• staphylococci
• steptococci
• enterococci

gram positives

gram negative

• E.coli
• klebseilla
• pseudomonas

atypicals

• chlamydia
• mycoplasm
• legionella

what is a theoretical benefit of targeting protein synthesis over cell wall destruction?

prevents release of toxins and chemicals from the cell thereby decreasing the inflammatoy response of the host to the bacteria

• erythromycin (macrolides)
• chloramphenical
• clindamycin

• tetracycline
• spectinomycin
• streptomycin
• gentamycin, tobramycin (aminoglycosides)
• aimikacin

• gentamycin
• amikacin

bind to 30S subunit

misreads/terminates genetic code

unable to penetrate gram + cell wall; works in SYNERGY with ß-lactams to gain entry into cell and halt synthesis

taken with ß-lactams because they cannot gain entry to gram + cells on their own to bind to the 30S subunit

what is the spectrum of activity for aminoglycosides on their own?

aminoglycosides=gram negative activity

they can act on gram positives only with the help of ß-lactams that compromise the integrity of the cell wall

• inactivated in acidic environments
  • NOT for use in abscesses
  • NOT for use in pneumonia (pH inhibits entry into lungs)

what are aminoglycosides especially good at treating?

high concentrations in the kidney and lung

aminoglycosides are great for UTIs

what are the main adverse effects of aminoglycosides?

• ototoxicity
  • high peak levels and duration in the ear
  • IRREVERSIBLE
  • cochlea: hearing loss
  • vestibule: balance loss
    
• nephrotoxicity/tubular necrosis
  • IRREVERSIBLE
  • increased risk with:
    • radiocontract
    • Amphotericin B
    • cyclosporin
    • vancomycin
  • variable damage
• MORAL OF THE STORY: cannot treat, and so PREVENT!!!!!

besides ototoxicity and nephrotoxicity, aminoglycosides present with another major adverse event. what is it and in what patients should aminoglycosides especially be avoided?

aminoglycosides can also cause a neuromuscular blockade.  as a result, these drugs should be avoided in patients with myasthenia gravis.

one outcome of aminoglycosides can also be respiratory depression that results from the neuromuscular blockade.

• gram negatives, when used alone
  • PSEUDOMONAS
• gram positives, when used along with ß-lactams (synergy), then covering:
  
  • S.aureus
  • Enterococci
• NO anaerobe coverage

outside of gram negative activity (when used alone), and gram positive activity (when used along with ß-lactams), what other microbes are aminoglycosides effective against?

• Mycobacterium (MTb)
• the plague
• tuleremia ("deer/rabbit fever"

• serious gram negative infections (ie: pseudomonas)
• rarely used alone (usually used in conjunction with ß-lactams to attack gram positives, too)
• IV administration only

• doxycycline
• tetracycline

• bind 30S subunit of ribosomes; blocks access of tRNA to mRNA
• gains entry to cell via LIPOPHILICITY of the drug --> GRAM NEGATIVE & GRAM POSITIVE activity

resistance against tetracyclines is common, limiting clinical activity; how is resistance acquired to bacteria againt the drug?

• PLASMID MEDIATED
• two mechanisms:
  • active efflux from bacterial cell (both gram negative and gram positive)
  • ribosomal protection proteins that bind the ribosome in a way that blocks tetracycline from binding, yet which does not disrupt protein synthesis (gram negative, gram positive, anaerobes)

what are some relevant details of tetracycline PK/PDs?

• BACTERIOSTATIC (since its RNA binding is *reversible*)
• dairy, Ca++ decrease absorption of the drugs
• binds to tissues undergoing calcification
  • concentrates in teeth, bones
  • DO NOT GIVE TETRACYCLINES TO PREGNANT WOMEN OR GROWING CHILDREN

in what group are tetracyclines contraindicated due to their preferential binding to tissues undergoing calcification?

• YOUNG CHILDREN (growing kids)
• PREGNANT WOMEN

DO NOT GIVE TETRACYCLINES

besides deposition of tetracycline in the bones and teeth (stained primary dentition, hypoplasia of teeth, and stunted growth), what is another common adverse event of tetracyclines?

• gram negatives
  • broad activity against community-acquired bugs
  • use limited by resistance
• gram positives
  • Staph (+ some CA-MRSA)
  • Strept
• some anaerobes
• some atypicals:
  • CHLAMYDIA
  • MYCOPLASMA (a type of bacteria that lacks a cell wall, and so is unaffected by penicillin and ß-lactams that target cell wall synthesis; causes atypical pneumonia among other infections...
    

what are the commonest clinical uses of tetracyclines?

most common tetracycline uses:

• bronchitis
• community-acquired pneumonia
• chlamydia

less common:

-lyme disease

-leptospirosis

-rickettsiae

-doxycycline: a malaria prophylaxis

-minocycline: acne

tigecycline is a commonly prescribed glycylcycline

• semi-synthetic derivative of tetracyclines; as such, similar mechanism as those drugs
  
  • reversibly binds 30S subunit of ribosome
  • inhibits bacterial protein translation/synthesis
• glycylcylines have some structural modifications that expand their spectrum of activity and oversome resistance commonly limiting for tetracycline use
  • rapid resistance may develop, still tho
  • mechanisms poorly understood

what are the commonest adverse events of glycylcyclines (tigecycline)?

• GI distress
• deposition in bone/teeth during calcification like tetracycline

what are notable exceptions to the broad spectrum of activity for glycylcylines?

glycylcyclines (tigecycline) have no activity against gram negatives:

• Pseudomonas
• Proteus

• gram negative (except pseudomonas, proteus)
• gram positive, including:
  • Staph, including MRSA
  • Strep
  • Enterococci, including VRE
• anaerobes, most

glycylcylines have VERY BROAD spectrum

• complicated skin/soft tissue infections
• complicated intra-abdominal infection
• community-acquired pneumonia

• IV-use ONLY
• ***remember there is no glycylcycline activity against PSEUDOMONAS OR PROTEUS***

• azithromycin
• clarithromycin
• erythromycin

• bind to 50S subunit
• blocks translocation --> inhibits bacterial protein synthesis

what are some types of microbial resistance against macrolides?

• decreased entry, permeability
• efflux pumps
• target site alterations
• enzymatic drug inactivation

what are special PK/PD considerations for macrolides?

• typically bacteriostatic, but may be bacteriocidal at high doses against some organisms like S. pyogenes, S. pneumoniae, H.influenzae
  
• wide tissue distribution
• azithromycin
  • long half life (less freq dosing possible)
• erythromycin
  • CYP450 metabolism
    • many drug-drug interactions

what are the most common macrolide adverse events?

• epigastric distress (erythromycin)
• QT prolongation (erythromycin)

• gram negatives, incld. community acquired
• gram positive
  • Staph
  • Strept (including pneumonococcus)
• anaerobes (some gram negative ones)
• atypicals:
  • mycoplasma
  • legionella
  • chlamydia

• CA-pneumonia/ bronchitis
• atypical pneumonia
• chlamydia
• travel's diarrhea
• mycobacterium avian complex (MAC) prophylaxis in HIV/AIDS

• mycobacterium avium complex (MAC) disease
• H. pylori

• binds to 50S subunit and blocks translocation
• same as MACROLIDES

• mediated by the erm-gene
• suspect if:
  • clindamycin sensitive, initially, AND
  • erythromycin resistant
• there is rapid development of clindamycin resistance *during* treatment

what is a common adverse event during clindamycin (lincosamides) treatment?

C. difficile associated disease

• NO GRAM NEGATIVE ACTIVITY
• gram positive
  • Staph, + CA-MRSA
  • Strep
• anaerobes
  • above the diaphragm (classic, but NOT absolute)
  • Bacteroides fragilis

• CA-pneumonia
• oral, ENT infections
• human bite wounds
• abscesses
• skin/soft tissue damage due to CA-MRSA