Antiinfectives I

1
Anti-infectives I

• Ch. 44
• Considered Synthetic Antimicrobial Agents. NOT
  Antibiotics
• Sulfonamides TMP/SMX Folate Reductase
  Inhibitors
• Quinolones
• UTI Agents
• Ch. 45 Already covered!
• Ch. 46
• Aminoglycosides
• Ch. 47
• Protein Synthesis Inhibitors Misc.
• Tetracyclines
• Chloramphenicol
• Macrolides
• Clindamycin
• Others
• Ch. 48
• TB Leprosy Agents
• Ch. 49
• Anti-fungal Agents

2
Sulfonamides Folate Reductase Inhibitors

• Discovery of sulfonamides was initiated by German
  chemists and their interest in Azo dyes
• In 1932, a physician names Gerhard Domagk was
  studying a bright red dye named Prontosil and
  found it cured Strep infections in mice
• Active in vivo only since azo finctional group
  was reduced to a sulfonamide
• Since this discovery literally thousands (4500 by
  1948 alone) were synthesized and tested
• Now only about two dozen are actually used
  worldwide
• Reasons for limitations
• Sulfonamide toxicity in some patients
• Resistant bacterial strains due to early world
  wide indiscriminant use

3
Sulfonamides Folate Reductase Inhibitors

• Mechanism of action
• Antimetabolite By chemical similarity to PABA
  they interfere with the role of an endogenous
  compound in cell metabolism.
• Sulfonamides Competitive inhibitors of PABA -
  these drugs are bacteriostatic
• Preventing folate coenzyme synthesis
• No deoxythymidine for DNA synthesis is produced
• Trimethoprim Folate reductase inhibitor
• Some affinity for human folate reductase ? side
  effects
• Microbes CAN NOT use dietary folic acid
• Use of two together ? synergistic antimicrobial
  effect blocks 2 points in the folate pathway
  sequential blockade

4
Sulfonamides Folate Reductase Inhibitors
5
Sulfonamides Folate Reductase Inhibitors

• Mechanisms of resistance
• Resistant bacteria have increased PABA
• Other possible mechanisms
• Acquired genetic material to cause resistance ?
  R-factors
• Usually resistance to one sulfonamide leads to
  resistance of all in the class
• Trimethoprim resistance
• Natural intrinsic resistance
• Acquired ability to use host deoxythymidine
  monophosphate
• R-factor transmission

6
Sulfonamides Folate Reductase Inhibitors

• Today these drugs alone or in combination with
  the antimetabolite
• trimethoprim have found use in the following
  infections
• AIDS patient opportunistic infections treatment
  and prophylaxis
• Pneumocystis carinni pneumonia (PCP)
• Cerebral toxoplasmosis
• UTI
• Burn therapy topicals
• Conjunctivitis and other ocular infections
• Chloroquine-resistant malaria Sulfadoxine
  (Fansidar)
• These drugs are generally NOT effective against
• Streptococcal infections
• Prophylaxis in rheumatic fever recurrences
• Other bacterial infections
• Reduction of intestinal flora
• Ulverative colitis
• Largely replaced by Antibiotics

7
Sulfonamide Chemistry

• Drugs with high pKa values prone to crystalluria
  (resulting kidney damage)
• To avoid
• Heterocyclic rings (e- withdrawing) are attached
  to the sulfonamide residue ? LOWERS the pKa value
  (ionized - water soluble)
• Use more than one type of sulfonamide (Triple
  sulfa)
• Amount of each does not reach a threshold amount
  leading to crystals - forcing fluids is not
  longer absolutely necessary

8
Sulfonamides Folate Reductase Inhibitors

• Toxicity and Side-Effects
• 5 of all patients have some degree of
  hypersensitivity
• Drug fever, skin rashes, photosensitivity,
  allergic myocarditis, analphylaxis
• Patients deficient in glucose-6-phosphate -
  hemolytic anemia
• Crystalluria if normal adequate fluid intake is
  not sufficient (2-3 liters per day)
• Competition for plasma protein binding sites
  increases warfarin concentrations
• Biotransformations
• With the exception of sulfonamides used for
  ulverative colitis and reduction of bowel flora -
  all sulfonamides and trimethoprim are absorbed
  quickly
• Protein binding ranges from 38 (sulfadiazine) to
  76 (sulfisoxazole), and for trimethoprim (45)
• Excreted as unchanged drug, N-acetyl and
  glucuronide derivatives
• Trimethoprim has 6 active metabolites
• Fixed dosages should not be used for patients
  with low creatinine clearance

9
Sulfonamides Folate Reductase Inhibitors

• Classes
• Rapidly absorbed/excreted (oral absorbable)
• Short-Acting Sulfisoxazole
• Intermediate-Acting Sulfamethoxazole
• Poorly absorbed (bowel active)
• Sulfasalazine
• Topical - Burns
• Sulfacetamide, Silver sulfadiazine
• Long-acting
• Sulfadoxine - Fansidar (See Anti-malarials)

10
Sulfonamides Folate Reductase Inhibitors
Sulfisoxazole opthalmic/otic prep - Gantrisin,
combo product for otitis media with erythromycin
ethylsuccinate - Eryzole, Pediazole Used almost
exclusively for UTI Also recommended as an
alternative regimen in patients that are unable
to tolerate erythromycin, azithromycin or
doxycycline for Chlamydia trachomatic infections
at 500 mg 4X daily for 10 days Available also in
combination with phenazopyridine Urinary tract
anesthetic
11
Sulfonamides Folate Reductase Inhibitors
SulfisalazineAzulfidine PO Used widely for
ulcerative colitis other inflammatory bowel
diseases Splits in vivo to sulfapyridine and
5-aminosalicylate (mesalamine) major effect is
antiinflammatory as mesalamine inhibits
cyclooxygenases and lipoxygenases
12
Azo Prodrugs (Prodrug Lecture)

• Bacterial reductases ? reductive cleavage
• Release of 2 amine compounds
• Occurs in colon ? discourages small intestine
  systemic absorption
• Concentrates the drug at the desired site of
  action

13
Sulfonamides Folate Reductase Inhibitors
Also a combo product with the decongestant
phenylephrine Vasosulf
14
Sulfonamides Folate Reductase Inhibitors
Indicated only for use in treatment of
Gardnerella vaginalis vaginititis
Treatment of Candida albicans vulvovaginitis only
15
Folate Reductase Inhibitors
Indications UTI - perform susceptibility
testing. May initiate therapy before results are
obtained e. Coli, Gram(-) rods. Use with
caution in renal/hepatic failure Phenytoin action
is increased due to inhibition of hepatic
metabolsim Indications moderate to severe
Pneumocystic carinii pneumonia but only with
concurrent leucovorin protection Modify dosage
based on hematological considerations -
neutrophil and platelet counts Leucovorin calcium
is given to prevent very serious bone marrow
suppression (also known as folinic acid or
citrovorum factor) ? high-dose methotrexate rescue
16
Pneumocystis Pneumonia Agents
Use with caution in renal/hepatic
failure Phenytoin action is increased due to
inhibition of hepatic metabolsim MOA Folate
reductase inhibitor - Some affinity for human
folate reductase - side effects Microbes CAN
NOT use dietary folic acid
1 / 5
MOA Competitive inhibitors of PABA drug is
bacteriostatic Prevent folate coenzyme synthesis
? no deoxythymidine for DNA synthesis
Use of two together results in a synergistic
antimicrobial effect ? blocks 2 points in the
folate pathway
17
Sequential Blockade
dTMP
18
Quinolones

• Early quinolones never achieved systemic levels
  high enough to be antibacterial
• Used to treat UTI
• Pro-convulsant activity
• Fluoroquinolones key members
• Active against a variety of Gram() (-)
• Relatively nontoxic, well-tolerated
• Developed because of good Gram(-) activity
• Modest Gram() activity ? improving!

19
Quinolones - 1st Generation
Indications UTI E. Coli Gram(-) MOA
bactericidal agent that interfers with DNA
polymerization DNA Girase or Topoisomerase
II 97 protein bound, hepatic metabolism with
urinary excretion-use caution in renal
failure Serious DI since effective as
displacement of anticoagulants from plasma
protein binding sites Will interfere with
Clinitest urinary glucose test, use the Clinistix
or Tes-Tape test Photosenitivity, contraindicated
if a history of convulsive disorders Pseudomonas
spp. Strains are generally resistant
Indications UTI MOA bactericidal agent that
interfers with DNA polymerization - DNA Girase or
Topoisomerase II gt60 protein bound, Dosage
adjustment necessary in renal failure NOT active
against Pseudomonas, Staphylococci, and
enterococci DI Probenecid will block tubular
excretion Photosensitivity
20
Fluoroquinolones 2nd Generation

• Active against
• Atypical pneumonias (mycoplasma, chlamydiae)
• Intracellular pathogens (legionella
  mycobateriae)
• Dosage adjustment for impaired renal function
• MOA block bacterial DNA synthesis
• Inhibit bacterial Topoisomerase II (DNA gyrase)
• Prevents relaxation of positively supercoiled DNA
  
• Resistance altered protein, reduced entry
  (porins)
• pseudomonas, staphylococcus
• Overuse has eroded the utility of these agents!

21
Fluoroquinolones

• Advise patients
• May cause dizziness or lightheadedness
• DO NOT use (4h before, 2 h after taking
  medication)
• Mg or Al containing antacids
• Fe or Zn containing products
• Multiple vitamins
• Do not take with milk or dairy products - use a
  glass of water
• Do NOT take ofloxacin with food, all others
  should be taken 1 hour before or 2 hours after
• Moderate to Severe photosensitivity can occur
  advise patients to use a sun screen
• NOT recommended for children/pregnant women
• Demonstrates cartilage problems in developing
  animals

22
Fluoroquinolones 4 Generations

• First
• Norfloxacin Least active
• Second
• Ciprofloxacin, Enoxacin, Lomefloxacin,
  Levofloxacin, Ofloxacin
• Excellent Gram(-), Modest Gram ()
• Third
• Gatifloxacin, Sparfloxacin
• Improved Gram(), Reduced Gram(-)
• Fourth
• Moxifloxacin, Trovafloxacin
• Enhanced Gram(), anaerobic activity

23
Fluoroquinolones

• Clinical Use Summary
• UTI caused by Gram(-) bacteria
• E. Coli, Klebsiella, Pseudomonas
• Alternatives to G3 cephalosporins
• Ciprofloxacin Ofloxacin
• Treatment of resistant gonorrhea
• Treat community-acquired pneumonia
• Mycoplasma pneumoniae (atypical)
• Levofloxacin
• Moxifloxacin Trovafloxacin widest spectrum
• Also activity against anaerobic bacteria
  (sparfloxacin)

24
Fluoroquinolones
M
Indications UTI (enterococcus, enterobacter,
and pseudomonas), sexually transmitted
disease, Least active in class! Can be used as
recommended by the CDC as one 800 mg single dose
for uncomplicated gonorrhea Eliminated by
metabolism, biliary and renal excretion
(glomerular and tubular secretion), 15 protein
bound Opthalmic/Otic preparation
Chibroxin Indications Acute sinusitis, lower
respiratory tract infections, nosocomial
pneumonia (IV only), skin and skin structure
infections, bone and joint infections, UTI,
chronic bacterial prostatitis, empirical therapy
for febrile neutropenia patients, complicated
intra-abdominal infections, infectious diarrhea
agent of choice, typhoid fever, sexually
transmitted diseases (oral dose form only) Best
Gram(-) activity in class! Admixture
incompatibility with aminophylline, amoxacillin,
clindamycin, floxacillin, heparin, mazlocillin
(Alkaline solutions) 40 protein bound, hepatic
metabolism, renal excretion Opthalmic/Otic
preparation Ciloxan
25
Fluoroquinolones
Indications UTI, sexually transmitted disease
except syphilis, prostatitis, lower respiratory
tract infections, skin and skin structure
infections Hepatic failure including cirrhosis
can lead to elevated serum concentratons Use
caution Eliminated by hepatic metabolism and
renal excretion, 32 protein bound, DO NOT take
with food Opthalmic/Otic preparation
Ocuflox Indications acute bacterial
exacerbation of chronic bronchitis, UTI,
preoperative prophylaxis, transrectal prostate
biopsy, transurethral surgical procedures Can be
used as recommended by the CDC as one 400 mg
single dose for uncomplicated gonorrhea 10
protein bound, minor hepatic metabolism, renal
excretionadjust dosage based on creatinine
clearance Worst photosensitivity of the
fluoroquinolines
26
Fluoroquinolones
Indications acute maxillary sinusitis, acute
bacterial exacerbation of chronic bronchitis,
community acquired pneumonia (S. Pneumoniae) skin
and skin structure infections, UTI, acute
pyelonephritis Oral or IV use only (no IM) Dosage
adjustment a function of creatinine
clearance Best against Gram() L-isomer of
Ofloxacin and twice as potent
27
Fluoroquinolones
Indications acute bacterial exacerbation of
chronic bronchitis, acute sinusitis, community
acquired and atypical pneumonia, UTI,
pyelonephritis, gonorrhea, skin and skin
structure infections, chronic prostatisis Oral
and IV use only, 20 protein bound, does not
appear to be a CYP inhibitor or inducer, excreted
unchanged in the urinedosage adjustment
necessary in renal failure as a function of
creatinine clearance, effects in severe hepatic
failure not known at this time Indications
acute bacterial exacerbation of chronic
bronchitis, community acquired pneumonia in
patients 18 years of age or less Oral use only
with once a day dosing due to long elimination
time of 18 hours Lowest potential for
phototoxicity
Think Improved Gram() activity (S. Pneumoniae)
28
Fluoroquinolones
Indications acute bacterial sinusitis, acute
bacterial exacerbation of chronic bronchitis,
community acquired pneumonia Oral use only Can
prolong the QT portion of an electrocardiogram in
some patients avoid use in patients with
hypokalemia or ones taking Class Ia or III
anti-arryhthmia drugs Not recommended for patient
with moderate or severe hepatic
failure Indications Sexually transmitted
diseases and other UTI Oral use only, 40 protein
bound Can be used as recommended by the CDC as
one 400 mg single dose for uncomplicated
gonorrhea Hepatic metabolism and CYP450 enzyme
inhibitor digoxin serum levels increased Renal
excretion of metabolites adjust dosage in renal
failure
Belongs with Cipro-, Lome-, Levo-, and Ofloxacin
Enoxacin is a bit out of place should be with
Cipro, ofloxacin, levofloxacin, etc.
29
Fluoroquinolones
Note This agent should be reserved for
situations where life threatening infections
occur where other antibiotics have failed. It
has been associated with serious liver injury
leading to transplantation and death. Indications
Nosocomial pneumonia, community-acquired
pneumonia, complicated intra-abdominal
infections, gynechological and pelvic infections,
complicated skin and skin structure infections Do
not administer for gt 2 weeks, hepatic failure
requires dosage adjustmentbiliary excretion
route Oral and IV use only - if taken orally on
empty stomach. Administer IV morphine gt 2 hours
later. If taken with food, administer IV
morphine gt4 hours later
30
Nitrofuran Antibacterial Agents
Indications UTI in susceptible strains of E.
coli, entercocci, Staphylococcus aureus,
Klebsiella and Enterobacter sp. MOA May inhibit
acetylcoenzyme A - interferes with bacterial
carbohydrate metabolism (cell wall
synthesis) Rapidly metabolized by nitro reduction
this product of reduction believed to damage
bacterial DNA Carcinogenic - interaction with
DNA, ineffective if creatinine clearance is lt 40,
may cause brown discoloration of the
urine Indications bacterial or protozoal
diarrhea and eneteritits caused by susceptible
organisms Unlabeled uses travelers diarrhea,
infantile diarrhea, typhoid fever, giardiasis,
bacteria salmonellosis Bactericidal effect by
interfering with severeal bacterial enzyme
systems - does NOT cause fungal overgrowth
Macrobid
31
Nitrofuran Methamine Agents
Indications Burns and skin grafting---activity
against gram () and (-) organisms Topical
external use only
Indications UTI Salt forms help to maintain
acidic urine Do NOT consume urinary alkalinizers
such as milk, antacids, bicarbonate,
acetazolamide (Carbonic anhydrase inhibitor)
32
Aminoglycosides

• Consider penicillins cephalosporins
• Multiple daily dosings
• Maintain a minimal inhibitory concentration (MIC)
  
• Unlike penicillins cephalosporins
• Concentration-dependant killing action
• As levels of AG increase above MIC, more cell
  killing occurs at a more rapid rate
• Given as single large dose
• AG have a postantibiotic effect
• Killing continues after drop below MIC

33
Aminoglycosides

• Most effective against Gram(-) rods
• E. Coli, enterobacter, klebsiella, pseudomonas
• Polar compounds poor oral absorption (IV/IM)
• MOA inhibit bacterial protein synthesis
• Delivery dependant on active transport (aerobic)
• Bind 30S ribosomal subunit to interfere in 3
  ways
• Block formation of initiation complex
• Cause misreading of code on the mRNA template
• Inhibit translocation
• Resistance - plasmid-mediated inactivating
  enzymes.
• Group transferases
• Acetylate amine on AG
• Transfer phosphoryl or adenyly groups to AG
  hydroxyls

34
Aminoglycosides
35
Ribosome Refresher
60S 40S 80S
50S 30S 70S
Procaryotic Eucaryotic
36
Aminoglycosides

• WARNING significant nephrotoxicity and
  ototoxicity
• Monitor both renal function and 8th cranial nerve
  function prior to and during therapy -
  discontinue drug is signs of toxicity occur
• Excreted primarily via glomerular filtration so
  dosages MUST be adjusted based on creatinine
  clearance
• Renal toxicity kanamycin amikacin
  gentamycin netilmicin gt tobramycin gt
  streptomycin
• Renal damage is usually reversible
• Ototoxicity is a neurotoxicity that is
  IRREVERSIBLE
• Ototoxicity Streptomycin kanamycin gt amikacin
  gentamycin tobramycin gt netilmicin
• Do NOT use aminoglycosides concurrently with
  other oto- or nephrotoxic drugs (unless
  unavoidable)
• Monitor serum drug levels!
• DO NOT co-mix in IV solutions with other drugs
  especially b-lactams
• Low protein binding except for streptomycin

37
Aminoglycosides

• Clinical applications
• Serious infections, aerobic Gram(-) bacteria
• E. Coli, enterobacter, klebsiella, pseudomonas
• Gentamicin, Amikacin, Tobramycin, Netilmicin
• TB (occasionally endocarditis)
• Streptomycin
• Bowel sterilization skin infections
• Neomycin, kanamycin (P.O or topical)
• Gonorrhea
• Spectinomycin

- technically not an aminoglycoside
38
Aminoglycosides
Indications Gram() Gram (-) including
Susceptible strains of E. coli, Enterobacter sp.,
Klebsiella sp., Serratia sp., Staphylococcus sp.,
Proteus sp., Pseudomonas aeruginosa, Citrobacter
sp., neonatal sepsis, septicemia, meningitis,
UTI, respiratory tract and skin and skin
structure infections Topical, IV or IM use
only Topical products including ophthalmic and
otic Garamycin and G-myticin Also a
syngergistic companion with b-lactams Useful
against Gram(-) rods resistant to other
antibiotics
39
Aminoglycosides
Indications Susceptible strains of bacteria
causing septicemia, meningitis, complicated and
recurrent UTI, lower respiratory tract,
intra-abdominal infections and skin and skin
structure infections Topical, IV or IM use
only Topical products including ophthalmic and
otic Tobrex TOBI is used in cystic fibrosis
patients to control Pseudomonas aeruginosa Some
cross-resistance with Gentamicin
Clinically, Tobramycin and Gentamicin are
interchangeable
40
Aminoglycosides
Indications Susceptible strains of bacteria
causing septicemia, meningitis, complicated and
recurrent UTI, lower respiratory tract,
intra-abdominal infections and skin and skin
structure infections, neonatal sepsis,
Mycobacterium avium complex infections in AIDS
patients IV or IM use only Synthetic analog of
Kanamycin
Indications Susceptible strains of bacteria
causing septicemia, complicated and recurrent
UTI, lower respiratory tract, intra-abdominal
infections and skin and skin structure
infections, IV or IM use only
41
Aminoglycosides
IM use drug only Indications Mycobacterium
tuberculosis, susceptible nontuberculous
infections such as tularemia, plague and
bacterial endocarditis Mycobacterium avium
complex infections in AIDS patients Has some
activity against other Gram(-) bacteria but is
largely replaced by Gentamicin.
42
Aminoglycosides - ORAL
Indications Acute and chronic intestinal
amebiasis (note NOT Extraintestinal) hepatic coma
(decrease ammonia in blood leads to neurological
improvement), strange parasitic infections
Indications suppression of intestinal bacteria
in preoperative bowel prep, hepatic coma
(decreased ammonia in blood leads to neurological
improvement) Topical product - Myciguent Too
toxic for parenteral use!!!
43
Aminoglycosides - ORAL
Used orally to suppress intestinal bacteria,
useful in hepatic comadecrease ammonia DO NOT
exceed 1.5 grams per day Carefully monitor for
ototoxicity in the elderly despite normal renal
function NOT indicated for tuberculosis due to
toxicity, NOT the drug of choice for
Staphylcoccal infections Indications
Susceptible strains of E. coli, Enterobacter
aerogenes, Klebsiella pneumonia, Serratia
marcescens, Acinetobacter sp. Mycobacterium
avium complex infections in AIDS patients Monitor
serum levels and creatinine clearance to adjust
dosage frequency Do to toxicity, parenteral admin
has been abandoned
44
Aminoglycoside-like Antibiotics
Indications Susceptible strains of Neiserra
gonorrhoeae gonococcal infections IM use only
single injection Structurally different from the
aminoglycosides MOA inhibits bacterial protein
synthesis by binding to the 30S ribosomal
subunit Primarily excreted unchanged in the
urine NOT effective against syphilis In the case
of pharyngeal infections, use this drug ONLY in
patients that are intolerant of cephalosporins or
fluoroquinolines - only 52 effective so follow
up with culturing after 3-5 days to verify
organism absence Back-up drug