Clindamycin

mechanism of action Clindamycin binds to the 50S subunit of bacterial ribosomes and suppresses protein synthesis. Although clindamycin, erythromycin, and chloramphenicol are not structurally related, they act at sites in close proximity (Figures 46-2 and 46-3), and ribosome binding by one of these drugs may inhibit the interaction of the others. Macrolide resistance due to ribosomal methylation also may produce resistance to clindamycin. Because clindamycin does not induce the methylase, there is cross-resistance only if the enzyme is produced constitutively. Clindamycin is not a substrate for macrolide efflux pumps; thus, strains that are resistant to macrolides by this mechanism are susceptible to clindamycin.

antibacterial activity Clindamycin resembles erythromycin in its in vitro activity against susceptible strains of pneumococci, S. pyogenes, and viridans streptococci. Ninety percent or more of strains of streptococci, including some that are macrolide-resistant, remain susceptible to clindamycin. Methicillin-susceptible strains of S. aureus usually are susceptible to clindamycin, but methicillin-resistant strains of S. aureus and coagulase-negative staphylococci frequently are resistant.

Clindamycin is more active than erythromycin or clarithromycin against anaerobic bacteria, especially B. fragilis, but resistance increasingly is encountered. Between 10—20% of clostridial species other than C. perfringens are resistant. Strains of Actinomyces israelii and Nocardia asteroides are sensitive. Essentially all aerobic gram-negative bacilli are resistant. M. pneumoniae is resistant. Clindamycin plus primaquine and clindamycin plus pyrimethamine are second-line regimens for Pneumocystis jiroveci pneumonia and T. gondii encephalitis, respectively.

absorption, distribution, and excretion

Absorption Clindamycin is nearly completely absorbed following oral administration. Food does not affect absorption significantly. The t1/2 of the antibiotic is ~3 hours.

Clindamycin palmitate, an oral prodrug, is hydrolyzed rapidly in vivo. Its absorption is similar to clindamycin. The phosphate ester of clindamycin, given parenterally, also is rapidly hydrolyzed to the active parent compound.

Distribution Clindamycin is widely distributed in many fluids and tissues, including bone. Significant concentrations are not attained in CSF, but concentrations sufficient to treat cerebral toxoplasmosis are achieved. The drug readily crosses the placenta. Ninety percent or more of clindamycin is bound to plasma proteins. Clindamycin accumulates in polymorphonuclear leukocytes and alveolar macrophages and in abscesses.

Excretion Only ~10% of clindamycin is excreted unaltered in the urine; small quantities are found in the feces. However, antimicrobial activity persists in feces for at least 5 days after therapy is stopped and growth of clindamycin-sensitive microorganisms may be suppressed for 2 weeks.

Clindamycin is inactivated by metabolism to N-de-methylclindamycin and clindamycin sulfox-ide, which are excreted in the urine and bile. Accumulation of clindamycin can occur in patients with severe hepatic failure, and dosage adjustments may be required.

therapeutic uses The oral dose of clindamycin (cleocin) for adults is 150-300 mg every 6 hours; for severe infections, it is 300-600 mg every 6 hours. Children should receive 8-12 mg/kg/day of clindamycin palmitate hydrochloride (cleocin pediatric) in three or four divided doses, or for severe infections, 13-25 mg/kg/day. However, children weighing <10 kg should receive half teaspoonful of this preparation (37.5 mg) every 8 hours as a minimal dose.

For serious infections due to aerobic gram-positive cocci and the more sensitive anaerobes, intravenous or intramuscular administration is recommended in dosages of 600—1200 mg/day, divided into three or four equal doses for adults. Clindamycin phosphate (cleocin phosphate) is available for intramuscular or intravenous use. For more severe infections, particularly those proven or suspected to be caused by B. fragilis, Peptococcus, or Clostridium species other than C. perfrin-gens, parenteral administration of 1.2—2.4 g/day of clindamycin is suggested. Daily doses as high as 4.8 g have been given intravenously to adults. Children should receive 10-40 mg/kg/day in three or four divided doses; in severe infections, a minimal daily dose of 300 mg is recommended, regardless of body weight.

Although many infections with gram-positive cocci respond to clindamycin, the high incidence of diarrhea and the occurrence of pseudomembranous colitis limit its use to infections where it is clearly superior to other agents. Clindamycin is particularly valuable for anaerobic infections, especially those due to B. fragilis. Clindamycin is not predictably useful for the treatment of bacterial brain abscesses; metronidazole, in combination with penicillin or a third-generation cephalosporin, is preferred.

Clindamycin is the drug of choice for lung abscess and anaerobic lung and pleural space infections. Clindamycin (600-1200 mg given intravenously every 6 hours) in combination with pyrimethamine (a 200-mg loading dose followed by 75 mg orally each day) and leucovorin is effective for treatment of encephalitis caused by T. gondii in patients with AIDS. Clindamycin (600 mg intravenously every 8 hours, or 300-450 mg orally every 6 hours for less severe disease) in combination with primaquine (15 mg of base once daily) is useful for mild-to-moderate cases of P. jiroveci pneumonia in AIDS patients.

Clindamycin also is available as a topical solution, gel, or lotion (cleocin t, others) and as a vaginal cream (cleocin). It is effective topically (or orally) for acne vulgaris and bacterial vaginosis.

untoward effects The incidence of diarrhea associated with clindamycin ranges from 2-20%. A number of patients have developed pseudomembranous colitis caused by C. difficile toxin, with abdominal pain, fever, and bloody diarrhea. This syndrome may be lethal. Drug discontinuation and treatment with metronidazole or vancomycin usually is curative, but relapses can occur. Agents that inhibit peristalsis (e.g.,opioids) may worsen the condition.

Rashes occur in ~10% of patients treated with clindamycin and may be more common in HIV-infected patients. Other uncommon reactions include reversible elevation of serum transaminases, granulocytopenia, thrombocytopenia, and anaphylactic reactions. Local thrombophlebitis may follow intravenous administration. Clindamycin may potentiate the effect of a neuromuscular blocking agent administered concurrently.

QUINUPRISTIN/DALFOPRISTIN

Quinupristin/dalfopristin (synercid) combines quinupristin, a streptogramin B, with dalfopristin, a streptogramin A, in a 30:70 ratio. These compounds are more soluble derivatives of pristinamycin and thus are suitable for intravenous administration.

antibacterial activity Quinupristin/dalfopristin is active against gram-positive cocci and organisms responsible for atypical pneumonia (e.g., M. pneumoniae, Legionella spp., and Chlamydia pneumoniae), but largely inactive against gram-negative organisms. The combination is bactericidal against streptococci and many strains of staphylococci, but bacteriostatic against E. faecium.

mechanism of action Quinupristin and dalfopristin are protein synthesis inhibitors that bind to the 50S ribosomal subunit. Quinupristin binds at the same site as macrolides and also inhibits polypeptide elongation. Dalfopristin binds at an adjacent site, changing the conformation of the 50S ribosome; this synergistically enhances the binding of quinupristin at its target site and also directly interferes with polypeptide-chain formation. The synergistic binding to the ribosome often results in bactericidal activity.

resistance Resistance to quinupristin is mediated by genes encoding a ribosomal methy-lase that prevents binding of drug to its target or encoding lactonases that inactivate type B strep-togramins. Resistance to dalfopristin is mediated by genes that encode acetyltransferases, which inactivate type A streptogramins, or by staphylococcal genes that encode ATP-binding efflux proteins that pump type A streptogramins out of the cell. Resistance determinants are located on plas-mids that may be transferred by conjugation. Resistance to quinupristin/dalfopristin always is associated with a resistance gene for type A streptogramins. Methylase-encoding genes can render the combination bacteriostatic instead of bactericidal, making it ineffective in infections where bactericidal activity is necessary (e.g., endocarditis).

absorption, distribution, and excretion Quinupristin/dalfopristin is administered by intravenous infusion over at least 1 hour. The t1/2 is 0.85 hour for quinupristin and 0.7 hour for dalfopristin. The volume of distribution is 0.87 L/kg for quinupristin and 0.71 L/kg for dalfopristin. Hepatic metabolism by conjugation is the principal means of clearance, with 80% of an administered dose eliminated by biliary excretion. Renal elimination of active compound accounts for most of the remainder. No dosage adjustment is necessary for renal insufficiency. Pharmacokinetics are not significantly altered by peritoneal dialysis or hemodialysis. Hepatic insufficiency increases the plasma AUC of active component and metabolites by 180% for quinupristin and 50% for dalfopristin.

therapeutic uses Quinupristin/dalfopristin is approved in the U.S. for treatment of infections caused by vancomycin-resistant strains of E. faecium and complicated skin and skin-structure infections caused by methicillin-susceptible strains of S. aureus or S. pyogenes. In Europe, it also is approved for treatment of nosocomial pneumonia and infections caused by methicillin-resistant strains of S. aureus. Cure rates for a variety of infections caused by vancomycin-resistant E. faecium were ~70% with quinupristin/dalfopristin at a dose of 7.5 mg/kg every 8-12 hours. Quinupristin/dal-fopristin should be reserved for treatment of serious infections caused by multiple-drug-resistant gram-positive organisms such as vancomycin-resistant E. faecium.

untoward effects The most common side effects are pain and phlebitis at the infusion site, which are minimized by infusion through a central venous catheter. Arthralgias and myalgias are more common in patients with hepatic insufficiency and are managed by reducing the dosing frequency from every 8 to every 12 hours. Quinupristin/dalfopristin inhibits CYP3A4. Coadministration of other CYP3A4 substrates with quinupristin/dalfopristin may cause significant toxicity. Caution and monitoring are recommended for drugs in which the toxic therapeutic window is narrow or for drugs that prolong the QTc interval.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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Responses

  • marcus
    Can clindamycin cause high blood pressure?
    2 years ago
  • george
    Does clindamycin raise blood pressure?
    1 year ago
  • Matthias
    Can clindamycin make blood pressure go up in a 70 year oldhealthtap?
    7 months ago
  • T Longhole
    Does clindamycin cause elevated blood pressure?
    2 months ago

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