Transcript PENICILLINS - UW Canvas - University of Washington

ANTIBACTERIAL DRUGS
PHARM 514
Douglas Black, Pharm.D.
Associate Professor
School of Pharmacy
University of Washington
[email protected]
WE HAVE LOTS TO COVER IN TWO DAYS
• Principles of antimicrobial chemotherapy
• ß-lactams
• Vancomycin
• Aminoglycosides
• Macrolides
• Tetracyclines
• TMP-SMX
• Clindamycin
• Linezolid
• Fluoroquinolones
• Nitrofurantoin
• Rifampin
• Metronidazole
• Antifungal drugs
THESE DEFINITIONS ARE IMPORTANT
• Bacteriostatic antibiotic: a compound that only
inhibits bacterial growth.
• Bactericidal antibiotic: a compound that exerts an
outright lethal effect. Some drugs are “rapidly”
bactericidal, others are “slowly” bactericidal.
• MIC (minimum inhibitory concentration): the
minimum concentration of antibiotic required to
inhibit growth of a specific organism. It is a
reflection of the potency of the antibiotic; the
lower the MIC, the more potent the antibiotic
toward that organism. Only occasionally does the
lab determine MICs for purposes of patient care.
THERE ARE FIVE GENERAL WAYS A MICROBE
CAN DEFEND ITSELF
• Synthesize enzymes that alter the antibiotic
(rendering it useless)
– ß-lactamases
– aminoglycoside-modifying enzymes
• Alter the bacterial target of the antibiotic
• Alter outer membrane permeability to the antibiotic
(Gram-negative organisms only)
• Pump (efflux) the antibiotic out of the bacterial cell
• Bypass the biochemical blockade caused by an
antibiotic (if that is its mechanism of action)
A β-LACTAM IS JUST A CHEMICAL CLASS
• Penicillins, cephalosporins, carbapenems,
and aztreonam are all ß-lactam antibiotics
• A ß-lactamase is a bacterial enzyme that
destroys the activity of a ß-lactam
antibiotic
THERE ARE FOUR TYPES OF “PENICILLINS,”
GROUPED HERE ACCORDING TO ANTIBACTERIAL
SPECTRUM
(*=oral)
NATURAL PENICILLINS
Penicillin G, penicillin V*
AMINOPENICILLINS
Ampicillin*, amoxicillin*
ANTISTAPHYLOCOCCAL
PENICILLINS (not MRSA)
Nafcillin, dicloxacillin*
ß-LACTAM/ß-LACTAMASE
INHIBITOR COMBOS
Amoxicillin/clavulanate*
Ampicillin/sulbactam
Piperacillin/tazobactam
THE PENICILLINS STILL HAVE LOTS OF USES
NATURAL PENICILLINS
Pen VK: strep pharyngitis
Pen G: serious streptococcal skin
infection, syphilis
AMINOPENICILLINS
Amox: acute otitis media (AOM),
acute bacterial sinusitis (ABS)
Amp: Listeria meningitis,
Enterococcus infection
ANTISTAPHYLOCOCCAL
PENICILLINS (not MRSA)
Diclox: skin infection (staph or
strep)
Naf: more serious staphylococcal
infection (e.g. endocarditis)
ß-LACTAM/ß-LACTAMASE
INHIBITOR COMBOS
Amox/clav: refractory AOM or ABS,
dog or cat or human bites
Amp/sulb: community-acquired
pneumonia, mild-moderate
intraabdominal infection
Pip/tazo: life-threatening infection
PHARMACOKINETICS HELPS US TO MAKE
PREDICTIONS ABOUT DRUG BEHAVIOR
• Penicillins are bactericidal (targeting enzymes involved in cell
wall synthesis)
• Tend to have short half-lives and frequent dose intervals
• Oral absorption isn't complete:
Drug
% absorbed
penicillin V
ampicillin
amoxicillin
dicloxacillin
amox/clav
60-73
30-55
75-90
35-76
75-90
• Most common toxicities: GI, allergic
• Rare side effects: drug fever, seizures, neutropenia, interstitial
nephritis, liver toxicity
BICILLIN IS AN ERROR WAITING TO HAPPEN
• Bicillin L-A 2.4 million units = 2.4 million units
of benzathine penicillin G
• Bicillin C-R 2.4 million units = 1.2 million units
of benzathine penicillin G + 1.2 million units of
procaine penicillin G
• 429 patients with documented syphilis
treated at a large clinic in Los Angeles from
1999-2004 received the wrong product and
were underdosed. 234 patients treated for
sexual contact with someone known or
suspected to have syphilis were also
administered the wrong product.
WE DO NOT NEED ALL 27 CEPHALOSPORINS THAT
ARE CURRENTLY ON THE US MARKET
• First generation (6)
– Cefazolin
– Cephalexin*
(*=oral)
• Second generation (10)
– Cefotetan
– Cefuroxime axetil*
• Third generation (9)
– Ceftriaxone
– Ceftazidime
– Cefpodoxime proxetil*
– Cefdinir*
– Cefixime*
• Fourth generation (1)
– Cefepime
• Fifth generation (1) – for MRSA
– Ceftaroline
Sardinia:
where
cephalosporins
were first
discovered in
1945
1st generation
2nd generation
G+
increasing
ß-lactamase
stability
G3rd generation
4th generation
CEPHALOSPORINS HAVE TYPICAL USES TOO
1st
2nd
3rd
Cefazolin
Surgical prophylaxis, skin infection
Cephalexin (po)
Skin infection
Cefotetan
GI surgery prophylaxis, mild-to-moderate
intra-abdominal infection
Cefuroxime (po)
Refractory AOM, ABS
Ceftriaxone
Meningitis, endocarditis, skin infection,
gonorrhea
Ceftazidime
Serious Pseudomonas infection
Cefpodoxime (po)
Refractory AOM, ABS
Cefdinir
Refractory AOM
4th Cefepime
Life-threatening infection in the ICU
CEPHALOSPORINS ARE SIMILAR TO PENICILLINS
IN SOME RESPECTS BUT DIFFERENT IN OTHERS
•
Mechanism of action: fundamentally the
same
•
Cephalosporins tend to have a bit longer
half-lives than penicillins
•
Cephalosporins tend to be eliminated from
the body by more mechanisms than simply
the kidney
•
Side effects are generally the same;
cephalosporins cause more diarrhea but less
rashes than penicillins
TWO TYPES OF PENICILLIN HYPERSENSITIVITY
ARE IgE-MEDIATED, BUT ONE IS NOT
Immediate
Within 30-60 minutes of penicillin
administration; IgE directed against minor
(5%) determinants (benzylpenicillin,
penicilloate, penilloate)
Accelerated
Within 1-72 hours of penicillin
administration; IgE directed against major
(95%) determinant (penicilloyl*)
Delayed
≥ 72 hours after penicillin administration;
type II-IV hypersensitivity (non-IgE)
*Pre-Pen is the penicilloyl hapten conjugated to protein
THIS IS A MACULOPAPULAR RASH (NON-IgE)
23S rRNA
THIS IS AN URTICARIAL RASH (IgE)
23S rRNA
HERE ARE SOME PENICILLIN CROSS-ALLERGY
PERCENTAGES WITH OTHER BETA-LACTAMS
(for IgE-mediated reactions)
• Cephalosporins: probably 0.5% or less
– We used to think it was much higher
– Applies only to drugs with R-group similarity
(cephalexin, cefadroxil, cefaclor)
• Imipenem
– Anaphylaxis: as high as 50%
– Urticaria: probably under 10%
– Not known for other carbapenems (might be less?)
• Aztreonam
– Almost zero
Rashes are often thought of as benign
drug hypersensitivity reactions that
resolve merely by stopping the likely
perpetrator.
In most cases, this is true.
However, there are some skin
reactions that are dangerous and even
fatal, such as Stevens-Johnson
syndrome (SJS) and toxic epidermal
necrolysis (TEN).
STEVENS-JOHNSON SYNDROME AND TOXIC
EPIDERMAL NECROLYSIS ARE RARE BUT AWFUL
• Horrendous drug reactions characterized by skin detachment
– SJS: <10% BSA; TEN: >30% BSA
• Common offenders: antibiotics, anticonvulsants,
antinflammatory agents, allopurinol, even OTC meds like
ibuprofen.
• Generally appears 1-3 weeks after the drug is started
• Course: prodrome → painful, burning rash → blistering → full
thickness skin sloughing. Mucus membranes almost always
involved. Complications likely. Patients are literally “burning”
from the inside out.
• Treatment (esp. TEN): fluid & electrolyte management,
nutrition, antibiotics for secondary infections, analgesics.
Corticosteroid use controversial.
• Long term complications: blindness, scarring, internal organ
damage, death (TEN: 25-44% mortality).
23S rRNA
23S rRNA
23S rRNA
THE CLOCK IS PROBABLY TICKING
FOR VENERABLE VANCOMYCIN
• Our only glycopeptide and still drug of choice for MRSA
(IV only, but patients drink the injection for C.
difficile)
• Slowly bactericidal
• Strictly a Gram-positive spectrum
• Predictable pharmacokinetics
• Serum concentration monitoring is commonly done
– Troughs 10-15 or 15-20 (µg/ml) depending on the
infection
• Toxicity
– Histamine-release reaction
– Ototoxicity (peaks >80, but we don't measure peaks
anymore)
– Nephrotoxicity (only in combination?)
– Reversible neutropenia
WE HAVEN’T HAD A NEW AMINOGLYCOSIDE
SINCE GERALD FORD WAS PRESIDENT
Drug
Year
Source organism
Streptomycin
1944
Streptomyces griseus
Neomycin
1949
Streptomyces fradiae
Kanamycin
1957
Streptomyces kanamyceticus
Paromomycin
1959
Streptomyces rimosus
Spectinomycin 1962
Streptomyces spectabilis
Gentamicin
1963
Micromonospora purpurea
Tobramycin
1968
Streptomyces tenebrarius
Sisomicin
1972
Micromonospora inyoensis
Amikacin
1972
Semisynth deriv of kanamycin
Netilmicin
1975
Semisynth deriv of sisomicin
WE AVOID AMINOGLYCOSIDES BECAUSE THEY ARE
TOXIC, NOT BECAUSE THEY DON’T WORK
• Generally used only when necessary (less toxic drugs are
preferred)
• IV/IM only (poorly absorbed)
• Bactericidal
• These are powerful drugs, usually combined with a β-lactam
for serious Gram-negative infections including Pseudomonas
• Also used (in lower doses) to help drugs for Gram-positive
infections work better
• TOXIC!!!
– nephrotoxic (probably due to drug abnormally
accumulating in the renal cortex)
– ototoxic
• auditory (starting at high frequencies)
• vestibular (can be extremely debilitating)
– enhancement of neuromuscular blockade (rare)
OTOTOXICITY FROM AMINOGLYCOSIDES IS
WORSE THAN NEPHROTOXICITY, I THINK
KIDNEY
EAR
Reversible
Irreversible
Well defined risk factors*
Poorly defined risk factors
Well defined time course
(see next slide)
Poorly defined time course
Creatinine can be monitored
No common labs to follow
Serum concentrations
correlate
Poor correlation with serum
concentrations
*advanced age, duration of therapy, hypotension,
concomitant liver disease, use of other nephrotoxins
AMINOGLYCOSIDE DOSES ARE ADJUSTED
ACCORDING TO BLOOD CONCENTRATIONS
Infection
Peak conc
(μg/ml)
Trough conc
(μg/ml)
Gram-positive
3
<1
Gram-negative
(except pneumonia)
5-8
<1
Gram-negative
pneumonia
10-12
<1
Critical: the peak is measured one hour after an
infusion begins; the trough is measured immediately
prior to the next dose (all done at steady state).
The above numbers are for gentamicin and
tobramycin.
THE DRUGS IN YELLOW ARE THE ONLY
MACROLIDES AVAILABLE IN THE US
12-membered ring
(methymycin)
16-membered ring
(spiramycin)
14-membered ring
erythromycin
15-membered ring
(azithromycin)
clarithromycin
dirithromycin
flurithromycin
roxithromycin
telithromycin
(the 1st ketolide)
THIS IS ERYTHROMYCIN, THE PROTOTYPE
“MACROLIDE.” THE CIRCLED –OH GROUP IS
RESPONSIBLE FOR ITS NOTORIOUS GI TOXICITY.
6
1
THERE IS NOT MUCH TO LIKE ABOUT
ERYTHROMYCIN
LIKE
DON’T LIKE
Cheap
Bacteriostatic
Safe in pen allergy
Short half-life (2 hours)
Safe in pregnancy
Doesn’t cover H. influenzae
Poor for penicillin-resistant
strains of S. pneumoniae
Lots of confusing preparations
Inhibits liver metabolic enzymes
Causes nausea and vomiting
Causes diarrhea
May cause arrhythmias
AZITHROMYCIN (The Z-PAK) IS VERY
POPULAR FOR MANY REASONS
ISSUE
Less GI side effects than erythromycin
AZ CL
x
New annoying toxicity: metallic taste
x
x
Longer half-life than erythromycin
x
x
Covers H. influenzae
x
x
Inhibits hepatic drug metabolism
x
Less propensity to cause arrhythmias
x
Pregnancy category B like erythromycin
x
x
SUMMARY: AZITHROMYCIN IS MORE
GENERAL-PURPOSE THAN CLARITHROMYCIN
• Oral erythromycin is still occasionally used, mainly for cost reasons.
IV erythromycin is only rarely used.
• Oral azithromycin (the Z-PAK) is HEAVILY used for communityacquired pneumonia. Zmax is a single-dose option for CAP. IV
azithromycin is used in CAP patients who are admitted to the
hospital. Oral azithromycin is also occasionally used for skin
infections.
• Single-dose azithromycin is the drug of choice for Chlamydia
cervicitis/urethritis.
• Azithromycin is popular for MAC (Mycobacterium avium complex)
prophylaxis in AIDS patients (1200 mg every week).
• Azithromycin is also approved for AOM, although some consider it a
poor choice.
• Clarithromycin is a key drug for treatment of peptic ulcer disease
(H. pylori) in combination with other drugs. It finds occasional use
in CAP and AOM. It is FDA-approved for sinusitis. It is only
available as an oral formulation.
THE TETRACYCLINES WERE RUINED PROBABLY BY
OVERUSE, ALTHOUGH DOXYCYCLINE IS STILL
HANDY TO HAVE AROUND
• Tetracycline, doxycycline, minocycline (PO only)
• Bacteriostatic
• Particularly useful for Chlamydia, Mycoplasma.
Resistance has limited their usefulness for Grampositive cocci (Staphylococcus, Streptococcus).
• Toxicities are a serious issue
– GI irritation (doxy → esophageal ulceration)
– Phototoxicity
– Brown discoloration of the teeth, retarded bone
growth (avoid in patients <12)
– Vestibular toxicity (minocycline)
– Candidal superinfection
• All tetracyclines are pregnancy category D
• Avoid milk or dairy products, antacids, iron
preparations (but doxycycline must be taken with
food)
NO ONE WANTS THIS WEIRD SIDE EFFECT
• Black hairy tongue: Defective desquamation and reactive
hypertrophy of the filiform papillae of the tongue (not a fungal
infection, although candidal infection may be superimposed).
Exact pathogenesis unclear.
• Normal papillae: 1 mm in length; may reach >15 mm in this condition
• Usually asymptomatic
• Etiologic factors include poor oral hygiene, smoking,
hyposalivation, broad spectrum antibiotics, head and neck
radiation, illicit drug use, heavy coffee/tea drinking
• Treatment options
– increasing hydration and salivation
– quitting smoking
– brushing the tongue with a soft toothbrush
– surgical excision as a last resort
23S rRNA
STAPHYLOCOCCUS AUREUS CAN DEAL WITH
ANYTHING WE THROW AGAINST IT
EVENT
YEAR
COMMENT
Penicillinase-producing S. aureus
appears in an Oxfordshire
constable
1942
Penicillin introduced into clinical
practice in 1942
Emergence of MRSA (UK)
1961
Methicillin approved in 1961
Emergence of VISA (GISA)
1996
Vancomycin approved in 1958
4 deaths of children in rural ND
and MN; no contact with the
healthcare system
1999
The beginning of the CA-MRSA
era
Emergence of VRSA
2002
Reported 11 times so far
TMP-SMX (BACTRIM): STILL GOOD FOR
SKIN INFECTIONS, UTI, AND PCP
•
•
•
•
•
TMP=trimethoprim, SMX=sulfamethoxazole
Potent combination working sequentially
Inexpensive
PO (SS and DS), also IV (inconvenient)
Still useful for UTI and Pneumocystis pneumonia (PCP) in
AIDS; not as useful anymore for otitis media (because of
resistance)
• Considered by many to be the drug of choice for skin
infections caused by CA-MRSA
• Toxicities
– GI
– dermatologic (including Stevens-Johnson Syndrome):
3-5% of patients
– blood dyscrasias
– hemolytic anemia in G6PD-deficient patients
“SULFA” OR “SULFONAMIDE” ALLERGY MEANS
WHAT, EXACTLY? THERE ARE A LOT OF NONANTIBIOTIC SULFONAMIDES, LIKE THESE.
acetazolamide (Diamox)
chlorpropamide (Diabinese)
chlorthalidone (Hygroton)
dapsone
diazoxide (Hyperstat)
furosemide (Lasix)
glipizide (Glucotrol)
glyburide (Micronase, Diabeta)
hydrochlorothiazide
metolazone (Zaroxolyn)
probenecid
tolazamide (Tolinase)
tolbutamide (Orinase)
torsemide (Demadex)
QUALITY DATA SUGGEST IT IS SAFE TO GIVE NONANTIBIOTIC SULFONAMIDES TO PATIENTS WITH
ALLERGIES TO SULFONAMIDE ANTIBIOTICS
• Retrospective cohort study using the UK’s General Practice
Research Database (over 8 million patients), established in 1987
(study period 1987-1999)
• Of 969 patients who reacted to a sulfonamide antibiotic and were
subsequently administered a sulfonamide nonantibiotic, 96 (9.9%)
had an allergic reaction (odds ratio=2.8)
• Of 5115 patients who reacted to a sulfonamide antibiotic and were
subsequently administered a penicillin, 717 (14%) had an allergic
reaction (odds ratio 3.9)
• Among those with an allergic reaction to a sulfonamide antibiotic,
the odds ratio for an allergic reaction to a subsequent sulfonamide
antibiotic, compared to a subsequent penicillin, was 0.7
• An allergic reaction to a sulfonamide nonantibiotic occurred in
9.1% of patients with prior evidence of sulfonamide
hypersensitivity, compared to 14.6% of patients with prior
evidence of penicillin hypersensitivity
Strom et al. NEJM 2003; 349: 1628-1635
CLINDAMYCIN HAS THE PERFECT SPECTRUM
FOR MANY SKIN INFECTIONS
• Good drug for anaerobic organisms; covers Grampositive aerobes also, plus a few protozoa
• Bacteriostatic
• Distributes widely throughout the body (except for
the CSF); penetrates abscess cavities well
• Uses: mixed aerobic-anaerobic infections, skin
infections. Very handy drug.
• Available PO and IV
• Considered safe in pregnancy
• Notorious toxicity: pseudomembranous colitis (PMC)
caused by Clostridium difficile
LINEZOLID (ZYVOX): A GOOD MRSA DRUG
BUT RIDICULOUSLY EXPENSIVE
• The first oxazolidinone antibiotic approved by the FDA
• Useful for resistant Gram-positive infections
• Recent data suggest superior clinical cure rates and
survival vs vancomycin for MRSA nosocomial pneumonia,
although vancomycin dosing may not have been optimal
(Chest 2003;124:1789)
• Synthetic drug with a unique mechanism of action
• Larger dose in patients <12 years of age (10 mg/kg q8h)
• Similar toxicities in adults and children (possibly less
thrombocytopenia)
• Available as injectable, tablets, and oral suspension
• Expensive!
• Becoming more and more useful as the prevalence of
MRSA in the community increases
THESE ARE THE FLUOROQUINOLONES. THERE ARE
FEWER ON THE MARKET THAN HAVE BEEN REMOVED
FROM THE MARKET!
FIRST1
All
obsolete
1nalidixic
SECOND2
THIRD3
Ciprofloxacin
Moxifloxacin
FOURTH4
None
Levofloxacin
Gemifloxacin
acid, cinoxacin, oxolinic acid
2obsolete:
norfloxacin, enoxacin, lomefloxacin, ofloxacin
3gatifloxacin
(Tequin) withdrawn from the market in 2006
4trovafloxacin
hepatotoxicity
(Trovan) withdrawn from the market because of
BAD NEWS: MMWR 2007; 56(14): 325-360 (April 13, 2007)
http://www.cdc.gov/mmwr
FQs ARE GREAT. WE NEED TO GET THEIR USE UNDER
CONTROL BEFORE THEY STOP WORKING FOREVER.
1. These are HEAVILY used drugs (usually PO, sometimes IV). There
is great fear that overuse will lead to the demise of the entire
class. Some evidence for this already exists.
2. FQs are popular because they are bactericidal against many
important pathogens, and they are very well tolerated.
3. Levofloxacin is the workhorse. It is the drug of choice in a growing
number of UTI patients. It is commonly used for communityacquired pneumonia and sinusitis. It has other uses as well, such as
traveler’s diarrhea and STDs.
4. Ciprofloxacin is similar to levofloxacin except that it is less potent
for Gram-positives, and its half-life is shorter. Moxifloxacin is
theoretically the best FQ for Gram-positive organisms.
5. The most common side effect is GI. Photosensitivity can be a
problem. FQs rarely have caused tendon rupture. They are
probably not toxic to developing cartilage in humans.
6. Only ciprofloxacin precipitates metabolic drug interactions. The
absorption of all FQs is affected by metal ions, however (e.g.
aluminum, magnesium).
NITROFURANTOIN (MACROBID,MACRODANTIN) CAN
BE QUITE USEFUL NOW AND THEN
• Only use: UTI (cystitis) due to susceptible strains of E. coli,
Enterococcus, S. aureus (plus a few others)
• Lower cure rates (85%) than firstline agents (90-95%)
• Won’t work for pyelonephritis, won’t work in renal insufficiency
(CrCl <50)
• Treatment dose: Macrodantin 100 mg po QID, Macrobid 100 mg po
BID
• Prophylaxis dose: 50-100 mg po qhs
• Duration of therapy: 5-7 days, not 3 days
• Good choice in pregnancy (category B)
• Side effects:
– Significant GI toxicity
– Peripheral neuropathy
– Liver, lung toxicity with longterm use
– Hemolytic anemia in G6PD-deficient patients
RIFAMPIN‘S ABILITY TO INTERACT WITH OTHER
DRUGS SHOULD ALWAYS GET YOUR ATTENTION
• Rifampin inhibits bacterial DNA-dependent RNA polymerase
• 3 major uses
– first line drug for tuberculosis
– combination therapy for Staphylococcus
– meningitis prophylaxis (Neisseria meningitidis)
• NEVER used alone (except for prophylaxis) because
resistance will emerge quickly
• Typical dose: 600-900 mg po qd (divided?)
• Available PO and IV
• Significant adverse effects
– widespread discoloration of body fluids and tissues
– nausea
– flu-like symptoms
– abnormalities in liver function tests
• EXTREMELY potent inducer of liver metabolism
METRONIDAZOLE IS A FREAK: AN ANTIPROTOZOAL
DRUG THAT ALSO KILLS ANAEROBIC BACTERIA
• Excellent for anaerobes and protozoa; no activity against
aerobic bacteria
• Bactericidal
• Excellent tissue penetration; penetrates abscesses well;
half-life 8 hours
• Uses: to provide antianaerobic activity in a combination
drug regimen; trichomoniasis; giardiasis; bacterial
vaginosis (Gardnerella vaginalis); treatment of C. difficile
colitis
• Available PO and IV
• May inhibit drug metabolism
• Toxicities: GI discomfort, metallic taste, peripheral
neuropathy, disulfiram-like effect, skin eruptions
• Considered safe in all trimesters