia caused by Legionella pneumophila.

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The Macrolides

Adverse Effects of Macrolides• GI system- abdominal cramping, anorexia, diarrhea,

vomiting and pseudomembranous colitis. HEPATOTOXICITY can occur if the drug is taken in high doses with other hepatotoxic drugs.

• CNS- confusion, abnormal thinking and uncontrollable emotions.

• Hypersensitivity reactions

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Some adverse effects of macrolide antibioticsInhibition of the cytochrome P450 system by erythromycin, clarithromycin, andtelithromycin. 97

The Macrolides

Contraindications and Precautions in the Use of Macrolides:-

These agents are contraindicated in the presence of known allergy to any macrolide, because cross-sensitivity occurs.

Caution should be used in patients with hepatic dysfunction that could alter the metabolism of the drug;

In lactating women because of drug excretion in breast milk and in pregnant women because potential adverse effects on the developing fetus.

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The Lincosamides These agents are similar to the Macrolides but are

more toxic. 1. Clindamycin2. Lincomycin

Lincomycin is less effective than clindamycin and is rarely used.

Lincomycin shouldn’t be used in the treatment of minor infections but would be used to treat serious respiratory or skin infections in the patient who’s allergic to other antibiotics indicated for the infection.

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The LincosamidesPharmacokineticsClindamycin is absorbed well orally and distributed widely throughout the body. It’s metabolized by the liver and excreted by the kidneys and biliary pathways. The bioavilability of lincomycin is about 20% to 30% .food delays its absorption. Lincomycin is partially metabolized in the liver and is excreted in the urine, stool, and bile.

PharmacodynamicsClindamycin and lincomycin inhibit bacterial protein synthesis by inhibiting the binding of bacterial ribosomes. At therapeutic concentrations, clindamycin is primarily bacteriostatic against most organisms.

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PharmacotherapeuticsBecause of their potential for causing serious toxicity and pseudomembranous colitis, these drugs are limited to a few clinical situations in which safer alternative antibacterials aren’t available.1.Clindamycin is potent against most aerobic gram-positive organisms, including staphylococci, streptococci (except Enterococcus faecalis), and pneumococci.2.Clindamycin is effective against most clinically important anaerobes and is used primarily to treat anaerobic intraabdominal, pleural, or pulmonary infections caused by Bacteroides fragilis. 3.It’s also used as an alternative to penicillin in treating Clostridium perfringens infections.4.Clindamycin and lincomycin may be used as alternatives to penicillin in treating staphylococcal infections in a patient who’s allergic to penicillin.

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The LincosamidesSide effects and Adverse Reactions:-1. GIT- GI irritation, diarrhea2. Nausea, vomiting and stomatitis3. Allergic reactions4. Pseudomembranous colitis (most serious reaction to

clindamycin)

Drug Interactions• Lincomycin and clindamycin are incompatible with

aminophyline, phenytoin, barbiturates and ampicillin.

Pseudomembranous colitis syndrome can be fatal ,characterized by severe diarrhea, abdominal pain, fever, and mucus and blood in stool and requires prompt discontinuation of the drug as well as aggressive fluid and electrolyte management

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The TetracyclinesThese agents were first isolated from Streptomyces

The following are the tetracyclines:-– Short-acting tetracyclines

tetracyclineoxytetracycline

– Intermediate acting tetracyclinesdemeclocyclinemethacycline

– Long acting tetracyclinesdoxycyclineminocycline

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Typical therapeutic applications of tetracyclines

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The TetracyclinesPharmacodynamics:-

The tetracyclines inhibit protein synthesis in susceptible bacteria leading to the inability of the bacteria to multiply.

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The TetracyclinesContraindications and Precautions in the use of Tetracyclines It is not recommended for use in pregnancy and

lactation because the drug can affect the bones and teeth, causing permanent discoloration and sometimes arrest of growth.

Tetracyclines are also avoided in children less than 8 (eight) years of age because of the potential damage to the bones and permanent discoloration of the teeth.

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The TetracyclinesAdverse Effects of the Tetracycline• GI system- nausea, vomiting, diarrhea, abdominal pain, glossitis

and dysphagia.

• Fatal hepatotoxicity related to tetracycline’s irritating effect on the liver cells has been reported.

• Musculoskletal- Tetracyclines have an affinity for teeth and bones; they accumulate there, leading to weakening of the bone/teeth and permanent staining and pitting.

• Skin- photosensitivity and rash are expected.

• Less frequent- bone marrow depression, hypersensitivity, super infections, pain and hypertension

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Some adverse effects of tetracycline

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The Tetracyclines

Drug-Drug Interactions• Penicillin- if taken with tetracyclines, will decrease

the effectiveness of penicillin.• Oral contraceptives- if taken with tetracycline, will

have decreased effectiveness. • Digoxin- digoxin toxicity rises when tetracyclines are

used together

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The TetracyclinesDrug-Food Interaction• Dairy products- can complex with tetracycline

and render unabsorbable. • Tetracyclines should then be given on an

EMPTY stomach 1 hour before meals or 2-3 hours after any meal or other medications.

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Tigecycline is the first available member of a new class of antimicrobial agents called glycylcyclines.

Tigecycline, a derivative of minocycline, is structurally similar to the tetracyclines and has a broadspectrum activity against multidrug-resistant gram-positive pathogens, some gram-negative organisms, and anaerobic organisms.

Tigecycline is indicated for treatment of complicated skin and soft tissue infections as well as complicated intra-abdominal infections

Glycylcyclines

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Mechanism of actionTigecycline exhibits bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting protein translation.Antibacterial spectrumTigecycline exhibits expanded broad-spectrum activity that includes methicillin-resistant staphylococciMultidrug-resistant Streptococcus pneumoniae vancomycin-resistant enterococciextended-spectrum B-lactamase producing gram-negative bacteria Acinetobacter baumanniimany anaerobic organisms.

N.B. tigecycline is not active against Proteus, Providencia,and Pseudomonas species.

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Adverse effectsTigecycline is well tolerated, with the main adverse effects being similar to those of the tetracycline class include:- nausea and vomiting(most common)photosensitivitypseudotumor cerebridiscoloration of permanent teeth when used during tooth developmentfetal harm(teratogenic)

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• Chloramphenicol is active against a wide range of gram-positive and gram-negative organisms.

• because of its toxicity, its use is restricted to life-threatening infections for which no alternatives exist.

Mechanism of actionThe drug binds to the bacterial 50S ribosomal subunit and

inhibits protein synthesis at the peptidyl transferase reaction

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.

Chloramphenicol

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Mechanism of action of chloramphenicol

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Antimicrobial spectrumChloramphenicol, a broad-spectrum antibiotic, is active against other microorganisms, such as rickettsiae. Pseudomonas aeruginosa is not affected, nor are the chlamydiae.Chloramphenicol has excellent activity against anaerobes. The drug is either bactericidal or (more commonly) bacteriostatic, depending on the organism.Interactions: •Chloramphenicol is able to inhibit some of the hepatic mixed-function oxidases•It blocks the metabolism of such drugs as warfarin, phenytoin, tolbutamide, and chlorpropamide( elevating their concentrations and potentiating their effects).

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1- Gastrointestinal upsets, overgrowth of Candida albicans on mucous membranes.2- Anemias: Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogenase. Aplastic anemia is independent of dose and may occur after therapy has ceased.

3- Gray baby syndrome: Neonates have a low capacity to glucuronylate the antibiotic, and they have underdeveloped renal function . neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes.This leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis

The Fluoroquinolones

The fluoroquinolones are broad-spectrum antibiotics. They are usually manufactured synthetically and are associated with mild adverse reactions.

The examples are:1)Nalidixic acid2)ciprofloxacin3)ofloxacin4)norfloxacin5)Levfofloxacin6)Sparfloxacin

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Pharmacodynamics: Mechanism of action of the Fluoroquinolones

These agents enter the bacterial cell by diffusion through cell channel.

Once inside they interfere with the action of DNA enzymes (DNA gyrase) necessary for the growth and reproduction of the bacteria. This will lead to cell death.

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Administration and fate of the fluoroquinolones

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Summary of antimicrobial spectrum of quinolones

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Typical therapeutic applications of ciprofloxacin

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FluoroquinolonesAdverse Effects of the Fluoroquinolones• CNS- dizziness, insomnia, headache,

and depression related to possible effects on the CNS membrane.

• GI system- nausea, vomiting, diarrhea and dry mouth related to the direct effect on the GIT

• Hema- bone marrow depression related to the direct effect of the drug on the cells of the bone marrow that rapidly turn over.

• Other effects- skin reactions, rash, fever and photosensitivity

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• Contraindications and Precautions:-

a) Pregnancy and lactation are also contraindications.

b) These agents are found to cause significant damage to the cartilages such that they are given cautiously to growing children and adolescents less than 18 years of age

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Sulfonamides

The following are the sulfonamides:

1.Sulfamethoxazole2.Sulfadiazine

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Inhibition of tetrahydrofolate synthesis by sulfonamides and trimethoprim

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Sulfonamides

Pharmacodynamics–The sulfa drugs competitively block the

para-amino benzoic acid to prevent the synthesis of folic acid in susceptible bacteria that synthesize their own folates for the production of RNA and DNA.

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Some adverse reactions to sulfonamides

Administration and fate of the sulfonamides

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Sulfonamides

Contraindications and precautions

– These agents are contraindicated to patients with known allergy to sulfa drugs, sulfonylureas and thiazide diuretics because they share similar structures.

– It is not recommended for use in pregnancy because it can cross the placenta and cause birth defects and kernicterus.

– Lactating women who take these drugs will excrete them in the breast milk potentially causing kernicterus, diarrhea and rash in the newborn.

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Sulfonamides

Adverse Effects of the Sulfonamides• GI system- nausea, vomiting, diarrhea, abdominal pain,

anorexia, stomatitis and hepatic injury, which are all related to the direct irritation of the GIT and death of normal flora.

• Renal system- crystalluria, hematuria and proteinuria which can progress to a nephrotic syndrome.

• CNS- headache, dizziness, vertigo, ataxia, convulsions and depression related to drug effects on the nerves

• Hema- bone marrow depression related to drug effects on the cells of the bone marrow that turn over rapidly.

• Dermatologic effects- photosensitivity and rash and hypersensitivity

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Trimethoprim a potent inhibitor of bacterial dihydrofolate reductase, exhibits an antibacterial spectrum similar to that of the sulfonamides.

Trimethoprim is most often compounded with sulfamethoxazole, producing the combination called cotrimoxazole

Trimethoprim

Synergism between trimethoprim and sulfamethoxazole133

Typical therapeutic applications of co-trimoxazole (sulfamethoxazole plus trimethoprim).

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The anti tubercular

• Isoniazid• Rifampicin• Pyrazinamide• Ethambutol

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Mechanisms of actionIsoniazid Interferes with DNA

synthesis of bacterium

Rifampicin Interferes with RNA synthesis

Pyrazinamide Interferes with bacterial wall synthesis

Ethambutol Prevent multiplication

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Common Side effectsIsoniazid Interferes with B6

Peripheral neuritisRifampicin Red-orange discoloration of the

secretionsHepatitis

Pyrazinamide Hyperuricemia

Ethambutol Optic neuritis

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PrecautionsIsoniazid Liver impairment

Rifampicin Liver impairment

Pyrazinamide Liver impairmentGoutPregnancy

Ethambutol Liver impairmentChildren less than 6 years old

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General Responsibilities

• Advise patient to take the DRUGS as prescribed

• Multiple drugs are taken to prevent RESISTANCE

• Periodically check the liver function tests• Supplemental Intake of Vitamin B6

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An elderly diabetic patient is admitted to the hospital with pneumonia. The sputum culture stains for a gram-negative rod. The patient is started on IV ampicillin. Two days later, the patient is not improving, and the microbiology laboratory reports the organism to be a B-lactamase producing H. influenzae. What course of treatment is indicated?

A. Continue with the IV ampicillin.B. Switch to IV cefotaxime.C. Switch to oral vancomycin.D. Add gentamicin to the ampicillin therapy.

Study Questions

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A 70-year-old alcoholic male with poor dental hygiene is to have his remaining teeth extracted for subsequent dentures. He has mitral valve stenosis with mild cardiac insufficiency and is being treated with captopril, digoxin, and furosemide. The dentist decides that his medical history warrants prophylactic antibiotic therapy prior to the procedure and prescribes which of the following drugs?

A. Vancomycin.B. Amoxicillin.C. Tetracycline.D. Cotrimoxazole.E. Imipenem. 142

A patient with degenerative joint disease is to undergo insertion of a hip prosthesis. To avoid complications due to postoperative infection, the surgeon will pretreat this patient with an antibiotic. This hospital has a significant problem with MRSA. Which of the following antibiotics should the surgeon select?

A. Ampicillin.B. Imipenem/cilastatin.C. Gentamicin/piperacillin.D. Vancomycin.E. Cefazolin 143

A 25-year-old male returns home from a holiday in the Far East and complains of 3 days of dysuria and a purulent urethral discharge. You diagnose this to be a case of gonorrhea. Which of the following is appropriate treatment?

A. Ceftriaxone IM.B. Penicillin G IM.C. Gentamicin IM.D. Piperacillin/tazobactam IV.E. Vancomycin IV.

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A patient with a gunshot wound to the abdomen, which has resulted in spillage of intestinal contents, is brought to the emergency room. Which antibiotic would you select to effectively treat an infection due to Bacteroides fragilis?A. Aztreonam.B. Clindamycin.C. Gentamicin.D. Azithromycin.E. Doxycycline.

Children younger than 8 years of age should not receive tetracyclines because these agents:A. Cause rupture of tendons.B. Do not cross into the CSF.C. Are not bactericidal.D. Deposit in tissues undergoing calcification.E. Can cause aplastic anemia. 145

A pregnant woman was hospitalized and catheterized with a Foley catheter. She developed a urinary tract infection caused by Pseudomonas aeruginosa and was treated with gentamicin. Which of the following adverse effects was a risk to the fetus when the woman was on gentamicin?

A. Skeletal deformity.B. Hearing loss.C. Teratogenesis.D. Blindness.E. Mental retardation.

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A 46-year-old woman is in the intensive care unit for treatment of a vancomycin-resistant strain of Enterococcus faecium caused bacteremia. You want to limit the risk of drug interactions in this woman, who is receiving five other medications. Which one of the following antibiotics would you choose?A. Azithromycin.B. Clindamycin.C. Doxycycline.D. Linezolid.E. Quinupristin/dalfopristin.

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A 30-year-old male is diagnosed to be human immunodeficiency virus (HIV) positive. His CD4+ count is 200 cells/mm3 and his viral load is 10,000 copies/mL. In addition to receiving antiviral therapy, which of the following is indicated to protect him against pneumonia due to Pneumocystis jiroveci?A. Trimethoprim.B. Ciprofloxacin.C. Cotrimoxazole.D. Clindamycin.A 26-year-old young man presents with the symptoms of gonorrhea. Because this condition is often associated with an infection due to Chlamydia trachomatis, which of the following quinolones would be the best choice for treating him?A. Ciprofloxacin.B. Nalidixic acid.C. Norfloxacin.D. Levofloxacin.

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In which one of the following infections is ciprofloxacin ineffective?

A. Urinary tract infections due to a B-lactamase producing strain of Klebsiella.B. Pneumonia due to Streptococcus pneumoniae.C. Exacerbation of chronic bronchitis due to Moraxella catarrhalis.D. UTI due to Escherichia coli.E. UTIs due to Pseudomonas aeruginosa.

Sulfonamides increase the risk of neonatal kernicterus, because they:A. Diminish the production of plasma albumin.B. Increase the turnover of red blood cells.C. Inhibit the metabolism of bilirubin.D. Compete for bilirubin-binding sites on plasma albumin.E. Depress the bone marrow.

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Health & Medicine

Pharmacology of Antibiotics