Mid - Antibiotics - Protein Synthesis Inhibitors

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Macrolides/Lincosamides

Back 1

The macrolides are a family of safe, bacteriostatic drugs that are generally used in the treatment of community acquired infections.
Erythromycin is the original agent and continues to be used in different iterations.

A second generation of these agents referred to as azalides have an extended spectrum of activity as well as different pharmacokinetics.
Azithromycin
Clarithromycin
Telithromycin
Lincosamides are limited to clindamycin, a drug primarily utilized for its anaerobic activity

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Macrolides/Azalides

Mechanism of Action

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Binds to the 50S ribosomal subunit reversibly blocking the binding of tRNA to the acceptor site. This blocks translocation of the peptide chain. Because in vitro studies also show macrolides interfering with binding of other protein synthesis inhibitors it is believed that these drugs (e.g., chloramphenicol) have overlapping binding sites

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Macrolides/Azalides

Mechanism of Resistance

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Bacteria may be macrolide resistant due to a permeability barrier (enterobacteriaceae).

Active efflux pumps can expel the drug in Gram positive species.

A single step mutation in the 50 rRNA gene can confer high level macrolide resistance in some species.

Modification of the 50S rRNA subunit decreases binding of erythromycin. This can be a plasmid mediated function.

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Macrolides/Azalides

Antibacterial spectrum

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Macrolides are active against Gram positive bacteria including streptococci, pneumococci, methicillin sensitive staphylococci.

The limited Gram negative spectrum includes bordetella and campylobacter.

The macrolides also have activity against mycoplasma, legionella, chlamydia and the treponemes.

Azalides have an increased spectrum that includes activity against hemophilus species, Mycobacterium avium intracellulare (MAI) and depending on the azalide increased activity against Gram positives (clarithromycin) or Gram
negatives (azithromycin)

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Macrolides/Azalides

Pharmacology

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Macrolides are generally given orally. Because they are not acid stable they are generally prepared with an acid resistant coating. Intravenous preparations are available for more serious infections. The t1/2 is 1.4h and for the azalides this is considerably extended allowing for single or twice daily therapy. This family of agents achieves good distribution and, of note, achieves high intracellular concentrations (especially the azalides).

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Macrolides/Azalides

Toxicity

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Toxicity is limited. GI symptoms (due in part to the role of macrolides as a motilin receptor agonist) are more common with macrolides than azalides.

Rare cholestatic hepatitis
Prolonged QT syndrome (primarily with erythromycin). Care must be taken when prescribing this medication to patient with a history of arrythmias.

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Macrolides/Azalides

Indications for use

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Atypical community-acquired pneumonia (mycoplasma, legionella, chlamydia infections); pertussis, ampylobacter gastroenteritis and MAI.

Legionnaires' disease

Second line for skin and soft tissue infections not due to MRSA. Also frequently used for upper respiratory tract infections (sinusitis, otitis media, bronchitis)

There is an investigational role in the use of these drugs as anti-inflammatory agents in cystic fibrosis and in the prevention of atherosclerotic cardiovascular disease.

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Aminoglycosides

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"A mean guy"

Bactericidal agents that are used for the treatment of serious infections. They are not used as single agents because of concerns about the emergence of resistance.

In addition they have a very narrow therapeutic to toxic ratio

Aminoglycosides must diffuse across the cell wall to enter the bacterial cell, so they are often used with penicillin, which breaks down this wall to facilitate diffusion

Most of the drugs end with -mycin:
Streptomycin
Gentamicin
Tobramycin
Amikacin (no mycin)
Neomycin
Netilmicin

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Aminoglycosides

Mechanism of Action

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A rapidly bactericidal agent with multiple mechanisms of action. The primary target is the 30S ribosome causing premature chain termination and RNA codon misreading. In addition causes leakage of the outer membrane of Gram negatives. The basis for the bactericidal activity is not completely understood.

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Aminoglycosides

Mechanism of Resistance

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The principal means of resistance is aminoglycoside modifying enzymes. These enzymes such as the adenyltransferases or phosphotransferases modify the aminoglycoside rendering them ineffective.
The genes for these enzymes are often plasmid borne and as a result are readily transferred among different bacterial species.
An additional mechanism of resistance is diminished uptake of the aminoglycoside via mutations in the electrochemical gradient.
Anaerobes are resistant because they lack an O2 dependent transport system

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Aminoglycosides

Antibacterial spectrum

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Aminoglycosides have a somewhat limited spectrum of activity. In general, they kill aerobic gram-negative enteric organisms. They are active against Enterobacteriaceae, pseudomonas species (including pseudonomas aeruginosa), and Gram positive bacteria including staphylococci and streptococci. Some of the aminoglycosides are active against mycobacteria.

They have no activity against anaerobes.

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Aminoglycosides

Pharmacology

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Aminoglycosides are primarily used for parenteral therapy. There is reasonable distribution into tissues because of its low protein binding and water solubility.

Penetration across the blood brain barrier is poor as is penetration into bronchial secretions.

Aminoglycosides are excreted virtually unchanged in the urine.

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Aminoglycosides

Toxicity

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"A mean guy" (aminoglycoside). Remember a mean boxer that hits a guy in the ear, in the kidneys, and knocks the guy out cold, causing neuromuscular block.

These drugs have significant toxicity.

This includes nephrotoxicity in 5-25% of patients, ototoxicity including both cochlear and vestibular damage, and, infrequently, neuromuscular blockade.

To reduce the risks of these complications drug levels are generally monitored in subjects with renal disease.

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Aminoglycosides

Indications for use

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Empiric combination therapy for life-threatening infections. Used as combination therapy for resistant bacterial infections, and combination (synergy) therapy for enterococcal infections that require bactericidal activity.
– Enterococcal endocarditis
– Pseudomonas infections

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Tetracyclines

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"The Tet offensive"

The tetracycline class of antibiotics is a large family of broad spectrum, bacteriostatic agents that have a limited but important role in the armamentarium of antibacterial agents.

Drug is used for all diseases you would expect a young soldied in the Tet offensive to get by crawling around in the jungle and mingling with prostitutes on leave.

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Tetracyclines

Mechanism of Action

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The primary target is the 30S ribosome, preventing binding of aminoacyl tRNA to the acceptor (A) site on mRNA.

Front 17

Tetracyclines

Mechanism of Resistance

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The primary mechanism of resistance to tetracyclines is decreasing penetration or increasing export of the drug via an efflux pump. This mechanism may be plasmid mediated and also confers resistance to all members of the class.

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Tetracyclines

Antibacterial spectrum

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Although these drugs have Gram positive activity, including pneumococcus, streptococci and enterococci, they are rarely used because of resistance. They have activity against Gram negatives – E. coli, but not other Enterobacteriaceae, neisseria, hemophilus and some shigella. They are also active against mycoplasma, rickettsia, legionella, spirochetes and chlamydia.

Drug is used for all diseases you would expect a young soldied in the Tet offensive to get by crawling around in the jungle and mingling with prostitutes on leave.
1) Venereal disease caused by Chlamydia trachomatis
2) Walking pneumonia caused by Mycoplasma pneumoniae (used as an alternative to erythromycin)
3) Animal and tick-borne diseases caused by Brucella and Rickettsia
4) Doxycycline also works wonders for acne

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Tetracyclines

Pharmacology

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Most tetracyclines are administered orally. There are both short and long acting agents. Most are lipophilic and have excellent tissue distribution. The most commonly used tetracyclines, minocycline (metabolized in the liver) and doxycycline (inactivated in the intestine), are cleared by nonrenal routes.

Tetracycline chelates with cations in milk and milk products, aluminum hydroxide, Ca++, and Mg++. When chelatede, it will pass through the intestine without being absorbed. Doxycycline is a tetracycline that chelates cations poorly and is thus better absorbed with food.

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Tetracyclines

Toxicity

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Although generally well tolerated, there is a long list of potential side effects. These include photosensitivity, discoloration of children’s teeth, hepatotoxicity and hypersensitivity reactions.

Picture a Vietcong soldier involved in the Tet offensive:
1) the soldier is very nervous during the Tet offensive so he had GI irritation wtih nausea, vomiting, and diarrhea
2) A grenade has blown up near him, burning his skin like a sunburn. Phototoxic dermatitis is a skin inflammation on exposure to sunlight
3) Shrapnel has struck his kidney and liver: renal and hepatic toxicity. These AEs are rare and usually occur in pregnant women receiving high doses by the IV route
4) Dark discolored teeth of the soldier. The drug will chelate to the calcium in the teeth and bones of babies and children under the age 7, resulting in brown teeth and depressed bone growth. Don't give the drug to pregnant women or their baby's teeth will look like those of the soldier.

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Tetracyclines

Indications for use

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Their principal role is for treatment of lyme disease, community- acquired pneumonia and acne.

Treatment of chlamydia, mycoplasma, brucella, vibrio, helicobacter, rickettsia, borrelia, ehrlichia (anaplasma) infections
Mycobacterium marinum infections
Acne
Skin and soft tissue infections due to methicillin resistant
staphylococci
• Rarely the first drug of choice

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Antibiotics that cover Psuedomonas aeruginosa

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Antipseudomonal penicillins
-Ticarcillin
-Timentin (ticarcillin & clavulanate)
-Piperacillin
-Zosyn (piperacillin & tazobactam)
-Carbenicillin

3rd Generation cephalosporins
-Ceftazidime
-Ceftizoxime
-Cefoperazone

Imipenem
Aztreonam

Quinolones
-Ciprofloxacin

Aminoglycosides
-Gentamicin
-Tobramycin
-Amikacin

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Antibiotics that cover the anaerobes (including Bacteroides fragilis)

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Penicillins with beta-lactamase inhibitor
-Augmentin (amoxicillin + clavulanate)
-Timentin (Ticarcillin + clavulanate)
-Unasyn (ampicillin + sulbactam)
-Zosyn (pipericillin +tazobactam)

2nd generation cephalosporins
-Cefoxitin
-Cefotetan
-Cefmetazole

Imipenem, Meropenem, Ertapenem

Chloramphenicol
Clindamycin
Metronidazole
Moxi Floxacin
Tigecycline

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Antibiotics that inhibit protein synthesis

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CLEan TAG

CLEan : 50s ribosome
C for Chloramphenicol and Clindamycin
L for Linezolid
E for Erythromycin

TAG for 30s
T for Tetracycline
AG for Aminoglycosides

All of the above, except Aminoglycosides are orally absorbed. Aminoglycosides amust be given IM or IV for systemic treatment of infections. (Tigecycline, the newest tetracycline is also only available in IV formulation)

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Linezolid

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Sole member of the Oxazolidinones class of bacteriostatic agents.

"The Godzilla Lizard" stamping out resistant gram positive bugs

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Linezolid

Mechanism of Action

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This family of drugs is active at the 50S ribosomal subunit. It inhibits formation of the initiation complex.

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Linezolid

Antibacterial spectrum

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It is active against Gram positive bacteria including MRSA and all vancomycin resistant enterococci.

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Linezolid

Route of administration

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It has the pharmacological advantage of being available both orally (with excellent absorption) and parenterally.

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Linezolid

Mechanism of Resistance

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Resistance has been described occurring by mutation of the ribosomal binding site.

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Linezolid

Adverse effects

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The drug is well distributed and well tolerated. Bone marrow supression, like thrombocytopenia and myelosuppression have occurred with prolonged administration (> two weeks therapy). Headaches and GI irritation are also commonly reported side effects.

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Linezolid

Usage

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Linezolid is frequently used in combination with a broad spectrum beta-lactam for empiric coverage of hospital acquired pneumonia and in documented S. aureus infections including MRSA. Also VRE.

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Clindamycin

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Lincosamide class (only drug in class).

Used against anaerobic bacteria

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Streptomycin

Back 33

Aminoglycoside

Oldest drug in class, many bugs are resistant to it

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Gentamicin

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Aminoglycoside

Most commonly used aminoglycoside. It is combined with penicillin to treat in-hospital infections. Also many bugs resistant to it.

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Tobramycin

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Aminoglycoside

Good against the terrible Pseudomonas aeruginosa

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Amikacin

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Aminoglycoside

Broadest spectrum aminoglycoside and is good for hospital-acquired (nosocomial) infections that have developed resistance to other drugs while in the hospital

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Neomycin

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Aminoglycoside

Very broad coverage but is too toxic, so it is used topically for skin infections

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Netilimicin

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Aminoglycoside

Preoperative coverage for GI surgery. Given orally before GI surgery because it cruises down the GI tract without being absorbed, killing the local inhabitants. This prevents spilling of organisms during surgery into the sterile peritoneal cavity.

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Streptogramins

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Combination of two drugs derived from pristinamycin. The first is quinupristin and the second is dalfopristin.

The drug is bactericidal if the isolate is macrolide susceptible.

It is only available parenterally.

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Streptogramins

Mechanism of action

Back 40

Protein synthesis inhibitors working at the 50S ribosomal subunit.

Front 41

Streptogramins

Antibacterial spectrum

Back 41

This combination is used exclusively to treat resistant Gram positive infections including vancomycin resistant enterococci (only E. faecium, not E. faecalis) and complicated methicillin resistant S. aureus (MRSA) infections where vancomycin cannot be used.

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Streptogramins

Mechanism of resistance

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Resistance has occurred primarily by ribosomal modification (methylation). This can be plasmid mediated.

Front 43

Streptogramins

Toxicity

Back 43

Toxicity includes phlebitis (inflammation of vein)/pain at the infusion site and arthralgias/myalgias which can be quite bothersome. Also hyperbilirubinemia

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Chloramphenicol

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Used mainly in the developing world

"The Chlorine"

Broad spectrum agent. Kills most clinically impt bacteria, liking pouring chlorine on them. Gram positive, gram-negative, and anaerobes (including bacteroides fragilis) are all susceptible.

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Chloramphenicol

Mechanism of Action

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It binds to the 50S ribosome preventing attachment to the acceptor (A) site on mRNA.

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Chloramphenicol

Adverse effects

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Chloramphenicol causes a dose related marrow depression (reversible and typically only causes anemia) and rarely aplastic anemia (irreversibly wipes out the bone marrow and is usually fatal) that is idiosyncratic. In neonates the Gray baby syndrome was a concern. Babies are unable to fully conjugate chloramphenical in the liver or excrete it through the the kidney, resulting in very high blood levels. Leads to vasomotor collapse (shock), abdominal distention, and cyanosis, which appears as an ashen gray color.

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Chloramphenicol

Indications

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Due to serious side effects, its use is limited:
Used to treat bacterial meningitis when the organism is not yet known and the patient has severe allergies to penicillin, including cephalosporins. It achieves high concentrations following oral administration including in the CSF. It has activity against agents that cause meningitis including pneumococcus, hemophilus and neisseria.

Used in young children and pregnant women who have Rocky Mountain spotted fever who cannot be treated with tetracycline due to the side effects of tetracycline

Front 48

Tigecycline

Back 48

Tetracycline derivative, is the first of a new class of antibiotics, with a similar broad spectrum of activity as the tetracyclines, but a reduced propensity to induce resistance.

Available only as IV.

Indicated for use in complcated skin and soft tissue infections and for the empiric treatment of intra-abdominal infections.

Has activity against MRSA, VRE.

Side effect is GI upset

Front 49

Spectinomycin

Back 49

"Spectacular Spectinomycin"

Not an aminoglycoside.

Inhibits the 30s ribosome to inhibit protein synthesis

Given as IM injection

Used to treat Neisseria gonorrhea, as an alternative to penicillin and tetracycline (doxycycline), since many strains are resistant

Side effects are infrequent and minor

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Treatment of gonorrhea urethritis

Back 50

Neisseria gonorrhea are gram negative, kidney shaped diplococci inside white blood cells

Treatment options:
1) Ceftriaxone (3rd gen cephalosporin, 1 IM injection) and doxycycline for the Chlamydia (Azithromycin can be used as an alternative to doxycycline)

2) Quinolone (ciprofloxacin, ofloxacin, 1 oral dose) + doxycycline

3) Spectinomycin (1 time IM injection) + doxycycline

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Macrolides/Azalides

Drug interactions

Back 51

erythromycin > clarithromycin interferes with the cytochrome P450 enzymes leading to increased levels of other drugs e.g. dilantin, warfarin, cyclosporine

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Clindamycin

Back 52

Lincosamide class (only drug in class).

Inhibits 50s ribosome to inhibit protein synthesis

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Clindamycin

Toxicity

Back 53

Diarrhea, allergy

Front 54

Clindamycin

Spectrum / Indications

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Bacteristatic activity against Spectrum - Gram positive bacteria
and anaerobes - also toxoplasma

Indications - Penicillin-resistant anaerobic infections

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Clindamycin

Pharmacology

Back 55

High bone concentrations

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Aminoglycosides

Route of administration / Metabolism

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Give parenterally

Minimal absorption in oral administration

Not metabolized, excreted by the kidney