MISCELLANEOUS ANTIBIOTICS

AARON DHANUKDHARRIESINGH

FLUOROQUINOLONES

FLUOROQUINOLONES • Novel group of synthetic antibiotics developed

in response to growing resistance• The fluorinated quinolones (FQs) represent a

major therapeutic advantages: Broad spectrum of activity Improved PK properties – excellent bioavailability,

tissue penetration, prolonged half-lives Overall safety

• Disadvantages: resistance, expense

MECHANISM OF ACTION: QUINOLONES

• Quinolone antibiotics inhibit bacterial DNA gyrase (Gram negative bacteria) or Topoisomerase IV (Gram positive bacteria) This blocks bacterial DNA synthesis

USES OF THE QUINOLONE ANTIBIOTICS

• Urinary Tract Infections: fluoroquinolones are more effective than trimethoprim-sulfamethoxazole

• Prostatitis• Respiratory tract infections• Gastrointestinal and Abdominal Infections

CLINICAL USES

Gram-positive – newer FQs with enhanced potency

• Methicillin-susceptible Staphylococcus aureus

• Streptococcus pneumoniae (including PRSP)

• Group A/B/C/G and viridans streptococci – limited activity

• Enterococcus sp. – limited activity

Gram-Negative – all FQs have excellent activity Enterobacteriaceae Including - E. coli, Klebsiella sp, Enterobacter sp,

Proteus sp, Salmonella, Shigella, Serratia marcescens, etc.• H. influenzae, M. catarrhalis, Neisseria sp.• Pseudomonas aeruginosa – significant resistance has

emerged; ciprofloxacin and levofloxacin with best activity

Atypical Bacteria – all FQs have excellent activity against atypical bacteria including:

• Legionella pneumophila - DOC• Chlamydia sp.• Mycoplasma sp.• Ureaplasma urealyticum

Other Bacteria – Mycobacterium tuberculosis, Bacillus anthracis

FLUOROQUINOLONESADVERSE EFFECTS

• Gastrointestinal – 5 % Nausea, vomiting, diarrhea, dyspepsia

• Central Nervous SystemHeadache, agitation, insomnia, dizziness, rarely,

hallucinations and seizures (elderly)• Hepatotoxicity

LFT elevation (led to withdrawal of trovafloxacin) • Phototoxicity (uncommon with current FQs)

More common with older FQs• Cardiac

Variable prolongation in QTc interval Led to withdrawal of grepafloxacin, sparfloxacin

FLUOROQUINOLONESADVERSE EFFECTS

• Articular Damage Arthopathy including articular cartilage damage,

arthralgias, and joint swelling Observed in toxicology studies in immature dogs Lead to contraindication in pediatric patients and

pregnant or breastfeeding women

• Other adverse reactions: tendon rupture, dysglycemias, hypersensitivity

VANCOMYCIN

Vancomycin is called a ‘glycopeptide’, meaning that it is a cyclic peptide, with sugar residues attached to it.

DISCOVERY

Vancomycin was discovered in a soil sample sent to the pharmaceutical company Eli Lilly by a missionary in Borneo in the 1950’s.

VANCOMYCINMECHANISM OF ACTION

• Inhibits bacterial cell wall synthesis at a site different than beta-lactams

• Inhibits synthesis and assembly of the second stage of peptidoglycan polymers

• Binds firmly to D-alanyl-D-alanine portion of cell wall precursors

MECHANISM OF ACTION OF VANCOMYCIN

Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits, preventing them from being incorporated into the cell wall by penicillin-binding proteins (PBPs). In many vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is replaced with D-alanyl-D-lactate, which is not recognized by vancomycin.

VANCOMYCINSPECTRUM OF ACTIVITY

Gram-positive bacteria• Methicillin-Susceptible AND Methicillin-Resistant

S. aureus and coagulase-negative staphylococci• Streptococcus pneumoniae (including PRSP),

viridans streptococcus, Group A/B/C/G streptococcus

• Enterococcus sp.• Corynebacterium, Bacillus. Listeria,

Actinomyces• Clostridium sp. (including C. difficile),

Peptococcus, PeptostreptococcusNo activity against gram-negative aerobes or

anaerobes

CLINICAL USES

• Infections due to methicillin-resistant staph including bacteremia, empyema, endocarditis, peritonitis, pneumonia, skin and soft tissue infections, osteomyelitis

• Serious gram-positive infections in -lactam allergic patients

• Infections caused by multidrug resistant bacteria

• Endocarditis or surgical prophylaxis in select cases

• Oral vancomycin for refractory C. difficile colitis

VANCOMYCINADVERSE EFFECTS

Red-Man Syndrome • flushing, pruritus, erythematous rash on face and upper

torso• related to RATE of intravenous infusion; should be infused

over at least 60 minutes• resolves spontaneously after discontinuation• may lengthen infusion (over 2 to 3 hours) or pretreat with

antihistamines in some cases

VANCOMYCINADVERSE EFFECTS

• Nephrotoxicity and Ototoxicity• rare with monotherapy, more common when administered

with other nephro- or ototoxins• risk factors include renal impairment, prolonged therapy,

high doses, ? high serum concentrations, other toxic meds• Hematologic - neutropenia and thrombocytopenia

with prolonged therapy• Thrombophlebitis

DAPTOMYCIN

• Daptomycin is called a lipopeptide antibiotic • Approved for use in 2003• Lipid portion inserts into the bacterial cytoplasmic membrane

where it forms an ion-conducting channel.• Marketed under the trade name Cubicin

Lipophilic Tail

DAPTOMYCIN

Mechanism of ActionDaptomycin binds to components of the

cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein.

Step 1: Daptomycin binds to the cytoplasmic membrane in a calcium-dependent manner

Step 2: Daptomycin oligomerizes, disrupting the membrane

Step 3: The release of intracellular ions and rapid death

USES OF DAPTOMYCIN (CUBICIN)• Daptomycin is active against many aerobic Gram-

positive bacteria

• Includes activity against MRSA, penicillin-resistant Streptococcus pneumoniae, and some vancomycin-resistant Enterococci (VRE)

• Daptomycin is not active against Gram negative strains, since it cannot penetrate the outer membrane.

• IV only• Primarily been used to treat skin and soft tissue infections

(complicated skin and skin structure infections, including MRSA).

• Also approved for S. aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis

• Poor activity in the lung, thus not used for pneumonia

DAPTOMYCINADVERSE EFFECTS

• Hematologic: Anemia (2% to 13%) • Gastrointestinal:

• Diarrhea (5% to 12%) • vomiting (3% to 12%) • constipation (6% to 11%)

TRIMETHOPRIM/SULFAMETHOXAZOLE

OCH3

OCH3

OCH3

H2C

N

N

NH2

H2N

Sulfamethoxazole Trimethoprim

•LINK•Most commonly used as a mixture of the sulfa drug Sulfamethoxazole and Trimethoprim•These two drugs work in synergy, with the combination being superior to either drug alone.•

• This combination is known as co-trimoxazole, TMP-sulfa, or TMP-SMX. Usually oral administration.

MECHANISM OF ACTION• Trimethoprim-sulfamethoxazole works by preventing the synthesis of tetrahydrofolate (THF), an essential cofactor in the synthesis of nucleic acid precursors.

Tetrahydrofolic Acid Biosynthetic Pathway

• In the first step of the pathway, the sulfonamides are mistaken for the natural substrate, p-aminobenzoic acid (PABA) and the drug acts as a competitive inhibitor of this enzyme

• In a later step, the trimethoprim acts as a structural analog of dihydrofolate and therefore inhibits dihydrofolate reductase

CLINICAL USES• Trimethoprim/sulfamethoxazole is an agent with

activity against both gram-positive and gram-negative organisms including:

• Infections caused by Listeria monocytogenes• Staphylococcus saprophyticus infections presenting

as urinary tract infection or cystitis• Staphylococcus aureus, including some methicillin-

resistant strains[6]

• Susceptible strains of Escherichia coli• Shigellosis• Traveler's diarrhea• P. jeroveci pneumonia – IV treatment in severe cases

ADVERSE EFFECTS

• Skin rashes

• Nausea and vomiting

• Megaloblastic anemia, leukopenia, thrombocytopenia. (reversed with simultaneous administration of folinic acid )

RESOURCES

• Lipincott’s ilustrated review of Pharmacology

• Lange/ Levinson Review of Medical Microbiology and Immunlogy