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208 Cards in this Set

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The goal of antibacterial therapy
Assist the body in ridding itself of the infecting organism
Incorrect usage of antibiotics?
Led to wide-spread development of antibiotic resistance in both hospitalized patients and the community (eg. MRSA)
nosocomial
infections acquired in the hospital
antibacterial spectrum
classes of bacteria or individual bacterium which are affected by the antibiotic drug

NARROW SPECTRUM -- mainly against aerobic and andarobic gram-positive cocci and some gram-negative cocci

BROAD SPECTRUM -- act against many gram-positive and gram-negative bacteria
bacteriostatic drugs
inhibit the multiplication of bacteria; the immune system does the rest

ex: macrolides and clindamycin
macrolide antibiotic drugs
erythromycin, clarithromycin, and azithromycin
MIC
Minimum Inhibitory Concentration -- different for different drug/bug combinations
Bactericidal drugs
kill bacteria

ex: beta-lactams, fluoriquinolones, and aminoglycosides
Beta Lactams
penicillin, cephalosporins, carbapenems, and aztreonam
The names of the fluoroquinolones end in...
-floxacin; levofloxacin
Time-dependent killing
depends on maintaining the plasma drug concentration above the MIC. Increasing the Cp above the MIC does NOT enhance killing

Ex: beta-lactams, and vancomycin
Concentration-dependent killing
The rate and efficiency of killing increases as the Cp increases.

Ex: fluoroquinolones and aminoglycosides (gentimicin, amikacin, and tobramycin)
Post-antibiotic effect
A drug continues to be bacteriostatic or bacteriocidal after the Co has fallen below the MIC.

Ex: fluoroquinolones and aminoglycosides
Antibiotic Synergism
describes the ability of two bactericidal drugs to cayse greater killing than either drug could by itself.

Usually occurs when two drugs inhibit sequential enzymatic steps in a synthetic pathway (trimethopam/sulfamethoxazole) or kill bacteria by two different mechanisms (aminoglycoside + a beta-lactam)
Antibiotic Antagonism
means that one drug decreases the antibiotic effect of another drug. Bacteria usually have to be multiplying for a bactericidal drug to kill them, so theoretically a bacteriostatic drug can antagonize the killing action of any bactericidal drug.
Antibiogram
Provides the sensitivity of the isolates of different bacterial species to a variety of different antibiotic drugs

Usually more than 890% of the isolates need to be sensitive for an antibiotic drug to be considered to be effective empiric therapy.
Susceptible (S)
Standard doses of static or cidal drugs are effective
Intermediate (I)
Increase the dose of the drug or use a different drug
Resistant (R)
The drug no longer exerts and antibacterial effect at readily achievable plasma concentrations.

UHS - more than 95% of the isolates of S. Aureus are resistant to penicillin

Some bacterial strains have become multi-drug resistant (MDR)
Antimetabolite MOA
Given singly they are static; given together they are bacteriostatic and sometimes bactercidal against susceptible organisms

Ex: teimethoprim + sulfamethoxazole, a.k.a., trim-sulfa
Inhibitors of protein synthesis
Bacteriostatic Drugs

Chloramphenicol
Tetracycline
Macrolides (e.g. erythromycin)
Clindamycin
Aminoglycosides EXCEPTION: gentamicin is bacteriocidal
Quinupristin/Dalfopristin (bactericidal against certain bugs)
Linezolid (bactericidal against certain bugs)
Inhibitors of cell wall synthesis
Bactericidal drugs

Penicillins
Carbapenems (imipenem and meropenem)
Monobactams (aztreonam)
Cephalosporans
Vancomycin
Isoniazid
Ethambutol
Bacitracin
Inhibitors of DNA/RNA synthesis
Bactericidal drugs

Fluroquinolones (levofloxacin)
Rifampin
Nitrofurantoin
Increase bacterial membrane permeability
Bactericidal drugs

Polymixin B
Colistin (polymixin E)
Name four mechanisms of resistance by bacteria.
1. Produce enzyme which destroys the drug

2. Bacterial mutation changes the binding (target) site for the drug.

3. Bacteria pumps the drug out (drug efflux)

4. A bacterial mutation prevents drug entry
Examples of bacteria which produce drug-destroying enzymes.
1. Staph aureus -- produces beta-lactamases which destroy the B-lactam ring of the penicillins to render the drugs inactive.
A plasmid codes for the B-lactamase in S. aureus
Examples of bacterial mutation changing the binding site of a drug.
1. Methicillin-resistant Staph aureus (MRSA) -- expresses an additional B-lactam binding site which is coded by a mutated gene....ALWAYS resistant to ALL beta-lactams

2. Step pneumo -- resistant strains to PCNs have high molecular weight PBPs with decreased affinity for B-lactams (genes acquired from other bacterial species)
Examples of bacteria who efflux drugs.
1. Gram(-) bugs such as Pseudomonas and Acinetobacter pump drugs out. Pseudomonas may have 20 pumps and 3-4 B-lactamases

2. Strep pneumo pumps out macrolides.
Example of bacterial mutation preventing drug entry.
Mutation in Pseudomonas decreases the number of porins which are the site of entry of the carbapenems.
How is resistance acquired?
1. mutation of bacterial genes which occur at random
2. sex = conjugation swaps DNA and plasmids
3. cannibalism = bacteria "eat" free bacterial DNA in env.
4. little visitors = transductino via plasmids carried by bacterial viruses
5. plasmids can swap DNA via transposons.
Gram positive normal resistance
Usually a change in the binding site of the drug which creates a high level of resistance

Exception: S. Aureus produces B-lactamase
Gram negative normal resistance
efflux pumps and B-lactamases (can generate a high concentration of B-lactamase between the cell wall and the cell membrane)
Usual suspects: G(+) aerobic cocci
Staphylococcus
coag positive = aureus
coag negative = epidermis, saprophyticus, and others

Strep pneumo (resp, otitis, meningitis)
Strep pyogenes (GAS - "flesh-eating bacteria")

Enterococcus faecalis and faecium (ICU infections)
Usual suspects: G(+) anaerobes
Peptococcus and Peptostreptococcus
Usual suspects: G(-) aerobes
Neisseria gonorrhoeae
Neisseria meningitidis
Moraxella catarrhalis
Usual suspects: G(+) aerobic bacilli
Listeria monocytogenes (processed meats)
Usual suspects: G(-) aerobic bacilli, ENTERICS
E. coli (UTI)
Klebsiella pneumoniae (UTI)
Proteus mirablis (UTI)
Salmonella
Shigella
Enterobacter (ICU)
Citrobacter (ICU)
Usual suspects: non-enteric G(-) aerobic bacilli
Pseudomonas aeruginosa (ICU)
Haemophilus influenzae
Legionella pneumophilia (CAP)
Campylobacter (chickens)
Acinetobacter baumanii (ICU)
Helicobacter pylori
Usual suspects: G(+) anaerobes
Clostridium
botulinum
tetani
difficile
perfringens
Usual suspects: G(-) anaerobes
Bacteroides fragilis
Other bad bugs
Mycobacterium tuberculosis
Chlamydia pneumoniae
Spirochetes
Borrelia burgdorferi
Treponema pallidum
Mycoplasma pneumoniae
The "knife and gun club" bacteria
The Gut Anaerobes:
Bacteroides
Clostridium
Peptostreptococcus
Enterococcus
Gut G(-) bugs
What are the bugs that cause community acquired pneumonia (CAP)?
Typical:
strep pneumo, H flu, and Moraxella catarrhalis

Atypical:
Mycoplasma, Chlamydia, and Legionella (all intracellular pathogens)
What are some common problems of antibiotic drug use?
Frequency of use
Inappropriate use
Sicker patients with incorrect perceptions (viral infections don't require antibiotics)
Superinfections (C. diff)
Antibiotic prophylaxis
Combination therapy
Explain superinfection
This is the appearance of a new bacterial or fungal infection during treatment of the primary infection.

Ex: pseudomembranous colitis caused by C. diff while on antibiotics.
Ex: a female patient developing a yeast infection while on an antibiotic
What enhances the likelihood of developing a superinfection?
Taking a broader spectrum antibacterial drug, using an antibiotic for prolonged periods, and if you have immune system suppression during antibiotic treatment.
When is it okay to use combination therapy?
Tx of endocarditis, meningitis, and infections caused by Pseudomonas and Acinetobacter
Gram positive problem pathogens?
methicillin-resistant Staph aureus (MRSA)

vancomycin resistant Enterococcus faecium (VRE or VREF)

penicillin resistant Strep pneumo (PRSP) - a marker for multi-drug resistant Strep pneumo
Gram negative problem pathogens?
Multidrug resistant (MDR) Pseudomonas aeruginosa

MDR Enterobacter

MDR Acinetobacter
What's the deal with MRSA?
You CANNOT use B-lactams for treatment.

In the past, MRSA only occurred in hospitals, now 50% of outpatient Staph infections are MRSA.

Four cases of S. aureus resistant to vanc have been reported (picked up gene from VREs)
Gram positive bacteria: General overview
The cytoplasmic membrane which contains penicillin-binding proteins (PCBs) is enclosed by a cell wall which consist of 50-100 layers of cross-linked peptidoglycan molecules
Gram negative bacteria: General overview
- Cell wall has two components: an outer bilipid mbrn and and an inner, thin peptidoglycan layer. Proteins called PORINS traverse the outer mbrn and ptovide aqueous channels which allow entry of antibiotics into the cell.
- The periplasmic space, which separates the thin peptidoglycan from the outer mbrn, may contain B-lactamases which will destroy B-lactam drugs before they are able to bind to the PBPs embedded in the cytoplasmic mbrn.
- Certain infections are treated with a combination of B-lactam and an aminoglycoside because inhib of cell wall synth by the B-lactam enhances penetration of the eminoglycoside into the cell.
MOA for penicillin?
A patent cell wall is necessary for the survival of G(+) bacteria and the PCNs inhibit cell wall synthesis resulting in cell lysis and death.
Explain the cell wall of G(+) bacteria.
- Consists of layers of peptidoglycan which form a rigid latticework.
- peptidoglycan layer consists of multiple, parallel peptide side chains projecting at right angles from the polysaccharide backbone
- peptide side-chains of one polysaccharide are linked covalently to the peptide side chains of the adjacent, parallel polysaccharide backbone and they are cross-linked via enzymatic transpeptidation.
- Transpeptidation catalyzed by penicillin binding proteins (PBPs)and they bind to the terminal D-Ala-D-Ala of the peptide side chains
How does PCN inhibit cell wall synthesis?
They (and cephalosporins) are structural analogs of the D-Ala-D-Ala substrate, and the PCNs bind covalently to the active site of the PBPs, thus producing irreversible inhibition of transpeptidation and cell wall synthesis.
3 mechanisms of bacterial resistance to PCNs
1. production of B-lactamases which destroy the B-lactam ring which allows PCN binding to the PBPs -- most common type resistance
2. Mutations which change the binding sites of PBPs -- decreasing ability of PCNs to bind (MRSA, Strep pneumo, and enterococci)
3. Bacterial efflux of PCNs -- some G(-) bugs
PCN distribution
Fluids -- good distribution

CSF -- questionable, bit will penetrate into CNS if meninges inflamed

Intracellular -- POOR - cannot be used to treat intracellular bugs. NONE of the B-lactams enter cells.
PCN elimination
Renal tubular secretion causes rapid urinary excretion so half life is about 30 minutes. This half life is increased in patients with renal failure.
Probenacid
inhibits renal acid transport system which secretes penicillin G and thus increases the half life of penG
What are the determinants of hypersensitivity to PCN?
major determinant = penicilloic acid + protein

minor determinant = penicillin or a metabolite + protein
Types of PCN hypersensitivity reactions?
immediate -- anaphylaxis, angioedema (avoid B-lactams)

accelerated -- uticaria, laryngeal edema (avoid B-lactams)

late -- rash, serum sickness (may consider use)
Toxicities and side-effects of PCNs?
hypersensitivity reactions -- immediate, accelerated, and late

seizures

5-10% of all patients claim to be allergic to PCNs, but only 5-10% of those who claim allergy actually have true, serious HS reactions to PCNs.
Penicillin G
The FIRST penicillin.
- always give i.v. because it is acid labile.
- DOC for B-hemolytic streps (ABCFG strains)
- give larger doses to cover strep pneumo
- effective in treatment of syphillis, gonorrhea, and N. menigitides
If strep pneumo is highly resistant to Pen G, then it is also resistant to...?
3rd generation cephalosporins
We do not Pen G for?
Staph aureus because 95% of the strains are resistant.
Penicillin V
- Must tx q 6h
- active when given p.o. because it is acid stable; however, F is low so you should use p.o. amoxicillin
- can be used p.o for strep throat, but amoxacillin has better F
- GAS killed quickly by Pen G and Pen VK
Depot PCNs
Pen G, benzathine, Procaine Pen G

- given i.m. for slow release
- used prophylactically to prevent GAS infections in military recruits
- used to treat syphillis but NOT neurosyphillis
What are the Penicillinase (B-lactamase) resistant penicillins?
Methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin
methicillin
- first B-lactamase resistant PCN
- No longer used clinically b/c nephrotoxic
- Prev use: Pen G resistant Staph, especially skin and soft tissue infections
- Name now used to designate a particular typed of drug-resistant staph aureus -- MRSA
- MRSA also called oxacillin resistant staph aureus (ORSA)
oxacillin, nafcillin, cloxacillin, and dicloxacillin
ox-naf given i.v.
clox-diclox given p.o.

used to treat soft tissue infections caused by penicillinase strains producing staph infections and infections caused by susceptible strains of strep b/c of their short half-life.
How do we generally treat MRSA?
outpatient -- clindamycin, trimethoprim-slfamethoxazole or doxycycline

inpatient -- i.v. vancomycin
ox, naf, clox, and dicyclox are always superior to ....
vancomycin because they kill quickly (when cultures are susceptible...otherwise, use vanc)
What are the B-lactamase (penicillinase and cephalosporinase) inhibitors?
clavulanate (clavulinic acid, sulbactam, tazobactam
How are the B-lactamase inhibitors used?
- Some PCNs and all of the cephalosporins are more resistant to degradatino by B-lactamases than others, but some PCNs are easily degraded by B-lactamases.
- Coadministration of an inhibior of B-lactamase protects the PCNs from inactivation by the bacterial enzymes.
Aminopenicillins?
ampicillin -- i.v. and p.o available; p.o. gives diarrhea

amoxicillin -- p.o.

These extend the spectrum of PCNs, but both are destroyed by B-lactamases
What type of coverage do aminopenicillins offer?
Their spectrum is extended to cover G(-) bugs E.coli and H.flu because these PCNs are better able to penetrate the outer mbrn of G(-) bacteria.
- MUST be combined with a B-lactamase inhibitor to treat infections caused by (MSSA) S.aureus and other B-lactamase producing drugs
Ampicillin
(i.v.) -- ampicillin + sulbactam
-- DO NOT give ampicillin p.o. because it causes diarrhea 8X/day
-- DOC for infections by Listeria and Enterococcus

NOT active against MRSA
What drugs are active against Enterococcus?
Ampicillin, vancomycin, tigecycline, quinupristin/dalfopristin, linezolid, and daptomycin
Amoxicillin
-- aminopenicillin available p.o.
absorption p.o not affected by presence of food
What are the antipseudomonal penicillins?
- carbenicillin and mezlocillin (no longer used)
- ticarcillin
- ticarcillin + clavulanate
- piperacillin
- piperacillin + tazobactam

All those currently used are give i.v. only
What is the antipseudomonal spectrum of activity?
- designed specifically to kill P. aeruginosa, but also exhibit activity against enterobacteriacea
- b/c strains of Pseudomonas often develop resistance to monotherapy, these PCNs are often used in combination with aminoglycosidic drug like gentamicin
- used in the ICU
- must be given i.v.; no p.o. equivalent
When are Pen G and V DOCs?
1. b-hemolytic strep (ABCFH)
2. susceptible strep pneumo, but actually use amoxicillin
3. meningococcal meningitis -- only Pen G at higher doses
When are oxacillin, nafcillin, cloxacillin, or dicloxacillin DOCs?
1. susceptible (non-MRSA) staph aureus infections -- cellulitis, abscesses, and other infections like endocarditis and meningitis
2. These PCNs are always preferred over broad-spectrum antibiotics (fluoroquinilones) in treatment of susceptible S.aureus infections
When is amoxacillin the DOC?
First line drug for otitis media.

If it does not work in treatment, use amoxacillin + clavulanate (B-lactamase inhibitor)
When are pip-tazo and ticar-clav the DOCs?
1. Given i.v. in the ICU
2. Used to treat Pseudomonas infections
Carbanepems MOA?
Same as PCNs, but these are available i.v. only!
Carbanepem spectrum?
- BROADEST spectrum B-lactam sntibiotic drugs
- cover many nosocomial G(-) rods including Pseudomonas, anaerobes, and G(+)
- NOT hydrolyzed by most B-lactamases, but ARE degraded by metallo-B-lactamases (carbanepamases)
Name the carbanepems.
Impenem (Impenem + cilastatin DHP inhibitor)
Meropenem
Ertapenem (aka "weinie"penem)
Imipenem
-- Mobilized by renal dihydropeptidases (DHP) and must be given in combo with the DHP inhibitor cilastatin.
-- Often called "seizurecillin" because it can cause seizures, espec with high doses in patients with renal failure and in neurosurgical patients
-- better for G(+) bugs
Meropenem
-- used for meningitis b/c less likely to cause seizures
-- better for G(-) bugs
Ertapenem
DOES NOT cover Pseudomonas, Acinetobacter or enterococci
What are the indications for carbanepems?
-- good tissue penetration
1. multi-resistant bugs -- drugs of last resort given to patients who have failed therapy with pip-tazo and cefepime
2. polymicrobial, life-threatening infections (intra-abdom and nosocomial infections caused by Citrobacter, Enterobacter, etc)
Are carbanepems indicated for febrile, neutropenic patients?
No -- use pip-tazo instead.
Aztreonam MOA
A monobactam with same MOA as PCNs but PCN cross-reaction does NOT occur.

- Only i.v.
- Only G(-)
Aztreonam clinical use?
Good G(-) activity including Pseudomonas (comparable to ceftazidime)

i.v. only

NO clinically useful activity against anaerobes and G(+) bugs, including MRSA

Exhibits cross-reactions with many 3rd generation cephalosporins, espec. ceftazidime and cefepime
Aztreonam spectrum of activity?
resembles that of aminoglycoside drugs (gentamicin) and was marketed in hopes it would replace aminoglycosides.
Give an example of Aztreonam use.
A patient with a severe G(-) infection who has a PCN allergy.
- little cross-rxn with other B-lactams
- good G(-)
Cephalosporin MOA?
same as PCNs -- inhibit peptidoglycan cross-linking by binding to the active site of the PBPs
Cephalosporin resistance?
same mech as with the PCNs -- changes in the binding PBP site; drugs are starting to make cephalosporinases
Cephalosporin spectrum of activity?
-- Varies btwn different generations
-- All are relatively resistant to hydrolysis by the B-lacamases and thus have broader spectrum of activity than the PCNs
-- NO activity against Enterococcus, Listeria, PCN resistant strep pneumo, or MRSA!
What are the first generation cephalosporins?
i.v. cefazolin
p.o. cephalexin
What are the second generation cephalosporins?
i.v. cefoxitin
i.v. cefotetan
What are the third generation cephalosporins?
i.v. cefotaxime
i.v. cetriaxone
i.v. ceftazidime
p.o. cefdinir
What are the fourth generation cephalosporins?
i.v. cefepime
What are the generational coverage trends?
1st - best against G(+)
2nd - G(+), but add some G(-) and anarobes (only cefoxitin and cefotetan)
3rd - increased G(-) at the expense of G(+) coverage
4th - moderate G(+) activity and excellent G(-) activity; resembes the spectrum of 1st plus 3rd generation (4=1+3)
Cephoxitin and cefotetan are the only cephalosporins with...?
i.v.

significant activity against anaerobic bugs -- used to treat PID and intra-abdom infections

DOC for prophylaxis for intra-abdom surgery

- slightly less G(+) activity than 1st gen drugs
- More G(-) activity than 1st gen drugs
Cephalosporin distribution and elimination?
- Good distribution to most body fluids, but do not enter cells!
- Good CNS penetration with ceftazidime(3), ceftriaxone(3), cefotaxime(3), and cefepime(4), so these drugs are used to treat bacterial meningitis.

Most are eliminated renally so dose must be decreased in patients with impaired renal fxn. EXCEPTION: ceftriaxone is metabolized by liver
Cephalosporin toxicity and S/Es?
1. X-rxn in patients with PCN allergy
- as generation increases, x-reactivity decreases
- signif x-rxn with 1st gen
- 1-2% x-rxn btwn 3rd and 4th gen
2. Thrombophlebitis - uncommon, but can occur when drugs, espec. cefoxitin are given by i.v."push"
3. Superinfection - more common when treated with a broad spec cephalosporin
4. Prolongation of PT time causing bleeding
- shown to inhibit vitamin K epoxide reductase which regenerates Vit K for synth of clotting factors 2,7,9,10
- rare S/E and most likely to occur with cefotetan freq used for intraabdominal prophylaxis
- Vit K therapy NOT req'd for patients receiving cephalosporins
Cephazolin
i.v.

- great G(+) drug with little G(-) activity
- covers S. aureus, streptococci, and G(-) E.coli and K.pneumoniae
- use to treat pyelonephritis in a pregnant woman
- DOC for surgical prophylaxis; good tissue penetration and cheap
- good for skin and soft tissue infections (SSTI) if not caused by MRSA
Ceftazidime
-covers G(-) bugs including P. aeruginosa, but little activity against G(+) bugs including strep pneumo (CAP)
Cephalexin
p.o.

- rarely the DOC for anything
- safe to use in pregnant women
Cefotaxime
i.v. half-life - 1 hr

- ceph of choice for treatment of strep pneumo infections (including meningitis) b/c effective against Pen G resistant strep pneumo and very potent (low MIC)
- used to treat meningitis caused by strep pneumo AND Neisseria
Ceftriaxone
i.v. half-life - 8 hrs

- can be given q12h or q24h
- ceph of choice for treatment of strep pneumo infections (including meningitis) b/c effective against Pen G resistant strep pneumo and very potent (low MIC)
- 3rd gen but good G(+) activity
- given in single large i.m. dose for treatment of cervical, urethral, oropharyngeal, or rectal gonorrhea
- used to treat meningitis caused by sterp pneumo and Neisseria
Cefdinir
p.o.

good for treatment of otitis media after two failures with amoxacillin or amoxacillin + clavlanate
Cefepime
i.v.

- moderate G(+) activity and excellent G(-) activity; resembles the spectrum of 1st+3rd generation
- active against P. aeruginosa
- good CNS penetration, so used to treat G(-) meningitis
- improved G(+) activity over ceftazidime
- increased resistance to degradation by B-lactamases

**use in ICU, esp. in neutropenic patients
Therapeutic use of Cefazolin?
i.v.

#1 drug for surgical prophylaxis

Skin and soft tissue infections, but not for MRSA
(NB: All SSTI are assumed to be caused by staph or strep unless otherwise proven)
Therapeutic use of Cefoxitin and Cefotetan?
i.v.

#1 drugs for intra-abdominal surgical prophylaxis

The 2nd generation p.o. drugs are not used much now b/c they have been replaced by the 3rd gen p.o. drugs
Therapeutic use of Ceftazidime?
i.v. for P. aeruginosa

NEVER treat life and limb-threatening Psudomonas with a single drug! ALWAYS use two drugs with different MOAs -- B-lactam + aminoglycoside (gentamicin)
Therapeutic use of Cefotaxime?
i.v.

1. strep pneumo infections including meningitis and B-hemolytic strep
2. community acquired minigitis = H. flu, strep pneumo, Neisseria
3. severe otitis media
4. inpatient comminity acquired pneumonia (CAP) = H. flu, strep pneumo, and Moraxella. A macrolide (clarithromycin) can be added to cover atypical bugs
Therapeutic use of Ceftriaxone?
1. strep pneumo infections including meningitis and B-hemolytic strep
2. severe otitis media
3. inpatient comminity acquired pneumonia (CAP) = H. flu, strep pneumo, and Moraxella. A macrolide (clarithromycin) can be added to cover atypical bugs
4. Treat gonorrhea with single i.m. dose
Therapeutic use of cefepime?
i.v.

1. febrile neutropenic patients -- G(-) bugs can kill these patients in two hours, so need a bactericidal drug w/ strong G(-) coverage
2. Inpatient strep pneumo
3. critically ill patients (ICU)
4. mixed infections
5. unknown infections
Cephalosporin rules to remember?
1. NONE of the currently available cephs cover enterococci or MRSA

2. G(+) activity:
1st>2nd>3rd generation

3. G(-) activity:
3rd>2nd>1st generation

4. Cefoxitin and cefotetan have good anaerobic activity
Vancomycin MOA?
Does NOT involve PBPs!
- covalently binds the D-ala-D-ala terminus of the peptide side chains, and this binding sterically hinders the action of peptidoglycan polymerase and transpeptidases: elongation of the peptidoglycan polymer ceases
Vancomycin issues?
BIG molecule with penetration problems

Bactericidal, but does not kill bugs as quickly as the B-lactams...always use B-lactam to treat MSSA
Vancomycin antibac activity?
MUST be given i.v.

- Covers G(+) bugs including anaerobes
- No G(-) activity
- DOC for severe MRSA infections
- Amp-resistant enterococci treatment -- although now up to 50% of E. faecium are resistant to vanc (almost always susceptible to ampicillin)
- Could theoretically use for PCN resistant strep pneumo but use fluroquinone instead as long as it's not meningitis -- use vanc for meningitis
Vancomycin resistance?
Resistant Enterococci (VRE) - 30-40% are now resistant
--involves an alteration in the structure of the D-Ala-D-Ala terminus of the peptide side chains where D-Ala replaced by a D-lactate preventing high-affinity binding of vanc
-- Five biochemical steps required for mutation in a gene cassette (VanA) which enterococci can give to staph

Vanc-resistant s. Aureus (VRSA) have been ID'd but still VERY rare

Use Vanc for G(+) multi-drug resistant (MDR) strains as long as bugs not enterococci
Vancomycin kinetics?
i.v. for systemic infections because NOT ABSORBED after p.o. dosing

p.o. for C. diff life threatening diarrhea

-- large molecule means poor penetration into CSF
-- Eliminated by urinary excretion, so monitor renal fxn
-- Adjust dose in renal failure patients
Vancomycin toxicity and S/Es?
1. ototoxicity causing deafness
-- rare w/out excessive plasma concentrations or prolonged use
-- early problem in 70s before improved drug purity
2. Renal toxicity
-- renal fxn can decline during use although toxicity is probably overstated
-- intersitial nephritis can occur but rare
3. "Red Man" Syndrome
-- NOT an allergic rxn
-- first i.v. dose given too rapidly elicits histamine release which causes flushing in neck and head
-- SE can be prevented by infusing dose over 1-2h or by pretreating with later dose of antihistamine diphenhydramine
4. Allergic rxns and rashes
Vancomycin therapeutic use?
1. MRSA hospital infections -- minimum 14 days of i.v. treatment
2. MDR strep pneumo infections (NB: fluroquinolones work better)
3. amp-resistant enterococcal infections (E faecalis)
4. Empiric therapy for bacterial meningitis
-- strep pneumo most common cause
-- treat w/ ceftriaxone + vancomycin; vanc added to cover small number of isolatres which exhibit high level of PCN resistance
-- add i.v. ampicillin to cover Listeria if patient is <2y.o. or elderly
Vanc therapeutic use continued...
5. Empiric therapy for febrile neutropenia
-- must treat with bactericidal with G(-) coverage such as pip-tazo or cefepime
-- vanc is added when you have evidence of G(+) or you are awaiting culture results
6. Empiric therapy for G(+) bacteremia
-- must use Vanc until you know what but causing the infection b/c of increased risk of MRSA
-- #1 bug cultured from blood samples is coag neg staph and 90% of time is skin contam S. epidermidis
-- Don't use Vanc for G(+) bacteremia until staph shows up in multiple blood cultures
Uses of p.o. Vancomycin?
Very poorly absorned after p.o. therapy, so oral therapy CANNOT be used for systemic infections

Use of p.o. therapy strongly linked to VRE emergence

Second-line therapy for pseudomembranous colitis caused by C. diff
-- DOC for C. diff is metronidazole
-- After two courses DOC fail, treat with p.o. Vanc
Tetracycline drugs?
doxycycline and minocycline
Tetracycline MOA?
Inhibition of protein synthesis

-- Binds 30S subunit of bacterial ribosome
-- binding blocks aminoacyl tRNA from having access to A site
-- BACTERIOSTATIC b/c inhibits protein synthesis
Tetracyclines: Spectrum of Action?
- moderately broad spectrum

- moderate G(+) activity
- 65% staph aureus suscep
- covers strep but not group B strep
- Avoid use in serious SSTI, but can be used for community acquired MRSA

- Moderate G(-) activity
- Greater activity than macrolides
- Good for outpatient trtmt of G(-) infections
Tetracycline spectrum specifics?
- Good activity against intracellular pathogens such as Mycoplasma, Chlamydia, Rickettsia
- Active against Borrelia burgdorferi (Lyme disease) and B. recurrentis (relapsing fever)
- Active against Yersinia pestis (plague), Entamoeba histolytica and Plasmodium falciparum (malaria)
Bacterial resistance to Tetracyclines?
- results from a mutation which protects the drug binding site from the tetracycline
- and/or an efflux pump
- Doxycycline may still work in this situation
- Tigecycline overcomes both causes of resistance
- widestock use in livestock food is increasing resistance of enterococci to these drugs
Tetracycline kinetics?
i.v. and p.o. preps available

- do not give p.o. preps with milk, multivitamins, Ca, Mg, Al, or Fe because these drugs chelate these cations which prevents absorption from the GI tract
- oral doxy and minocycline has F=100%
- Doxycycline and minocycline have long half-lives and slow elimination so they can be dosed once daily
- Tetracyclines highly concentrated in bile -- check LFTs
- Monocycline partially metabolized by the liver
- Doxycycline is largely eliminated via fecal excretion and is DOC for patients with renal dysfxn
Tetracycline toxicity and S/Es?
- GI problems common: n/v, epigastric distress, abdominal cramping, diarrhea; can be reduced if taken with food, but cations in food reduce absorption
- bind to Ca in newly-forming teeth causing discoloration and deformity; do NOT use in pregnant females or children <15 y.o.
- photosensitization, espec. fair-skinned patients
- Large doses - hepatotoxic
- little chance nephrotoxicity
- Superinfections - suppress fecal coliforms allowing growth of other bugs
- c. diff, staph, candida
- disturbed GI fxn
- oral, anal, vaginal candidiasis
- pseudomembranous colitis (tx with metronidazole)
Doxycycline
- good drug for all community acquired pneumonia (CAP)
- typicals (extracellular): S. pneumo, H. flu, M. catarrhalis
- atypicals (intracellular): Mycoplasma pneumoniae, Chlamydia, Legionella

- eliminated by fecal excretion so DOC for patients with renal dysfxn
- 100% oral bioavailability
- long half-life and slow elimination so daily dosing
- covers 95% MRSA strains
- DOC for rickettsial infections
- acne treatment (although minocycline preferred)
Minocycline
- 100% oral availability
- long half-life and slow eliminaton so daily dosing
- partially metabolized by the liver
- covers all typical and atypical drugs causing CAP
- DOC for rickettsial infections
- covers 95% MRSA strains
- acne treatment
- Future uses - Minocycline covers MRSA and Acinetobacter
Tigecycline
given i.v. for infections caused by MDR Acinetobacter, MRSA, and Stenotrophomonas maltophilia
- high incidence nausea/vomiting
Name the macrolide drugs
erythromycin i.v. (hurts) and p.o.
clarithromycin p.o. only
azithromycin i.v. and p.o.
Macrolide MOA
- inhibits protein synthesis
- binds to 50S subunit at peptidyl transferase site
- binding inhibits translocation, so amino acid most recently added to peptide chain does not move from the A site to the P site
- peptide elongation stops and protein synth terminated
- BACTERIOSTATIC
Macrolide Antibacterial Spectrum
- Good G(+) activity, including MMS and strep pneumo
- NO activity against enterococcus
- Some G(-) activity: H. flu, M. catarrhalis
- NOT active against MRSA or VRE
- Slighly improved G(-) activity with clarithromycin and azithromycin
Macrolide resistance?
- "ribosomal protection" - macrolides cannot bind well to the bacterial ribosome b/c the drug binding site has been modified by a bacterial methylase
- drug efflux pumps
Macrolide kinetics
ERYTHROMYCIN
- acid labile which limits p.o. availablity
- esters are less acid labile and have p.o. bioavailability (estolate ester has highest F)
- excreted in bile
CLARITHROMYCIN
- well absorbed
- metabolized by liver and urine excretion
AZITHROMYCIN
- well absorbed
- long half-life and large Vd
- excreted in bile
Macrolide distribution in body fluids?
-- Excellent intracellular concentrations -- why these are DOCs for atypical pathogens in CAP
- azi>clari=erythro
-- Azithromycin is NOT good for extracellular paths so do not use to treat CAP; instead, ise clarithromycin b/c good intra and extracellular concentrations
-- penetrates well into most tissues except brain and CSF
Erythromycin S/Es?
- stimulates gastrin motilin receptors causing persistant GI upset and cramping
- Cholestatic jaundice (rare)
Erythromycin drug interactions?
- inhibits CYP450 and thus prevents the hapetic metabolism of many other drugs
Clarithromycin S/Es?
causes GI upset and metallic taste
Clarithromycin drug interactions?
Has fewer CYP450 drug interactions than erythromycin
Azithromycin S/Es?
Large doses (2g) will stimulated motilin receptors and cause emesis, so DON'T use 2g dose to treat gonorrhea
Azithromycin drug interactions?
Has the least CYP450 interactions of the macrolides.
Therapeutic uses of macrolides?
-- Gold standard for treatment of Legionella infections
-- Excellent for treatment of intracellular pathogens such as M. avium (though NOT M. tuberculosis), Chlamydia, and Mycoplasma
-- A reasonable alternative for PCN allergic patients w/ staph and streo infections (URI)
-- NOT good for staph and strep SSTIs b/c only 40% of staph isolates are susceptible to macrolides
-- NOT for treatment of pediatric otitis media
**Clarithromycin is DOC for outpatient treatment of CAP b/c high intracellular concentrations for atypical bugs, and sufficient extracellular concentrations to cover the typical bugs
**erythromycin pads used to topically treat acne
Clindamycin MOA?
- Binds to 50S subunit at the peptidyltransferase site
- binding here inhibits translocation, so the a.a. does not move from the A site to the P site (binds to same site as macrolides, so resistance to clindamycin usually means resistance to macrolides)
- peptide elongation stops and protein synth is terminated
- BACTERIOSTATIC
Clindamycin spectrum of activity?
-- Excellent for G(+) infections, inhibits toxin production
- good for SSTI caused by staph aureus and B-hemolytic streps
- covers MRSA and can be used for outpatient treatment of MRSA cellulitis in adults and children
- If patient has PCN or sulfonamide allergy, can treat safely with clindamycin
-- No G(-) activity
-- Does NOT cover VRE
-- Good coverage for anaerobes, so can be used to treat aspiration pneumonia
Clindamycin kinetics?
-- good p.o. availability
-- penetrates well into most body fluids/tissues except CSF and brain
-- Good intracellular conc
-- A very high bone/serum conc
-- Hepatic metabolism
Clindamycin toxicity, S/Es?
1. Rash
2. Diarrhea due to change in composition of bowel flora
3. C. diff pseudomembraneous colitis is potentially fatal infection which can be caused by any antibiotic drug. Treat with metronidazole.
Therapeutic use of clindamycin?
1. At one time DOC for treatment of infections by B. fragilis, but no longer b/c of development resistance
2. Very good for pulm anaerobic infections
- aspiration pneumonia
- infections from penetrating abdom wounds
3. Excellent for SSTI infections, espec if patient allergic to PCN
4. Reasonable choice for patients with PCN or sulfonamide allergy who requires G(+) coverage
5. Good for outpatient treatment of community acquired MRSA in adults and children
6. Cream used to topically treat asthma
Name the fluoroquinolones (FQ's)?
ciprofloxacin
gemifloxacin (50% patients develop rash after 7 days, do not use)
levofloxacin
moxifloxacin
FQ MOA?
Inhibit DNA synthesis

- Inhibit topoisomerases II and IV
- Topo II (DNA gyrase) catalyzes relaxation of the positively supercoiled DNA allowing normal gene transcription and DNA repl
- Topo IV is required for separation of replicated DNA into the resulting daughter cells
- FQ's are rapidly bactericidal = concentration dependent killing
FQ Spectrum of activity?
1. good G(-); limited G(+)
2. definite coverage differences within the class
3. G(+): moxi=gemi>levo>cipro NEVER use cipro for G(-) infections
4. Antipseudomonal activity: levo=cipro>moxi=gemi although 50% of pseucomonal isolates are now resistant to cipro
FQ spectrum of activity continued...
5. Other G(-) activity: levo=cipro=moxi=gemi, but only levo and cipro are active against Pseudomonas
- E.coli, Klebsiella, and Enterobacter are becoming resistant
6. Anaerobic activity: moxi>levo=cipro, but do not use FQs for anaerobic infections. Use pip-tazo or metronidazole
7. All are good for intracellular paths (atypical pathogens causing CAP)
8. Resistance arises from mutation of drug binding site on the bacterial topos.
FQ and MRSA?
NO! usually not active against MRSA

Use p.o. clindamycin, trim-sulfa, or doxycycline; use i.v. vancomycin for serious MRSA infections
FQ and MDR S. pneumoniae?
- FQs are the DOC's since levo, moxi, and gemi are effective
- Do not use cipro for strep pneumo infections
- FQ resistant strep pneumo originates in patients in nursing homes, so do not use FQ to treat those patients
- treat as if nosocomial pneumonia with antipseudomonial B-lactam with strep pneumo activity like pip-tazo or cefepime
- in critically ill, consider double coverage by adding treatment with aminoglycoside (gentamicin) or an antipseudomonal FQ
Why are macrolides the DOC for outpatient CAP treatment, while FQs are the DOC for inpatient treatment of CAP?
- a matter of the low risk of CAP being caused by MDR strep pneumo
- activity of FQs against MDR strep pneumo is not required for outpatient CAP treatment
- CDC strongly discourage FQ use for outpatiend CAP b/c will lead to increased resistance strep pneumo to the FQs
FQs are NOT effective against...?
Enterococcus, especially VREs.
cipro, levo, and Pseudomonas
-- cipro and levo can be used, but are no longer reliable unless you have antibiotic sensitivities
-- pip-tazo (antipseudomonal B-lactam)needs to be added to therapy with FQ in order for FQ to be effective in pseudomonal infections
FQs and E. coli?
-- used to be essentially 100% effective in UTI treatment and are usually still effective for outpatient treatment
-- resistance becoming problem in hospitals
-- some strains resistant to FQs alone and still susceptible to ampicillin
-- Ciprofloxacin is effective against 85% E. coli strains at UH
FQ admin and absorption?
-- 90% bioavailability, so p.o.=i.v.
-- Oral Fe and Ca supplements and Al and Mg antacids are chelated by FQs, so these cations decrease GI absorption
-- Ca-fortified milk, antacids, milk, and yogurt decrease bioavailability, but dietary Ca has no effect
-- No effect of dairy products and food on Gi absorption of levo and gemi
-- dairy products and food delay absorption of moxi
FQ metab and drug interactions?
CIPRO:
- 20% metap by CYP1A2 in liver
- numerous CYP450 drug interactions including inhib of caffeine metab
- produce therapeutic urinary conc and are used to treat UTIs
LEVO:
- eliminated renally, so no CYP450 interactions
- produces therapeutic urinary conc and used to treat UTIs
MOXI:
- undergoes signif hepatic metab, but does not cause CYP450 drug interactions
- avoid for UTIs since p.o. dosing produces only small amount drug in urine
FQ toxicity and S/Es?
-- may damage growing cartilage, but probably not problem in children 'cause only given short time
-- tendon rupture
-- Phototoxicity: problem with cipro
-- Q-T prolongation: may occur in patients with congenital prolonged Q-T interval or patients taking other drugs which increase Q-T interval
--occurs b/c drugs slow K-mediated repol current
--prolongation can precip type of polymorphic ventricular tachy caled torsade de pointes
-- Levo and moxi do not signif effect Q-T interval unless other risk factors present (decreased GFR or electrolyte imbalance)
Therapeutic uses FQs?
--levo and moxi recommended as 1st line in inpatient CAP
- alternative would be cephalosporin like ceftriaxone or cefotaxime + macrolide such as clarithromycin)
-- systemic infections caused by Salmonella (FQ resistant come from chickens treated with FQ)
-- Infections by MDR strep pneumo (NOT meningitis)
- DOC - levo or moxi
- Do NOT use cipro
-- Tx diarrhea caused by salmonella, shigella, campylobacter, and E. coli
--DO NOT use for SSTIs b/c they do not work predictably against MRSA
FQs and UTIs?
1st line drugs for outpatient treatment of complicated UTIs.

--infection in UT with functional and structural abnormalities including calculi or indwelling catheter
--UTIs in men, pregnant women, children, and patients hospitalized or in health-care setting considered "complicated"
--Some people consider pyelonnephritis to be complicated UTI
--In complicated UTIs, offending bacteria more likely to be resistant to first-line antibiotic drugs
Name the aminoglycosides
streptomycin
neomycin
gentamicin
tobramycin
amikacin
What is the aminoglycoside MOA?
- enter G(-) bacterial cell via aqueous porin channels in outer mbrn
- deeper penetration requires active transport via oxygen-dep process which involves a proton gradient
- low oxygen (anaerobic) conditions or low extracellular pH decreases this cell mbrn transport
- binds 30S subunit of bacterial ribosome
- blocks initiation of peptide synth
- causes misreading of mRNA codons so that incorrect a.a. added to chain making nonfxnal protein
- prevents translation of mRNA b/c fxnal polysomes are broken up in to nonfxnal monosomes
- BACTERICIDAL
What other antibiotics work synergistically with aminoglycosides?
PCNs, cephalosporins, and vancomycin exert synergistic antibac effect b/c they inhib cell wall synth and make it easier for AGs to penetrate G(-) cell.
AGs antibac activity
- Broad G(-) spectrum and are rapidly bactericidal

- Will cover G(+) bugs if used in combo with inhib of cell wall synth
AGs and G(+) infections
- low doses needed
- always use with B-lactam or vanc to achieve antibac synergy
- treat endocarditis caused by staph, strep or enterococcus (with synergistic drug, of course)
AGs and G(-) infections
- need to use high doses
- usually given with another class of drugs which cover G(-) infections
-
AGs vs B-lactams and their killing styles
-- AGs such as gentimicin exert both a post-antibiotic effect and concentration dependent killing
-- rate and efficiency of killing increases as Cp increases
-- larger doses less ofter (q12 or qd) increases bactericidal effects
-- treatment qd is effective and safer

-- B-lactams exhibit time-dependent killing
-- bactericidal effect depends on keeping the Cp above the MIC
Aminoglycoside S/Es and nephrotoxicity?
- toxicity is both time and concentration dependent

- NEPHROTOXICITY - reversible after prolonged therapy (2wks) and damages proximal tubules which can regenerate with time
- Causes a reversible decrease in renal fxn with is accomp by increased plasma creatine conc
- likelihood increased by cotreatment with other nephrotoxic drugs (vancomycin, ampho B, cyclosporin, NSAIDS)
Aminoglycoside S/Es and oto/neurotoxicity?
OTOTOXICITY -- irreversible
- hearing loss, tinnitus, vestibular damage, ataxia, vertigo, loss of balance
- occurs when plasma conc remain elevated over period of 5+ days; why now given in large qd doses instead of constant i.v.
- renal dysfxn predisposes to ototoxicity
- gentimicin -- primarily vestibular damage
- furosemide -- also toxic to VIII CN
- NEUROMUSC BLOCKADE -- especially when used with conventional agents in OR or ICU
Bacterial resistance to AGs
- INACTIVATE - adding a phosphate, adenyl or acetyl group to the drug; most common method of resistance; used by enterococci
- DECREASED CELL TRANSPORT - mutations alter porin structure and transport proteins; Pseudomonas has up to 40 diff efflux pumps
- CHANGE BINDING SITE -- of 30S subunit of the ribosome
What is the "ace in the hole" for bacteria resistant to gentimicin and tobramycin?
Amikacin -- b/c it is not affected by the same resistance levels as the other two drugs
Key points to remember with aminoglycosides
1. AGs have very good G(-) spectrum including against enterics
2. Almost always used in combo with inhibitor of cell wall synth (B-lactam, vanc)
3. VERY toxic if not dosed correctly
4. When dosing obese patients, adjusted body weight should be used b/c it does not distribute into fat
5. Poorly absorbed from GI tract and must be given i.v. for systemic infections
6. Gentimicin widely used in antibac ear drops, eye drops, and ointment
7. Neomycin given p.o. to decontam gut prior to surgery
8. Don't be afraid to use, just show respect!
Linezolid: what is it?
- A synthetic antibiotic
- the first oxazolidione
Linezolid antibac coverage?
Excellent G(+) - covers MRSA, VRE, PCN resistant strep pneumo

Minimal G(-) coverage
Linezolid bioavailability?
100% p.o. -- dosed 600mg i.v. or p.o.
Linezolid MOA?
- bacteriostatic inhib of protein synth
- binds to unique site on 23S ribosomal RNA of the 50S subunit to block assembly of the 70S ribosomal complex needed to initiate protein synth
- unique MOA means no cross-resistance with other drugs
Linezolid clinical uses?
- treat resistant G(+) bugs, including MDR bugs
- treat VRE, especially E. faecium
- Treat MRSA when patient cannot tolerate vanc
- treat complicated SSTIs
Linezolid strengths?
- easy i.v. and p.o. conversion
- patients on i.v. vanc in hospital can be sent home on p.o. linezolid
- good activity against MDR G(+) bugs
- relatively well-tolerated
Linezolid weaknesses?
- bacteriostatic againsy MRSA, VRE
- Does not work well in deep-seated infectinos (endocarditis, osteomyelitis) b/c bacteriostatic
- reversible bone marrow depression
- is irreversible MAOI, so coadmin of SSRI can precipitate serotonin syndrome
- may cause periph neuropathy or irreversible optic neuritis
- EXPENSIVE
quinupristin/dalfopristin activity?
- seldom used

- excellent G(+) activity including MRSA, VRE, and PCN resistant s. pneumo

- exert prolonged antibac effect
quinupristin/dalfopristin MOA?
- inhibits protein synthesis
- QUINUPRISTIN - binds 50S subunit at peptidyl transferase site to prevent elongation of peptide chain
- DALFOPRISTIN - binds different site on 50S which induces conformational change which enhances binding of quinupristin to the peptidyltransferase site
- rapidly bactericidal except in case of E. faecium which is killed slowly
When do you use Q/D?
YES -
- critically ill patients
- documented VRE infections
- MRSA infections

No -
- Uncomplicated SSTIs
- CAP
- UTIs
Q/D vs linozelid
Q/D
- difficult to give b/c requires central line
- 30% develop arthralgias/myalgias NOT relieved by NSAIDs or opiates
- drugs inhib metab of many others by CYP3A4
- Q/D has 50/50 chance of being "-cidal" against MRSA
- bacteriostatic against enterococcus including VREs
- does not cover E. faecalis (10%), but most VREs are E. facium
LINEZOLID
- 100% p.o. bioavb
- watch platelets, H&H, WBCs
- fewer drug-drug interactions
- is "-static" against MRSA
- is bacteriostatic against enterococcus including VREs and covers both E. faecalis and E. faecium so you don't have to worry about which the patient has
Trimethoprim/sulfamethoxazole (trim-sulfa, Bactrim) overview
- given p.o. w/ excellent F
- given p.o. even in serious infections to avoid giving huge volumes of fluid i.v.
Trim-sulfa MOA?
-- SULFA inhibits dihydropteroate synthetase by being a competitive antagonist of PABA
--stops conversion PABA into DHF
-- TRIM inhibits dihydrofolate reductase to prevent conversion of DHF to THF
- BOTH drugs preferentially inhibit bacterial enzymes with little effect on mammalian enzymes
- singly bacteriostatic, but combo bactericidal
- sequential inhibition two different enzymes limits resistance development
Trim-sulfa strengths?
- Broad spec activity
1. Staph aureus including MRSA
2. Enterobacter in ICU
3. E.coli and Klebsiella
- drugs conc in urine so good for UTIs
- use to treat uncomplicated UTI in healthy woman
- 65% E.coli isolates at UH are susceptible
3. DOC for Pneumocystis jiroveci
4. DO NOT USE to treat P.aeruginosa, enterocci or Bacteroides b/c these bugs are usually resistant
Trim-sulfa weaknesses?
1. Sulfonamide induced "allergic" rxns of skin
- rash (30% after 2 wks therapy)
- fever, photosensitivity, urticaria, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome
2. Blood dyscrasias (more likely w/ lg doses)
- thrombocytopenia, leukopenia, hemolytic anemia (espec w/ genetic deficiency G-6-P dehy)
3. Hyperkalemia b/c trim acts like K sparing diuretic

All S/Es likely to occur w/ large doses; HIV patients usually require large doses
Current medical uses Trim-sulfa?
1. Uncomplicated UTIs
2. DOC for P.jiroveci
3. Effective in MRSA
4. DOC for Nocardia infections
5. used when ICU infections caused by Stentrophomonas maltophilia are resistant to carbapenems
6. use for prophylaxis of toxoplasmosis in patients with AIDS
How do I treat outpatient MRSA infections?
- consist primarily of SSTIs which are caused by staph or strep
- culture and treat with clinda, trim-sulfa, or doxy p.o.
- Clinda preferred over Tiim-sulfa b/c it covers staph and Grp A and B strep, whereas Trim-sulfa does not cover strep.
- Trim-sulfa works well in the treatment of MRSA abscesses after they are drained surgically
- if the culture reveals MSSA, d/c primary drug and treat with B-lactam p.o.
How do I treat inpatient MRSA infections?
- For SSTIs cause by MRSA, use clind, trim-sulfa, or doxy given i.v. or p.o.
- F of all three drugs are 90+ percent, so treatment with p.o. yields high Cp comparable to i.v.
- Critically ill or more severe MRSA infections, first-line trtmt is vanc i.v.
- Linezolid reserved for patient who cannot tolerate vanc or who need to complete few days therapy for uncomplicated (NOT osteomyelitis or endocarditis) MRSA infections
- Daptomycin also used for MRSA in fashion similar to linezolid, but may change
Nitrofurantoin overview
- use in uncomplicated UTIs
- bacterial enzymes rapidly reduce it to a reactive intermediate which causes DNA damage and cell death
- is bacteriostatic at lower conc, and bactericidal at higher conc
Nitrofurantoin strengths?
- High F and macrocrystalline form has increased duration of action
- Concentrated in urine to yield values greater than req'd for bactericidal activity
- most active in acidic urine
- no cross resistance with other classes antibac drugs
- safe to use in pregnant women (others safe include amoxacillin and cephalexin)
Nitrofurantoin coverage?
- Excellent activity against many of the G(-) and G(+) bugs which cause UTIs
- acts against most strains E.coli, Klebsiella, and Enterococcus including VREs
- some strains Proteus are resistant
Nitrofurantoin weaknesses?
- therapeutic effect limited to URINE
- drug causes urine to be brown
- S/Es with prolonged use are hepatitis, neuropathies, and pulmonary fibrosis (after long-term treatment for recurrent UTIs)
- Does not work for pyelonephritis or prostatitis