Transcript Gram-Negative

Common Bacteria by Site of Infection
Mouth
Skin/Soft Tissue
Bone and Joint
Peptococcus
Peptostreptococcus
Actinomyces
S. aureus
S. pyogenes
S. epidermidis
Pasteurella
S. aureus
S. epidermidis
Streptococci
N. gonorrhoeae
Gram-negative rods
Abdomen
Urinary Tract
Upper Respiratory
E. coli, Proteus
Klebsiella
Enterococcus
Bacteroides sp.
E. coli, Proteus
Klebsiella
Enterococcus
Staph saprophyticus
S. pneumoniae
H. influenzae
M. catarrhalis
S. pyogenes
Lower Respiratory
Community
Lower Respiratory
Hospital
Meningitis
S. pneumoniae
H. influenzae
K. pneumoniae
Legionella pneumophila
Mycoplasma, Chlamydia
K. pneumoniae
P. aeruginosa
Enterobacter sp.
Serratia sp.
S. aureus
S. pneumoniae
N. meningitidis
H. influenza
Group B Strep
E. coli
Listeria
Beta-Lactam Structure
ANTIBIOTICS ACTING ON CELL
WALL OF BACTERIA
• Beta lactams:
• Penicillins, cephalosporins, carbapenems,
monobactam
• Glycopeptides:
• Vancomycin, teicoplanin
PENICILLIN IS GENERALLY
VERY SAFE BUT….
• Allergic reactions not uncommon-rashes
• Most severe reaction being anaphylaxis
• A history of anaphylaxis, urticaria, or rash immediately
after penicillin indicates risk of immediate hypersensitivity
after a further dose of any penicillin or cephalosporin
(therefore these must be avoided)
• Allergy is not dependent on the dose given ie, a small dose
could cause anaphylaxis
• Very high doses of penicillin can cause neurotoxicity
• Never give penicillin intrathecally
What antibiotics can be used in
penicillin allergy?
• Macrolides: erythromycin, clarithromycin
• (mainly gram positive cover)
• Quinolones: ciprofloxacin, levofloxacin
(mainly gram positive cover)
• Glycopeptides (serious infections)
• Fusidic acid, rifampicin, clindamycin
(mainly gram positive)
-Lactam





Same MOA: Inhibit cell wall synthesis
Bactericidal (except against Enterococcus sp.)
Short elimination half-life
Primarily renally eliminated (except nafcillin,
oxacillin, ceftriaxone, cefoperazone)
Cross-allergenicity - except aztreonam
-Lactams
Adverse Effects
• Hypersensitivity – 3 to 10 %
 Higher
incidence with parenteral administration
or procaine formulation
 Mild to severe allergic reactions – rash to
anaphylaxis and death
 Cross-reactivity exists among all penicillins and
even other -lactams
 Desensitization is possible
-lactams
Pharmacology
• Absorption: Variable depending on product
• Distribution


Widely distributed into tissues and fluids
Pens only get into CSF in the presence of inflamed
meninges; parenteral 3rd and 4th generation cephs,
meropenem, and aztreonam penetrate the CSF
• Elimination



most eliminated primarily by the kidney, dosage adj
required in the presence of renal insufficiency
Nafcillin, oxacillin, ceftriaxone-eliminated by the liver
ALL -lactams have short elimination half-lives except for
a few cephalosporins (ceftriaxone)
-Lactams
Adverse Effects
• Neurologic – especially with penicillins and
carbapenems (imipenem and meropenem)
 Especially
in patients receiving high doses in
the presence of renal insufficiency
 Irritability, confusion, seizures
• Hematologic
neutropenia, thrombocytopenia –
prolonged therapy (> 2 weeks)
 Leukopenia,
-Lactams
Adverse Effects
• Gastrointestinal
 Increased
LFTs, nausea, vomiting, diarrhea,
pseudomembranous colitis (C. difficile diarrhea)
• Interstitial Nephritis
 Cellular
infiltration in renal tubules (Type IV
hypersensitivity reaction – characterized by
abrupt increase in serum creatinine; can lead to
renal failure
 Especially with methicillin or nafcillin
Natural Penicillins
(penicillin G, penicillin VK)
Gram-positive
Gram-negative
pen-susc S. pneumoniae
Group A/B/C/G strep
viridans streptococci
Enterococcus
Neisseria sp.
Other
Treponema pallidum (syphilis)
Anaerobes
Above the diaphragm
Clostridium sp.
Penicillinase-Resistant
Penicillins
(nafcillin, oxacillin, methicillin)
Developed to overcome the penicillinase
enzyme of S. aureus which inactivated
natural penicillins
Gram-positive
Methicillin-susceptible S. aureus
Penicillin-susceptible strains of Streptococci
Aminopenicillins
(ampicillin, amoxicillin)
Developed to increase activity against
gram-negative aerobes
Gram-positive
Gram-negative
pen-susc S. aureus
Pen-susc streptococci
viridans streptococci
Enterococcus sp.
Listeria monocytogenes
Proteus mirabilis
Salmonella,
some E. coli
L- H. influenzae
Carboxypenicillins
(carbenicillin, ticarcillin)
Developed to further increase activity
against resistant gram-negative aerobes
Gram-positive
marginal
Gram-negative
Proteus mirabilis
Salmonella, Shigella
some E. coli
L- H. influenzae
Enterobacter sp.
Pseudomonas aeruginosa
Ureidopenicillins
(piperacillin, azlocillin)
Developed to further increase activity
against resistant gram-negative aerobes
Gram-positive
Gram-negative
viridans strep
Group strep
some Enterococcus
Proteus mirabilis
Salmonella, Shigella
E. coli
L- H. influenzae
Enterobacter sp.
Pseudomonas aeruginosa
Serratia marcescens
some Klebsiella sp.
Anaerobes
Fairly good activity
-Lactamase Inhibitor Combos
(Unasyn, Augmentin, Timentin, Zosyn)
Developed to gain or enhance activity against lactamase producing organisms (some better than
others). Provides some or good activity against:
Gram-positive
Gram-negative
S. aureus (MSSA)
H. influenzae
E. coli
Proteus sp.
Klebsiella sp.
Neisseria gonorrhoeae
Moraxella catarrhalis
Anaerobes
Bacteroides sp.
Classification and Spectrum of
Activity of Cephalosporins
• Divided into 4 major groups called
“Generations”
• Are divided into Generations based on
 antimicrobial
activity
 resistance to beta-lactamase
First Generation Cephalosporins
Best activity against gram-positive aerobes,
with limited activity against a few gramnegative aerobes
Gram-positive
Gram-negative
meth-susc S. aureus
pen-susc S. pneumoniae
Group A/B/C/Gstreptococci
viridans streptococci
E. coli
K. pneumoniae
P. mirabilis
Second Generation Cephalosporins
Spectrum of Activity
Gram-positive
Gram-negative
meth-susc S. aureus
pen-susc S. pneumoniae
Group A/B/C/G strep
viridans streptococci
E. coli
K. pneumoniae
P. mirabilis
H. influenzae
M. catarrhalis
Neisseria sp.
Second Generation Cephalosporins
Spectrum of Activity
The cephamycins (cefoxitin and cefotetan)
are the only 2nd generation cephalosporins
that have activity against anaerobes
Anaerobes
Bacteroides fragilis
Bacteroides fragilis group
Third Generation Cephalosporins
Spectrum of Activity
• In general, are even less active against grampositive aerobes, but have greater activity
against gram-negative aerobes
• Ceftriaxone and cefotaxime have the best
activity against gram-positive aerobes,
including pen-resistant S. pneumoniae
Third Generation Cephalosporins
Spectrum of Activity
Gram-negative aerobes
E. coli, K. pneumoniae, P. mirabilis
H. influenzae, M. catarrhalis, N. gonorrhoeae (including
beta-lactamase producing); N. meningitidis
Citrobacter sp., Enterobacter sp., Acinetobacter sp.
Morganella morganii, Serratia marcescens, Providencia
Pseudomonas aeruginosa (ceftazidime and cefoperazone)
Fourth Generation Cephalosporins
• 4th generation cephalosporins for 2 reasons
 Extended


spectrum of activity
gram-positives: similar to ceftriaxone
gram-negatives: similar to ceftazidime, including
Pseudomonas aeruginosa; also covers beta-lactamase
producing Enterobacter sp.
against -lactamases; poor inducer of
extended-spectrum  -lactamases
 Stability
• Only cefepime is currently available
Carbapenems
(Imipenem, Meropenem and Ertapenem)
• Most broad spectrum of activity of all antimicrobials
• Have activity against gram-positive and gramnegative aerobes and anaerobes
• Bacteria not covered by carbapenems include
MRSA, VRE, coagulase-negative staph, C. difficile,
Nocardia
Monobactams
Spectrum of Activity
Aztreonam bind preferentially to PBP 3 of
gram-negative aerobes; has little to no
activity against gram-positives or anaerobes
Gram-negative
E. coli, K. pneumoniae, P. mirabilis, S. marcescens
H. influenzae, M. catarrhalis
Enterobacter, Citrobacter, Providencia, Morganella
Salmonella, Shigella
Pseudomonas aeruginosa
Fluoroquinolones
• Novel group of synthetic antibiotics
• The fluorinated quinolones (FQs) represent
a major therapeutic advance:
Broad spectrum of activity
 bioavailability, tissue penetration, prolonged

FQs Spectrum of Activity
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
FQs Spectrum of Activity
Gram-Negative – all FQs have excellent
activity (cipro=levo>gati>moxi)
• 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
FQs Spectrum of 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
Fluoroquinolones
Pharmacology
• Concentration-dependent bacterial killing
• Absorption

Most FQs have good bioavailability after oral
administration
• Distribution


Extensive tissue distribution – prostate; liver; lung;
skin/soft tissue and bone; urinary tract
Minimal CSF penetration
• Elimination – renal and hepatic; not removed by HD
Fluoroquinolones
Adverse Effects
• Gastrointestinal – 5 %

Nausea, vomiting, diarrhea, dyspepsia
• Central Nervous System

Headache, 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 (halogen at position 8)
• Cardiac


Variable prolongation in QTc interval
Led to withdrawal of grepafloxacin, sparfloxacin
Fluoroquinolones
Adverse Effects
• Articular Damage
 Arthopathy
including articular cartilage damage,
arthralgias, and joint swelling
 Observed in toxicology studies in immature dogs
 Led to contraindication in pediatric patients and
pregnant or breastfeeding women
 Risk versus benefit
• Other adverse reactions: tendon rupture,
dysglycemias, hypersensitivity
Macrolides
• Erythromycin is a naturally-occurring macrolide
derived from Streptomyces erythreus – problems
with acid lability, narrow spectrum, poor GI
intolerance, short elimination half-life
• Structural derivatives include clarithromycin and
azithromycin:



Broader spectrum of activity
Improved PK properties – better bioavailability, better
tissue penetration, prolonged half-lives
Improved tolerability
Macrolides
Mechanism of Action
 Inhibits
protein synthesis by reversibly binding
to the 50S ribosomal subunit

Suppression of RNA-dependent protein synthesis
 Macrolides
typically display bacteriostatic
activity, but may be bactericidal when present
at high concentrations against very susceptible
organisms
Macrolide Spectrum of Activity
Gram-Positive Aerobes – erythromycin and
clarithromycin display the best activity
(Clarithro>Erythro>Azithro)
• Methicillin-susceptible Staphylococcus aureus
• Streptococcus pneumoniae (only PSSP) – resistance is
developing
• Group A/B/C/G and viridans streptococci
• Bacillus sp., Corynebacterium sp.
Macrolide Spectrum of Activity
Gram-Negative Aerobes – newer macrolides
with enhanced activity
(Azithro>Clarithro>Erythro)
• H. influenzae (not erythro), M. catarrhalis,
Neisseria sp., Campylobacter jejuni, Bordetella
pertussis
• Do NOT have activity against any
Enterobacteriaceae or Pseudomonas
Macrolide Spectrum of Activity
Anaerobes – activity against upper airway anaerobes
Atypical Bacteria – all macrolides have excellent
activity against atypical bacteria including:
•
•
•
•
Legionella pneumophila - DOC
Chlamydia sp.
Mycoplasma sp.
Ureaplasma urealyticum
Other Bacteria – Mycobacterium avium complex
(MAC – only A and C), Treponema pallidum,
Campylobacter, Borrelia, Bordetella, Brucella.
Pasteurella
Macrolides
Pharmacology
Absorption
– variable absorption (15-45%);
food may decrease the absorption
 Erythromycin
•
Base: destroyed by gastric acid; enteric coated
• Esters and ester salts: more acid stable
– acid stable and well-absorbed,
55% bioavailable regardless of presence of food
 Azithromycin –acid stable; 38% bioavailable; food
decreases absorption of capsules
 Clarithromycin
Macrolides
Pharmacology
Distribution


Extensive tissue and cellular distribution – clarithromycin
and azithromycin with extensive penetration
Minimal CSF penetration
Elimination



Clarithromycin is the only macrolide partially eliminated by
the kidney (18% of parent and all metabolites); requires
dose adjustment when CrCl < 30 ml/min
Hepatically eliminated: ALL
Variable elimination half-lives (1.4 hours for erythro; 3 to 7
hours for clarithro; 68 hours for azithro)
Macrolides
Adverse Effects
• Gastrointestinal – up to 33 %
 Nausea,
vomiting, diarrhea, dyspepsia
 Most common with erythro; less with new agents
• Cholestatic hepatitis - rare
>
1 to 2 weeks of erythromycin estolate
• Thrombophlebitis – IV Erythro and Azithro
 Dilution
of dose; slow administration
• Other: ototoxicity (high dose erythro in
patients with RI); QTc prolongation; allergy
Macrolides
Drug Interactions
Erythromycin and Clarithromycin ONLY–
are inhibitors of cytochrome p450 system in
the liver; may increase concentrations of:
Theophylline
Carbamazepine
Cyclosporine
Phenytoin
Warfarin
Digoxin, Disopyramide
Valproic acid
Terfenadine, Astemizole
Cisapride
Ergot alkaloids
Aminoglycosides
Mechanism of Action
• Multifactorial, but ultimately involves
inhibition of protein synthesis
• Irreversibly bind to 30S ribosomes
– must bind to and diffuse through outer membrane
and cytoplasmic membrane and bind to the
ribosome
– disrupt the initiation of protein synthesis,
decreases overall protein synthesis, and produces
misreading of mRNA
• Are bactericidal
Aminoglycosides
Spectrum of Activity
Gram-Positive Aerobes
most S. aureus and coagulase-negative staph (but not DOC)
viridans streptococci (in combination with a cell-wall agent)
Enterococcus sp. (only in combination with a cell-wall agent)
Gram-Negative Aerobes (not streptomycin)
E. coli, K. pneumoniae, Proteus sp.
Acinetobacter, Citrobacter, Enterobacter sp.
Morganella, Providencia, Serratia, Salmonella, Shigella
Pseudomonas aeruginosa (amik>tobra>gent)
Mycobacteria
– tuberculosis - streptomycin
– atypical - streptomycin or amikacin
Aminoglycosides
Pharmacology
• Absorption - poorly absorbed from gi tract
• Distribution
– primarily in extracellular fluid volume; are widely
distributed into body fluids but NOT the CSF
– distribute poorly into adipose tissue, use LBW for dosing
• Elimination
– eliminated unchanged by the kidney via glomerular
filtration; 85-95% of dose
– elimination half-life dependent on renal fxn


normal renal function - 2.5 to 4 hours
impaired renal function - prolonged
Aminoglycosides
Adverse Effects
Nephrotoxicity
– nonoliguric azotemia due to proximal tubule damage;
increase in BUN and serum Cr; reversible if caught early
– risk factors: prolonged high troughs, long duration of
therapy (> 2 weeks), underlying renal dysfunction, elderly,
other nephrotoxins
Ototoxicity
– 8th cranial nerve damage - vestibular and auditory toxicity;
irreversible and saturable
– vestibular: dizziness, vertigo, ataxia
– auditory: tinnitus, decreased hearing
– risk factors: same as for nephrotoxicity
Vancomycin
Mechanism of Action
• Inhibits bacterial cell wall synthesis at a site
different than beta-lactams
• Bactericidal (except for Enterococcus)
Vancomycin
Spectrum 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,
Peptostreptococcus
No activity against gram-negative aerobes or
anaerobes
Vancomycin
Pharmacology
• Absorption
– absorption from GI tract is negligible after oral
administration except in patients with intense colitis
– Use IV therapy for treatment of systemic infection
• Distribution
– widely distributed into body tissues and fluids, including
adipose tissue; use TBW for dosing
– inconsistent penetration into CSF, even with inflamed
meninges
• Elimination
– primarily eliminated unchanged by the kidney via
glomerular filtration
– elimination half-life depends on renal function
Vancomycin
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
Vancomycin
Adverse 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
Vancomycin
Adverse 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
• Dermatologic - rash
• Hematologic - neutropenia and
thrombocytopenia with prolonged therapy
• Thrombophlebitis
Oxazolidinones
• Linezolid (Zyvox®) is the first available
agent which received FDA approval in April
2000; available PO and IV
• Developed in response to need for agents
with activity against resistant gram-positives
(MRSA, VRE)
Linezolid
Mechanism of Action
• Binds to the 50S ribosomal subunit near to
surface interface of 30S subunit – causes
inhibition of 70S initiation complex which
inhibits protein synthesis
• Bacteriostatic (cidal against some bacteria)
Linezolid
Spectrum of Activity
Gram-Positive Bacteria
– Methicillin-Susceptible, Methicillin-Resistant AND
Vancomycin-Resistant Staph aureus and coagulasenegative staphylococci
– Streptococcus pneumoniae (including PRSP), viridans
streptococcus, Group streptococcus
– Enterococcus faecium AND faecalis (including VRE)
– Bacillus. Listeria, Clostridium sp. (except C. difficile),
Peptostreptococcus, P. acnes
Gram-Negative Aerobes – relatively inactive
Atypical Bacteria
– Mycoplasma, Chlamydia, Legionella
Linezolid
Pharmacology
• Concentration-independent bactericidal
activity
• Absorption – 100% bioavailable
• Distribution – readily distributes into wellperfused tissue; CSF penetration  70%
• Elimination – both renally and nonrenally, but
primarily metabolized; t½ is 4.4 to 5.4 hours;
no adjustment for RI; not removed by HD
Linezolid
Adverse Effects
• Gastrointestinal – nausea, vomiting,
diarrhea (6 to 8 %)
• Headache – 6.5%
• Thrombocytopenia – 2 to 4%
– Most often with treatment durations of > 2
weeks
– Therapy should be discontinued – platelet
counts will return to normal
Linezolid (Zyvox®)
Drug–Drug/Food interactions
Linezolid is a reversible, nonselective inhibitor of
monoamine oxidase. Tyramine rich foods, adrenergic
drugs and serotonergic drugs should be avoided due to the
potential drug-food and drug-drug interactions. A
significant pressor response has been observed in normal
adult subjects receiving linezolid and tyramine doses of
more than 100 mg. Therefore, patients receiving linezolid
need to avoid consuming large amounts of foods or
beverages with high tyramine content.
Clindamycin
Mechanism of Action
 Inhibits
protein synthesis by binding
exclusively to the 50S ribosomal subunit

Binds in close proximity to macrolides –
competitive inhibition
 Clindamycin
typically displays bacteriostatic
activity, but may be bactericidal when present
at high concentrations against very susceptible
organisms
Clindamycin
Spectrum of Activity
Gram-Positive Aerobes
• Methicillin-susceptible Staphylococcus
aureus (MSSA)
• Methicillin-resistant Staphylococcus
aureus (MRSA) – some isolates
• Streptococcus pneumoniae (only PSSP) –
resistance is developing
• Group and viridans streptococci
Clindamycin
Spectrum of Activity
Anaerobes – activity against Above the Diaphragm
Anaerobes (ADA)
Peptostreptococcus
some Bacteroides sp
Actinomyces
Prevotella sp.
Propionibacterium
Fusobacterium
Clostridium sp. (not C. difficile)
Other Bacteria – Toxoplasmosis gondii, Malaria
Clindamycin
Pharmacology
Absorption – available IV and PO
 Rapidly
and completely absorbed (90%); food with
minimal effect on absorption
Distribution
 Good serum
concentrations with PO or IV
 Good tissue penetration including bone; minimal CSF
penetration
Elimination
 Clindamycin
primarily metabolized by the liver; halflife is 2.5 to 3 hours
 Clindamycin is NOT removed during hemodialysis
Clindamycin
Adverse Effects
• Gastrointestinal – 3 to 4 %
 Nausea,
vomiting, diarrhea, dyspepsia
• C. difficile colitis – one of worst offenders
 Mild
to severe diarrhea
 Requires treatment with metronidazole
• Hepatotoxicity - rare
 Elevated
transaminases
• Allergy - rare
New Guys on the Block
• Tigecycline (Tygacil®)
• Daptomycin (Cubicin®)
Tigecycline
Mechanism of Action
Binds to the 30S ribosomal subunit
of susceptible bacteria, inhibiting
protein synthesis.
Tigecycline
Spectrum of Activity
Broad spectrum of activity
• Treatment of complicated skin and skin structure
infections caused by susceptible organisms,
including methicillin-resistant Staphylococcus
aureus and vancomycin-sensitive Enterococcus
faecalis; treatment of complicated intraabdominal infections
Tigecycline
Pharmacokinetics
• Metabolism: Hepatic, via glucuronidation, Nacetylation, and epimerization to several metabolites,
each <10% of the dose
• Half-life elimination: Single dose: 27 hours;
following multiple doses: 42 hours
• Excretion: Urine (33%; with 22% as unchanged
drug); feces (59%; primarily as unchanged drug) –
No dose adjustment required in renal dysfunction
Tigecycline
Adverse Effects
•
•
•
•
•
•
•
•
•
•
•
>10%: Gastrointestinal: Nausea (25% to 30%), diarrhea (13%)
2% to 10%:
Cardiovascular: Hypertension (5%), peripheral edema (3%), hypotension (2%)
Central nervous system: Fever (7%), headache (6%), dizziness (4%), pain
(4%), insomnia (2%)
Dermatologic: Pruritus (3%), rash (2%)
Endocrine: Hypoproteinemia (5%), hyperglycemia (2%), hypokalemia (2%)
Hematologic: Thrombocythemia (6%), anemia (4%), leukocytosis (4%)
Hepatic: SGPT increased (6%), SGOT increased (4%), alkaline phosphatase
increased (4%), amylase increased (3%), bili increased (2%), LDH increased
(4%)
Neuromuscular & skeletal: Weakness (3%)
Renal: BUN increased (2%)
Respiratory: Cough increased (4%), dyspnea (3%)
Daptomycin
Mechanism of Action
 Daptomycin
binds to components of the cell
membrane of susceptible organisms and causes
rapid depolarization, inhibiting intracellular
synthesis of DNA, RNA, and protein.
 Daptomycin is bactericidal in a concentrationdependent manner
Daptomycin
Spectrum of Activity
Gram-Positive Aerobes
Treatment of complicated skin and skin
structure infections caused by susceptible
aerobic Gram-positive organisms;
• Staphylococcus aureus bacteremia, including rightsided infective endocarditis caused by MSSA or MRSA
Daptomycin
Pharmacokinetics
• Absorption – available IV only
• Half-life elimination: 8-9 hours (up to 28 hours in
renal impairment)
• Excretion: Urine (78%; primarily as unchanged
drug); feces (6%)
• Dosage adjustment in renal impairment:
– Clcr <30 mL/minute: Administer dose q48hr
Daptomycin
Adverse Effects
• Hematologic: Anemia (2% to 13%)
• Gastrointestinal:
– Diarrhea (5% to 12%)
– vomiting (3% to 12%)
– constipation (6% to 11%)
FDA Categorization of Antibiotics in Pregnancy
• Category A
–
Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no
evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.
• Category B
–
Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in
pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in
fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no
evidence of a risk in later trimesters).
• Category C
–
•
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other)
and there are no controlled studies in women, or studies in women and animals are not available. Drugs
should be given only if the potential benefit justifies the potential risk to the fetus.
Category D
–
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be
acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease
for which safer drugs cannot be used or are ineffective).
• Category X
–
Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal
risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly
outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Antibiotics in Pregnancy
FDA Category
Antibiotics in Category
A
B
Penicillins, Cephalosporins, Carbapenems (except Imipenem),
Daptomycin, Vancomycin (oral), Clindamycin, Erythromycin,
Azithromycin, Metronidazole (avoid first trimester),
Nitrofurantoin, Acyclovir, Amphoterocin B, Ethambutol
C
Quinolones, Chloramphenicol, Clarithromycin, Imipenem,
Linezolid, Trimethoprim/Sulfa (D if used near term),
Vancomycin (IV), Rifampin, INH, PZA, PAS, Fluconazole,
Caspofungin
D
Tetracyclines (Doxy, Tige, Mino), Voriconazole,
Aminoglycosides (some put gentamicin as a category C)
X
Ribavarin
Antibiotics Penetration into Eucaryotic Cells (esp.
Macrophages)
Antibiotic Class
Intracellular
Accumulation Ratio
Predominant
Subcellular Localization
Beta Lactams
<1
Cytosol
Glycopeptides
(Vancomycin)
8 (after 24 hrs)
Lysosomes
Oxazolidinones
(linezolid)
1
Unknown
Aminoglycosides
2-4 (after several days)
Lysosomes
Macrolides
4-300
Lysosomes/cytosol
Fluoroquinolones
4-10
Cytosol
Clindamycin
5-20
Unknown
Tetracyclines
1-4
Unknown
Antibiotics in bold print are generally considered most
effective for intracellular organisms
• Sulfonamide or sulphonamide is the basis
of several groups of drugs. The original
antibacterial sulfonamides (sometimes
called sulfa drugs or sulpha drugs) are
synthetic antimicrobial agents that contain
the sulfonamide group. Some sulfonamides
are also devoid of antibacterial activity, e.g.,
the anticonvulsant sultiame. The
sulfonylureas and thiazide diuretics are
newer drug groups based on the
antibacterial sulfonamides
• Allergies to sulfonamide are common,[3]
hence medications containing sulfonamides
are prescribed carefully. It is important to
make a distinction between sulfa drugs and
other sulfur-containing drugs and additives,
such as sulfates and sulfites, which are
chemically unrelated to the sulfonamide
group, and do not cause the same
hypersensitivity reactions seen in the
sulfonamides.
• Because sulfonamides displace bilirubin
from albumin, kernicterus (brain damage
due to excess bilirubin) is an important
Sulfonamides: antimicrobial
activity
•
•
•
•
•
Gram positive and negative bacteria
Nocardia, chlamydia trachomatis
Some protoza
Some enteric bacteria
Rickettisiae stimulated!
Sulfonamides: clinical uses
• Oral absorbable agents
– Sulfisoxazole, sulfamethoxazole
• To treat urinary tract infection
– Sulfadiazine: toxoplasmosis
– Sulfadoxine: long acting, in a combination for treatment of malaria
• Oral nonabsorbable agents
– Ulcerative colitis, enteritis, other inflammatory bowel disease
• Topical agents
– Sulfacetamide: ophthalemic
– Mafenide & silver sulfadiazine: topically
Sulfonamides: adverse reactions
• Cross allergenic sulfonamide drugs:
– Thiazide, furosemide, diazoxide, sulfonylurea hypoglycemic
agents, and others
– Fever, skin rashes, exfoliative dermatitis,photosensivity, urticaria,
nausea, vomiting, diarrhea
– Stevens-Johnson syndrom
• Urinary tract disturbances
– Crystalluria, hemturia, obstruction
• Hematopoietic disturbance
–
–
–
–
Hemolytic or aplastic anemia
Granulocytopenia, thrombocytopenia, leukmoid reaction
Hemolysis in G-6PDH deficient patients
Kernicterus in newborn of mothers have taken near the end of
pergnancy
Clinical use
• Oral trimethoprim
– Acute urinary infection
• Oral trimethoprim-sulfamethoxazole
– P jiroveci pneumonia, shigellosis, systemic salmonella infection,
complicated urinary tract infection,
– Active against many respiratory pathogens
• Intravenous trimethoprim-sulfamethoxazole
– Gram negative sepsis, pneumocystis pneumonia
– Shigllosis, typhoid fever
• Oral pryrimethamine with sulfanamide
– With sulfadiazine in Leishmaniasis, toxoplasmosis
– With sulfadoxine in malaria
Adverse effects
•
•
•
•
Megaloblastic anemia
Leukopenia, granulocytopenia
Can be prevented by folinic acid
The AIDS patients have high frequency of
unwanted reactions