ANTIMICROBIAL AGENTS

Cynthia Whitener, MD

Antimicrobials to be reviewed:
Penicillins Cephalosporins Carbapenems Vancomycin Quinupristin-dalfopristin Linezolid Daptomycin Tigecycline Quinolones Macrolides Bactrim Doxycycline

Gram Positive Organisms

Staphylococcus Streptococcus Enterococcus Corynebacteria Listeria Proprionibacteria Peptostreptococcus Clostridia Bacillus

Gram Negative Organisms

Escherichia coli Klebsiella Proteus Pseudomonas Enterobacter Acinetobacter Stenotrophomonas Neisseria Haemophilus Moraxella Legionella Bacteroides Prevotella

Penicillins - General scheme

Penicillin
Strep, enterococcus, and GP anaerobes

Penicillins - General scheme- 2

Penicillin
Strep, enterococcus, and GP anaerobes

Amp/Amoxicillin

All above + some simple GNRs (E. coli, proteus, salmonella, shigella)

Penicillins - General scheme - 3

Penicillin
Strep, enterococcus, and GP anaerobes

Amp/Amoxicillin

All above + some simple GNRs (E. coli, proteus, salmonella, shigella)

Mezlo/Pip/Ticarcillin

All above + more resistant GNRs (Pseudomonas, Enterobacter, Acinetobacter)

Penicillins - General scheme - 4

Penicillin (Strep, enterococcus, and GP
anaerobes)

Amp/Amoxicillin (All above +

some simple GNRs - E. coli, proteus, salmonella, shigella)

Mezlo/Pip/Ticarcillin(All above +
more resistant GNRs Pseudomonas, Enterobacter, Acinetobacter)

Penicillins - General scheme - 5

Penicillin (Strep, enterococcus, and GP
anaerobes)

Amp/Amoxicillin (All above +

some simple GNRs - E. coli, proteus, salmonella, shigella)

+ MSSA

Amp/sulbactam & Amox/clavulanate

+ all anaerobes

Mezlo/Pip/Ticarcillin (All above +

more resistant GNRs Pseudomonas, Enterobacter, Acinetobacter)

Penicillins - General scheme - 6

Penicillin (Strep, enterococcus, and GP
anaerobes)

Amp/Amoxicillin (All above +

+ MSSA

some simple GNRs - E. coli, + all anaerobes proteus, salmonella, shigella)

Amp/sulbactam & Amox/clavulanate

+ GNRs

+ MSSA

Mezlo/Pip/Ticarcillin(All above +

more resistant GNRs + all anaerobes Pseudomonas, Enterobacter, Acinetobacter)

Pip/tazobactam & Ticar/clavulanate

Penicillins - General scheme - 7

Penicillin (Strep, enterococcus, and GP
anaerobes)

+ MSSA

Dicloxacillin/Nafcillin/ Oxacillin

Amp/Amoxicillin (All above +

some simple GNRs - E. coli, proteus, salmonella, shigella)

+ MSSA + all anaerobes

Amp/sulbactam & Amox/clavulanate

+ GNRs

Mezlo/Pip/Ticarcillin(All above +
more resistant GNRs Pseudomonas, Enterobacter, Acinetobacter)

+ MSSA + all anaerobes

Pip/tazobactam & Ticar/clavulanate

Penicillins Made Easy

Penicillin G
Strep, enterococcus, some anaerobes + MSSA

Nafcillin/Dicloxacillin/ Oxacillin/Methicillin
(No enterococcus)

+ simple GNRs

Ampicillin/ Amoxicillin
+ nosocomial GNRs incl. Pseudomonas

+ MSSA
+ all anaerobes + all H. flu

Ampicillin/Sulbactam Amoxicillin/Clavulanate
+ nosocomial GNRs incl. Pseudomonas

Mezlocillin/Piperacillin/ Ticarcillin
(No enterococcus)

+ MSSA + all anaerobes + all H. flu

Piperacillin/tazobactam/ Ticarcillin/clavulanate

CEPHALOSPORINS

AS MOVE FROM 1ST TO 3RDs: LOSE GRAM + COVERAGE AND GAIN GRAM - COVERAGE

1ST GENERATION CEPHALEXIN, CEPHALOTHIN, CEFAZOLIN, CEFADROXIL, OTHERS

2ND GENERATION CEFACLOR, CEFOTETAN, CEFOXITIN, CEFUROXIME, OTHERS

3RD GENERATION CEFTAZIDIME, CEFOPERAZONE, CEFOTAXIME, CEFTRIAXONE, CEFIXIME, CEFPODOXIME, OTHERS

(cephalexin - po; cefazolin - iv)

1st Generation Cephalosporins

Strep, MSSA, simple GNRs

No MRSA, no enterococcus, minimal anaerobic coverage, not extensive GNR coverage

Clinical uses: skin and soft tissue infections (strep and MSSA), some UTIs, surgical prophylaxis; alternative for PCN or diclox/nafcillin

2nd Generation Cephalosporins: (better gram neg coverage) 2 main types

Better resp coverage including H.flu, M.cattarrhalis, Neisseria; some Strep and Staph; no pseudomonas, no enterococcus

Better anaerobic coverage

Clinical uses: community acq resp trt infections (cefuroxime)

Clinical uses: mixed aerobic/anaerobic infections or abd/pelvic surgical prophylaxis (cefoxitin)

3rd Generation Cephalosporins (better gram neg coverage Enterobacteriaceae): 2 types of 3rd generations

Those that are active against Pseudomonas (ceftazidime)

Those that do not have reliable activity vs. Pseudomonas (ceftriaxone)

Excellent gr neg rod coverage, no additional GP coverage (generally weak against Staph, fair against Strep), no enterococcus, fair/weak vs. anaerobes

Clinical uses: serious GNR infections, often nosocomial

Excellent gr neg rod coverage but NOT Pseudomonas, fair/good against Staph/Strep (surprise), no enterococcus, fair/weak vs. anaerobes

Clinical uses: serious GNR infections, meningitis (community and hospitalacquired), comm acq pneumonia, CNS Lyme disease

4th Generation Cephalosporins

(Cefepime)

Provides the gram pos coverage of a 1st gen PLUS the gram neg coverage of a classic 3rd (1+3=4)

Excellent GNR coverage incl. Pseudomonas, very good MSSA and Strep, no enterococcus, minimal anaerobes

Clinical uses: broad empiric coverage for GNs and GPs, usually in the hospital setting

CEPHALOSPORINS
As move from 1st to 3rds: Gain GNR coverage and lose GP (esp. MSSA) coverage 1st Generation cephalexin, cephalothin, cefazolin, cefadroxil, others Streptococci MSSA simple GNRs No enterococcus Clinical uses: PCN alternative for skin/soft tissue, simple GNR surgical prophylaxis 2nd Generation cefuroxime, cefaclor, ceprozil cefoxitin, cefotetan, others cefuroxime/cefaclor better respiratory coverage incl. H.flu, M.catarrhalis, Neisseria No Pseudomonas, no enterococcus Clinical uses: comm-acq resp trt infections cefoxitin/cefotetan better anaerobic activity No Pseudomonas (or other R GNRs) No enterococcus Clinical uses: mixed aerobic/anaerobic infections, abd/pelvic surg prophylaxis 3rd Generation ceftazidime, cefoperazone, ceftriaxone, cefotaxime, cefixime, others ceftazidime/cefoperazone GNR coverage includ Pseudomonas Poor against GPs No enterococcus Clinical uses: Healthcare-associated GNR infections ceftriaxone/cefotaxime GNR coverage except Pseudomonas Okay against MSSA No enterococcus Clinical uses: Healthcare-associated infections, Comm acq pneumonia, Comm acq meningitis

4th Generation Cefepime GP coverage of a 1st plus GNR coverage of a classic 3rd MSSA, Strep, GNRs including Pseudomonas; not enterococcus, partial anaerobic coverage only Clinical uses: Broad empiric coverage

New broad spectrum cephalosporin a 5th generation

Ceftaroline (Teflaro)
Strep (including S pneumoniae) Staph (MSSA, MRSA) Some GNRs (NOT Pseudomonas; limited activity against Enterobacter, Proteus, Providencia)
Vulnerable to many resistance mechanisms of GNs

Indicated for comm acq PNA and complicated SSTI

(due to MRSA, MSSA, Strep, Haemophilus, Klebs, E. coli)

Cephalosporins
Divided into 1st, 2nd, 3rd, 4th and (5th) generations - as move from 1st to 3rds, increase gram neg coverage and lose gram pos coverage
(mainly S aureus)

1st generation (cephalexin, cephalothin, cefazolin, cefadroxil, others)

Strep, MSSA, simple aerobic gram neg rods Not MRSA, not enterococcus Clinical uses: alternative for PCN for S.aureus and nonenterococcal Strep; surgical prophylaxis

Cephalosporins - 2
2nd generation (cefaclor, cefprozil, cefotetan, cefoxitin, cefuroxime)
Better respiratory gram neg coverage, now including H. flu, M. catarrhalis, Neisseria Better anaerobic activity, esp. with cefoxitin No Pseudomonas (or other more R gram negs), no enterococcus coverage Clinical uses: community acq resp trt infections; mixed aerobic/anaerobic infections (cefoxitin)

Cephalosporins - 3
3rd gen (ceftazidime*, cefoperazone*, cefotaxime, ceftriaxone, cefixime, others)
Broad gram neg rod coverage (those that get Pseudomonas reliably have an *) No additional GP activity - usually less (ceftriaxone is an exception - good vs. gram positives) No enterococcus coverage Anaerobic activity no better/likely worse than 2nd gen

Cephalosporins - 4
3rd generation
Clinical uses serious GNR infections - often nosocomial meningitis (community and hospital acquired) due to good CNS penetration pneumonia Lyme disease (ceftriaxone)

Cephalosporins - 5
4th generation (cefepime, cefpirome)
Broad coverage - gram positives, including MSSA, and gram negs, including Pseudomonas Think of these drugs as having the coverage of a 1st gen plus a 3rd gen

Questions
Does penicillin cover S. aureus? Does piperacillin? Is pip-tazobactam good for anaerobes? Whats the difference in coverage between amp-sulbactam and pip-tazo? Does cefazolin cover enterococcus? What is the drug class of choice for enterococcus? Is any drug cidal against it? Whats the difference in coverage between ceftriaxone and ceftazidime? Ceftriaxone and cefepime? Cefepime and pip-tazo?

Questions
Does penicillin cover S. aureus? Usually not (<5% of the time, so you would not use it empirically) Does piperacillin? Same answer as for PCN Is pip-tazobactam good for anaerobes? Yes, it is excellent Whats the difference in coverage between amp-sulbactam and pip-tazo? Gram neg coverage (Pseud, Acinetobacter, Enterobacter, etc) is
more broad for P-T MSSA, Strep, anaerobe coverage is the same

Does cefazolin cover enterococcus? NO! What is the drug class of choice for enterococcus? Penicillins Is any drug cidal against it? PCNs combined with aminoglycosides are
required for cidal activity

Whats the difference in coverage between ceftriaxone and ceftazidime? CTX better for MSSA, CTZ better for Pseud Ceftriaxone and cefepime? CFP better for Pseud (and more potent for MSSA) Cefepime and pip-tazo? P-T better for enterococcus, anaerobes (they are the same for Strep,
MSSA, GNRs including Pseud)

Quick antibiotic cases

Is penicillin an appropriate treatment for strep throat?

(Streptococcus pyogenes Grp A Strep)

Images: Google

Quick antibiotic cases

Is penicillin an appropriate treatment for strep throat?

(Streptococcus pyogenes Grp A Strep) Answer: YES
Images: Google

 Is penicillin usually the appropriate treatment for viridans Streptococcus endocarditis?

 Is penicillin usually the appropriate treatment for viridans Streptococcus endocarditis?

YES
Usually iv PCN is used as a single agent combine iv PCN with low dose gentamicin (if the MIC to PCN is >0.1 mcg/mL)

 Is penicillin an appropriate treatment for Enterococcus faecalis endocarditis?

 Is penicillin an appropriate treatment for Enterococcus faecalis endocarditis?

YES (or iv ampicillin)
BUT you must combine it with low dose iv gentamicin to have cidal activity against enterococcus

 Is penicillin the appropriate empiric treatment for MSSA endocarditis?

 Is penicillin the appropriate empiric treatment for MSSA endocarditis?

NO
PCN is not active against 95% of MSSA Requires iv nafcillin/oxacillin or iv cefazolin

 How good is penicillins coverage of Streptococcus pneumoniae?

Pleural exudate (Gram stain). Red Book

Penicillin and Streptococcus pneumoniae

Up to 40% have reduced susceptibility to penicillin

Clinically not usually relevant except when the infection is in the CNS Cross-resistance exists to ceftriaxone, macrolides, clindamycin, TMP-SMX
Pleural exudate (Gram stain). Red Book

 A patient just had an LP for suspected communityacquired bacterial meningitis. The patient has no drug allergies. The resident orders ceftriaxone and vancomycin. Is this appropriate?

YES
Pneumococcus is the most common bacterial cause of meningitis 30-40% chance PCN resistance 10-30% of PCN R pneumococci are also R to ceftriaxone 100% are S to vancomycin Ceftriaxone penetrates the CNS better than vancomycin Clinically ceftriaxone is superior to vancomycin if pneumococcus is S to PCN or ceftriaxone, so dont use vanc alone DC vanc if sensies show the organism is S to CTX or PCN Risk of death increases if APPROPRIATE therapy is delayed so RX must be correct up front Also give dexamethasone to decrease meningitis complications

Carbapenems
imipenem/cilastatin, meropenem, ertapenem Very broad spectrum - includes MSSA, strep, Enterococcus faecalis, GNRs, anaerobes Holes:
MRSA, Corynebacterium jeikeium, coag neg staph, Enterococcus faecium, Stenotrophomonas maltophilia, atypicals Ertapenem does not cover Pseudomonas

Toxicities - similar to penicillins

*seizures esp. in patients with low sz threshold &/or elevated creat

Resistant GNRs emerge readily with frequent use

Antibiotics that mainly kill Gram Positive bacteria

Vancomycin
A glycopeptide - inhibits cell wall synthesis Spectrum
almost all gram +s (rods or cocci), aerobic and anaerobic Exception: VRE - its in the name!

Adverse effects
irreversible ototoxicity nephrotoxicity esp. with other nephrotoxic drugs red man syndrome

Vancomycin
Correct response for treatment of red man syndrome: slow down infusion
Clinical uses:
MRSA, coag neg staph, corynebacterium jk infections PCN R S. pneumoniae CNS infections (if also R to ceftriaxone) Enterococcus infections if patient is PCN allergic C. diff diarrhea for moderate to severe disease, and use it p.o.

Limit empiric use due to selection for VRE

Quinupristin/dalfopristin (Synercid)
A streptogamin - IV form only Indications (GP organisms)
serious infections due to VREF complicated skin infections due to Strep or S. aureus (including MRSA) coag neg Staph, Strep, corynebacterium jk

Not active against E. faecalis* (ampicillin S)

Quinupristin-Dalfopristin- 2
Adverse effects occur frequently so not used often
venous irritation so need a central line N/V arthralgias, myalgias (can be severe) drug interactions (inhibits cytochrome P450 metabolism)

Main clinical use - treatment of VREF infections

Linezolid

) (Zyvox

A synthetic oxazolidinone - IV & po - 600 mg bid Activity (GP organisms):

enterococcus (VREF & sensitive enterococcus), S. aureus (includes MRSA), coag neg Staph, Streptococcus (includes PCN R pneumococcus) no GNR coverage

Clinical studies suggest it MAY be superior to vanc for MRSA pneumonia Adverse effects: cytopenias* esp. thrombocytopenia Try to reserve use for circumstances of true need to decrease spread of resistance (emerging in VRE, CoNS, others)

Daptomycin

) (Cubicin

A cyclic lipopeptide binds to bacterial membrane causing rapid depolarization which inhibits protein, RNA, and DNA synthesis IV form only, once daily Spectrum (Gram +s):
In vitro and in vivo*: E. faecalis (non-VRE), S. aureus (including MRSA), Streptococcus (In vitro: VRE, CoNS, Corynebacterium jeikeium) no indication

Indicated for complicated skin/skin structure infections caused by organisms listed,* and SA bacteremia/R sided IE Should not be used for pneumonia inactivated by surfactant Adverse events: well tolerated; myopathy - monitor CPK weekly

Newer Antimicrobial
Tigecycline (Tygacil) - IV
The first glycylcycline (binds to ribosome); similar to tetracyclines Broad coverage: gram negs (but not Pseudomonas), gram pos (MRSA, MRSE, & VRE), and anaerobes The 1st MRSA/VRE drug to also be active vs. GNs Initially thought to be unaffected by most bacterial R mechanisms (but already seeing R GNs) Unclear role as of yet; one use: broad coverage in patients with multiple allergies

Wake up!

Bear with me a little longer

More Questions
Does imipenem cover MRSA? Coag Neg Staph? Anaerobes? Pseudomonas? E. faecalis? Legionella? Stenotrophomonas? Does vancomycin have any gram neg coverage? What antibiotic options are there for treatment of a VRE bloodstream infection? What are the main set of organisms you are trying to cover for empiric treatment of neutropenic hosts? What is the main significant possible adverse event from linezolid?

More Questions
Does imipenem cover MRSA? No Coag Neg Staph? No Anaerobes? Yes Pseudomonas? Yes E. faecalis? Yes Legionella? No Stenotrophomonas? No Does vancomycin have any gram neg coverage? No What antibiotic options are there for treatment of a VRE bloodstream infection? Q-D, linezolid, (daptomycin), (tigecycline) What are the main set of organisms you are trying to cover for empiric treatment of neutropenic hosts? GNRs What is the main possible significant adverse event from linezolid? Cytopenias, esp plts after 2 wks of Rx check CBC, diff, plts wkly

Brief Case
A man in the ICU for 1 week develops ventilatorassociated pneumonia due to MRSA He has no allergies and is currently on no antibiotics What should you treat him with?

Brief Case
A man in the ICU for 1 week develops ventilatorassociated pneumonia due to MRSA He has no allergies and is currently on no antibiotics What should you treat him with? Answer: vancomycin or linezolid (not daptomycin
inactivated by surfactant)

Miscellaneous Antibiotics

Macrolides
erythromycin use limited by GI side effects clarithromycin and azithromycin (Biaxin and Zithromax)
Macrolide cogeners:
less GI side effects, less frequent dosing, improved potency against H. flu (esp. azithro), MSSA, moraxella, chlamydia, legionella, some mycobacteria

Clinical uses: Comm acq resp tract infections MAC infections Chlamydia urethritis/cervicitis (1 dose azithro)

Fluoroquinolones
3 main groups:
Norfloxacin
Not well absorbed systemically Main use: UTIs

Older agents - ciprofloxacin, ofloxacin

Main use: GNR infections

Newer agents - levofloxacin, moxifloxacin, gatifloxacin

Main use: respiratory trt infections (gets some GPs including S. pneumoniae)

Mechanism of action - inhibit DNA gyrase

Fluoroquinolones - 2
Spectrum:
aerobic GNRs
*only ciprofloxacin & ofloxacin get Pseudomonas

some Staph and Strep

Fairly good with the newer quinolones Ciprofloxacin & ofloxacin - low activity vs. S. pneumoniae and Staph

chlamydia, mycoplasma, legionella some mycobacteria low activity vs. anaerobes S. aureus often become resistant with exposure

Toxicities:
CNS (altered sensorium, etc) QTc prolongation Erratic glucose control in diabetics Potential for cartilage erosion and arthropathy (try not to use in young
children/pregnancy)

Fluoroquinolones - 3
Most common appropriate uses:
Norfloxacin
UTI, travelers diarrhea prophylaxis

Cipro/oflox
GU infections, diarrheal syndromes, gonorrhea and chlamydia

Levo/gati/moxi
resp trt infections

Extensive inappropriate use is contributing to increasing bacterial resistance

Trimethoprim-sulfamethoxazole (Bactrim, Septra)

A combination that blocks the folic acid pathway Broad spectrum aerobic activity Staph aureus (many MRSA), simple GNRs, assortment of others Main clinical uses:
comm acq resp trt infections, GU infections, comm acq MRSA, PCP, Nocardia, Stenotrophomonas maltophilia

Tetracycline, Doxycycline
Tetracycline, doxycycline Broad spectrum static drugs used for:
mycoplasma, chlamydia resp trt infections, community-acquired MRSA skin and soft tissue infections urethritis/cervicitis, acne (Proprionibacterium acnes), spirochetes
lyme dz (borrelia), RMSF & ehrlichia (rickettsia)

Dont use in children/pregnancy due to bone growth retardation

Brief Clinical Cases

Healthy middle aged male with LE cellulitis:
Main organisms to consider? Antibiotic options (empiric)? Antibiotic options if PCN/ceph allergic?

Diabetic woman with a foot ulcer with surrounding cellulitis:

Main organisms to consider? Antibiotic options (empiric)? Antibiotic options if PCN/ceph allergic?

Brief Clinical Cases

Healthy middle aged male with LE cellulitis:
Main organisms to consider? Strep (and MSSA) Antibiotic options (empiric)? 1st gen ceph or diclox/nafcillin Antibiotic options if PCN/ceph allergic? Clindamycin,
levofloxacin, bactrim, doxycycline (NOT ciprofloxacin)

Diabetic woman with a foot ulcer with surrounding cellulitis:

Main organisms to consider? Strep, Staph, GNRs, possibly
anaerobes and enterococcus (very few regimens will cover all possiblities use clinical judgement depending on the patients situation)
cefepime/flagyl; po cipro+clinda, augmentin (would miss some GNs)

Antibiotic options (empiric)? IV amp/sulbactam (?) or pip/tazo, Antibiotic options if PCN/ceph allergic? vanc+cipro+flagyl or
vanc+aztreonam+flagyl; po only cipro+clindamycin

Brief Clinical Cases

Healthy woman with recurrent small skin abscesses on her legs, arms, low abdomen, and groin regions. Her boyfriend who is a college wrestler has a history of MRSA skin infections What are the main antibiotic options to treat an active large skin abscess that has partially drained?

Brief Clinical Cases

Healthy woman with recurrent small skin abscesses on her legs, arms, low abdomen, and groin regions. Her boyfriend who is a college wrestler has a history of MRSA skin infections What are the main antibiotic options to treat an active large skin abscess that has drained? Answer: bactrim, doxycycline, clindamycin (depends on local antimicrobial susceptibility patterns) If an abscess has drained and is small, no antibiotics may be needed

Brief Clinical Cases

Outpatient with possible acute bacterial sinusitis:
Main organisms? Antibiotic options?

65 year old man with presumed bacterial meningitis:

Main organisms? Antibiotic options?

Elderly woman with a non-catheter associated cystitis (dysuria with + office dipstick):
Main organisms? Antibiotic options?

Brief Clinical Cases

Outpatient with possible acute bacterial sinusitis:
Main organisms? H.flu, M.cattarrhalis, S.pneumo, Chlamydia, others Antibiotic options? doxyxycline, bactrim, amoxicillin, cefuroxime; if fail, can try amox-clav, azithromycin, clarithromycin

65 year old man with presumed bacterial meningitis:

Main organisms? S.pneumo, H.flu, N.meningitidis, Listeria Antibiotic options? Vanc + ceftriaxone + ampicillin(for Listeria) adjust antibiotics after culture results return

Elderly woman with a non-catheter associated cystitis (dysuria with + office dipstick):
Main organisms? E. coli, Proteus, other GNRs, less likely coag neg Staph, less likely enterococcus without a foley Antibiotic options? Bactrim or cipro/oflox or amox/clav for 3 days; UA with UC if relapses

The SECRET to learning antibiotics

Repetition Repetition Repetition
For the next 3-6 months: remind yourself the main organisms an antibiotic generally has activity against every time you write it in a progress note (or order it, or say it) if you do this, you will know more about antibiotic coverage than most of your colleagues and superiors, and you will do your patients a huge favor (and what they expect) for years to come

The end!
Questions/Comments Welcome