Gram-positive cocci
Staphylococcus aureus (MSSA)
Methicillin-susceptible S. aureus is best treated with anti-staphylococcal beta-lactams when feasible.
Vancomycin is active but inferior to beta-lactams for serious MSSA infection.
Ceftriaxone may be convenient but is not preferred for serious bacteremia/endocarditis.
PCefazolin
Preferred for many serious MSSA infections.
PCephalexin
Oral option for mild susceptible skin/soft tissue infection.
PNafcillin/Oxacillin
Preferred for serious MSSA infections when tolerated.
AAmox-clav
No specific caveat listed.
AAmp-sulbactam
No specific caveat listed.
ACefepime
Active but broad and not preferred for definitive therapy.
ACeftaroline
Active against MSSA and MRSA.
ACeftriaxone
May be active; not preferred for serious MSSA bacteremia/endocarditis.
ADaptomycin
Not for pneumonia.
ALinezolid
No specific caveat listed.
AMeropenem
Active but unnecessarily broad.
APip-tazo
Active but unnecessarily broad for definitive MSSA therapy.
AVancomycin IV
Use when beta-lactams cannot be used or MRSA not excluded.
VCiprofloxacin
Resistance emerges; not a preferred anti-staphylococcal agent.
VClindamycin
Use only if susceptible; inducible resistance may matter.
VDoxycycline
No specific caveat listed.
VLevofloxacin
Resistance emerges; not a preferred anti-staphylococcal agent.
VTMP-SMX
No specific caveat listed.
Gram-positive cocci
Staphylococcus aureus (MRSA)
MRSA is resistant to routine beta-lactams; use MRSA-active agents and interpret oral options by syndrome and susceptibility.
Ceftaroline is the major beta-lactam exception.
Daptomycin is not used for pneumonia.
PDaptomycin
Preferred alternative for bacteremia/right-sided endocarditis; not pneumonia.
PLinezolid
Useful for MRSA pneumonia and oral step-down in selected cases.
PVancomycin IV
Standard IV therapy for many serious MRSA infections.
ACeftaroline
MRSA-active cephalosporin.
VClindamycin
Only if susceptible and D-test negative when relevant.
VDoxycycline
Often used for mild SSTI if susceptible; not for bacteremia.
VMinocycline
No specific caveat listed.
VTMP-SMX
Often used for mild SSTI if susceptible; not preferred for bacteremia.
Gram-positive cocci
Streptococcus pyogenes (GAS)
Group A Streptococcus remains predictably beta-lactam susceptible.
Add clindamycin for toxin suppression in necrotizing fasciitis or streptococcal toxic shock.
PAmpicillin
No specific caveat listed.
PCefazolin
No specific caveat listed.
PCephalexin
No specific caveat listed.
PPenicillin G
Drug of choice when narrow therapy is appropriate.
ACeftriaxone
No specific caveat listed.
AClindamycin
Use with beta-lactam for toxin suppression in severe toxin-mediated disease.
ALinezolid
No specific caveat listed.
AVancomycin IV
Active but broader than needed if beta-lactams tolerated.
VAzithromycin
Macrolide resistance varies.
XDoxycycline
Not reliable for GAS.
XTMP-SMX
Not reliable for GAS.
Gram-positive cocci
Streptococcus pneumoniae
Therapy depends heavily on syndrome, breakpoints, and resistance phenotype.
Meningitis breakpoints differ from non-meningitis breakpoints.
Daptomycin is not used for pneumonia.
PCeftriaxone
Common preferred agent for invasive susceptible disease; meningitis requires specific breakpoints.
ACefepime
No specific caveat listed.
ACeftaroline
No specific caveat listed.
ALevofloxacin
Respiratory fluoroquinolone option.
ALinezolid
No specific caveat listed.
AVancomycin IV
Used with ceftriaxone empirically for meningitis until susceptibilities return.
VAmpicillin
Susceptibility and syndrome dependent.
VAzithromycin
Macrolide resistance is common in many regions.
VDoxycycline
No specific caveat listed.
VPenicillin G
Susceptibility and syndrome dependent.
VTMP-SMX
No specific caveat listed.
XDaptomycin
Not for pneumonia.
Gram-positive cocci
Enterococcus faecalis
E. faecalis is often ampicillin susceptible; cephalosporins are intrinsically inactive.
Cephalosporins do not treat Enterococcus.
Bactericidal synergy may be needed for endocarditis.
PAmp-sulbactam
No specific caveat listed.
PAmpicillin
Preferred when susceptible.
ADaptomycin
No specific caveat listed.
ALinezolid
No specific caveat listed.
APip-tazo
No specific caveat listed.
AVancomycin IV
Use for susceptible isolates when beta-lactams cannot be used.
SFosfomycin PO
Cystitis only; verify susceptibility if available.
SNitrofurantoin
Cystitis only if susceptible.
XTMP-SMX
Not reliable clinically despite possible in vitro appearance.
-Cefepime
Cephalosporins are intrinsically inactive.
-Ceftriaxone
Cephalosporins are intrinsically inactive.
Gram-positive cocci
Enterococcus faecium / VRE
E. faecium is frequently ampicillin resistant and may be vancomycin resistant.
Use species and susceptibility data; E. faecium assumptions differ from E. faecalis.
Cephalosporins are intrinsically inactive.
PDaptomycin
Common preferred option for VRE bacteremia; dose matters.
PLinezolid
Useful for VRE, including pneumonia when true infection.
ATigecycline/Eravacycline
Not for bacteremia.
SNitrofurantoin
Cystitis only if susceptible.
VAmpicillin
Some isolates susceptible, but many E. faecium are resistant.
VVancomycin IV
Inactive for VRE; active only if vancomycin susceptible.
-Cefepime
Cephalosporins are intrinsically inactive.
-Ceftriaxone
Cephalosporins are intrinsically inactive.
Gram-positive rods
Listeria monocytogenes
Listeria is intrinsically resistant to cephalosporins; ampicillin is the classic therapy.
Cephalosporin-based meningitis regimens miss Listeria.
PAmpicillin
Preferred backbone therapy.
AGent/Tobra
Sometimes used for synergy.
AMeropenem
No specific caveat listed.
APenicillin G
No specific caveat listed.
ATMP-SMX
Alternative in severe beta-lactam allergy.
-Cefepime
Cephalosporins do not cover Listeria.
-Ceftriaxone
Cephalosporins do not cover Listeria.
Enterobacterales
Escherichia coli / susceptible Enterobacterales
Susceptibility is increasingly local and isolate-specific; separate resistant phenotypes matter.
Do not assume fluoroquinolone or TMP-SMX susceptibility empirically.
Nitrofurantoin and fosfomycin are cystitis-only.
PCeftriaxone
Common preferred IV option when susceptible.
AAztreonam
If susceptible; no gram-positive or anaerobe coverage.
ACefepime
No specific caveat listed.
AErtapenem
Active but broad; reserve when narrower options unsuitable.
AMeropenem
Active but broad.
APip-tazo
No specific caveat listed.
SFosfomycin PO
Uncomplicated cystitis, strongest for E. coli.
SNitrofurantoin
Uncomplicated cystitis only.
VAmikacin
No specific caveat listed.
VAmox-clav
No specific caveat listed.
VAmp-sulbactam
No specific caveat listed.
VAmpicillin
Often resistant.
VCiprofloxacin
No specific caveat listed.
VGent/Tobra
No specific caveat listed.
VLevofloxacin
No specific caveat listed.
VTMP-SMX
No specific caveat listed.
Enterobacterales
Klebsiella pneumoniae / Klebsiella oxytoca
Klebsiella is intrinsically ampicillin resistant; ESBL and CRE phenotypes must be recognized separately.
Ampicillin does not cover Klebsiella.
Oral fosfomycin is less reliable for Klebsiella because fosA is common.
PCeftriaxone
If susceptible and no ESBL/CRE concern.
AAztreonam
No specific caveat listed.
ACefepime
No specific caveat listed.
AErtapenem
No specific caveat listed.
AMeropenem
No specific caveat listed.
APip-tazo
No specific caveat listed.
SNitrofurantoin
Cystitis only if susceptible.
VAmikacin
No specific caveat listed.
VAmox-clav
No specific caveat listed.
VAmp-sulbactam
No specific caveat listed.
VCiprofloxacin
No specific caveat listed.
VGent/Tobra
No specific caveat listed.
VLevofloxacin
No specific caveat listed.
VTMP-SMX
No specific caveat listed.
XFosfomycin PO
Not reliable for Klebsiella cystitis because fosA is common.
-Ampicillin
Intrinsic resistance.
Enterobacterales
ESBL-producing Enterobacterales
ESBLs inactivate most penicillins, cephalosporins, and aztreonam; carbapenems are preferred for invasive infection.
Piperacillin-tazobactam and cefepime may test susceptible but are not preferred for invasive ESBL infection.
UTI-only agents do not treat pyelonephritis or bacteremia.
PErtapenem
Preferred for many non-critically ill invasive ESBL infections.
PMeropenem
Preferred for critical illness, hypoalbuminemia, CNS infection, or Pseudomonas concern.
ACiprofloxacin
Use only if susceptible and appropriate site.
ALevofloxacin
Use only if susceptible and appropriate site.
ATMP-SMX
Use only if susceptible and appropriate site.
SFosfomycin PO
Uncomplicated E. coli cystitis only; not pyelo/bacteremia.
SNitrofurantoin
Uncomplicated cystitis only.
VAmikacin
No specific caveat listed.
VGent/Tobra
No specific caveat listed.
XCefepime
Not preferred for ESBL infection outside select low-risk urinary scenarios.
XPip-tazo
Not preferred for invasive ESBL infection even if reported susceptible.
-Aztreonam
No specific caveat listed.
-Ceftriaxone
No specific caveat listed.
Enterobacterales
AmpC-risk Enterobacterales
Enterobacter cloacae complex, K. aerogenes, C. freundii, and related organisms can derepress AmpC during therapy.
Ceftriaxone may appear active initially but can fail in invasive disease through AmpC derepression.
Cefepime is often preferred when susceptible.
PCefepime
Preferred beta-lactam when susceptible for many invasive AmpC-risk infections.
AErtapenem
Active if no Pseudomonas/Acinetobacter concern.
AMeropenem
Use for severe illness, high MICs, or ESBL co-production concern.
VAmikacin
No specific caveat listed.
VCiprofloxacin
No specific caveat listed.
VGent/Tobra
No specific caveat listed.
VLevofloxacin
No specific caveat listed.
VPip-tazo
May be suboptimal for invasive infections caused by moderate-risk AmpC organisms.
VTMP-SMX
No specific caveat listed.
XCeftazidime
Avoid for invasive infection because of inducible AmpC risk.
XCeftriaxone
Avoid for invasive infection because of inducible AmpC risk.
-Amox-clav
No specific caveat listed.
-Amp-sulbactam
No specific caveat listed.
-Ampicillin
No specific caveat listed.
Enterobacterales
CRE / KPC-producing Enterobacterales
CRE therapy depends on carbapenemase mechanism; KPC producers are often treated with newer beta-lactam/beta-lactamase inhibitors.
Do not treat CRE from a matrix alone; identify carbapenemase when possible.
Use AST and ID consultation.
PCeftaz-avibactam
Preferred for many KPC-producing CRE when susceptible.
ACefiderocol
Active against many CRE; role depends on mechanism/site.
ATigecycline/Eravacycline
Not for bacteremia or UTI as monotherapy.
VAmikacin
No specific caveat listed.
VCiprofloxacin
No specific caveat listed.
VGent/Tobra
No specific caveat listed.
VLevofloxacin
No specific caveat listed.
VTMP-SMX
No specific caveat listed.
XMeropenem
Usually unreliable for CRE unless specific susceptible/non-carbapenemase scenario.
-Cefepime
No specific caveat listed.
-Ceftriaxone
No specific caveat listed.
-Ertapenem
No specific caveat listed.
-Pip-tazo
No specific caveat listed.
Enterobacterales
NDM / metallo-beta-lactamase Enterobacterales
Metallo-beta-lactamases hydrolyze most beta-lactams but do not hydrolyze aztreonam; avibactam protects aztreonam from co-produced serine beta-lactamases.
Aztreonam alone is often insufficient because other beta-lactamases are co-produced.
Use mechanism-guided therapy and AST.
ACefiderocol
Potential option depending on susceptibility and syndrome.
ACeftaz-avibactam
Used with aztreonam when aztreonam-avibactam unavailable.
ATigecycline/Eravacycline
Not for bacteremia or UTI as monotherapy.
VAmikacin
No specific caveat listed.
VAztreonam
Requires protection from co-produced serine beta-lactamases; often paired with ceftaz-avibactam.
-Cefepime
No specific caveat listed.
-Ertapenem
No specific caveat listed.
-Meropenem
No specific caveat listed.
Non-fermenters
Pseudomonas aeruginosa
Pseudomonas requires antipseudomonal agents; ertapenem, ceftriaxone, and oral beta-lactams do not cover it.
Susceptibility is essential.
Ceftazidime lacks gram-positive activity; aztreonam lacks gram-positive/anaerobe coverage.
PCefepime
No specific caveat listed.
PCeftazidime
No specific caveat listed.
PMeropenem
No specific caveat listed.
PPip-tazo
No specific caveat listed.
AAztreonam
No specific caveat listed.
ACefiderocol
Reserve for resistant isolates when susceptible.
ACeftaz-avibactam
Reserve for resistant isolates when susceptible.
ACeftolo-tazo
Reserve for resistant isolates when susceptible.
VAmikacin
No specific caveat listed.
VCiprofloxacin
No specific caveat listed.
VGent/Tobra
No specific caveat listed.
VLevofloxacin
No specific caveat listed.
-Ceftriaxone
No specific caveat listed.
-Doxycycline
No specific caveat listed.
-Ertapenem
No Pseudomonas activity.
-TMP-SMX
No specific caveat listed.
Non-fermenters
DTR Pseudomonas aeruginosa
Difficult-to-treat resistant Pseudomonas requires susceptibility-guided newer agents.
Use AST and local resistance mechanisms.
Combination therapy decisions depend on syndrome and available active agents.
PCeftolo-tazo
Often preferred when susceptible, especially for pneumonia.
ACefiderocol
Option when susceptible.
ACeftaz-avibactam
Option when susceptible.
VAmikacin
No specific caveat listed.
VCiprofloxacin
No specific caveat listed.
VGent/Tobra
No specific caveat listed.
VLevofloxacin
No specific caveat listed.
-Cefepime
No specific caveat listed.
-Meropenem
No specific caveat listed.
-Pip-tazo
No specific caveat listed.
Non-fermenters
Acinetobacter baumannii / CRAB
Acinetobacter susceptibility is unpredictable; carbapenem-resistant A. baumannii is a distinct high-risk phenotype.
Ampicillin-sulbactam activity reflects sulbactam, not ampicillin.
CRAB often requires specialist input and newer agents when available.
ACefiderocol
Potential option for resistant isolates; interpret by syndrome and guidance.
ATigecycline/Eravacycline
Not for bacteremia as monotherapy.
VAmikacin
No specific caveat listed.
VAmp-sulbactam
May be useful for susceptible A. baumannii; sulbactam is the active component.
VCefepime
No specific caveat listed.
VGent/Tobra
No specific caveat listed.
VMeropenem
Only if susceptible; often resistant in CRAB.
VMinocycline
No specific caveat listed.
VPip-tazo
No specific caveat listed.
Non-fermenters
Stenotrophomonas maltophilia
Stenotrophomonas is intrinsically resistant to carbapenems and many broad gram-negative agents.
Distinguish colonization from infection.
Treatment is susceptibility-guided; invasive disease guidance is evolving.
PTMP-SMX
Traditional preferred agent when susceptible.
ACefiderocol
Increasingly important option for invasive infection when susceptible.
ACeftaz-avibactam
With aztreonam may be an option in selected resistant infections.
AMinocycline
Common alternative when susceptible.
VAztreonam
Often considered with avibactam protection, not alone.
VLevofloxacin
Resistance can emerge.
-Cefepime
No specific caveat listed.
-Meropenem
Intrinsic resistance.
-Pip-tazo
No specific caveat listed.
Respiratory / GN diplococci
Haemophilus influenzae
Beta-lactamase production is common enough that ampicillin is not reliable empirically.
Use syndrome-specific therapy; meningitis differs from otitis/sinusitis/COPD exacerbation.
PAmox-clav
No specific caveat listed.
PAmp-sulbactam
No specific caveat listed.
PCeftriaxone
No specific caveat listed.
AAzithromycin
No specific caveat listed.
ACefepime
No specific caveat listed.
ACiprofloxacin
No specific caveat listed.
ADoxycycline
No specific caveat listed.
ALevofloxacin
No specific caveat listed.
VAmpicillin
Only reliable if beta-lactamase negative and susceptible.
VTMP-SMX
No specific caveat listed.
Respiratory / GN diplococci
Neisseria meningitidis
Ceftriaxone is standard empiric/definitive therapy for invasive meningococcal disease.
Ciprofloxacin, ceftriaxone, or rifampin are used for prophylaxis depending local guidance; rifampin is not in this matrix.
PCeftriaxone
No specific caveat listed.
ACiprofloxacin
Useful for prophylaxis in selected settings, not primary severe disease therapy.
AMeropenem
No specific caveat listed.
APenicillin G
If penicillin susceptible.
VAzithromycin
Not standard treatment.
Anaerobes
Bacteroides fragilis group
B. fragilis group requires anaerobe-active therapy; many cephalosporins and fluoroquinolones are unreliable.
Ceftriaxone requires metronidazole for intra-abdominal anaerobic coverage.
Clindamycin resistance is common.
PAmox-clav
No specific caveat listed.
PAmp-sulbactam
No specific caveat listed.
PErtapenem
No specific caveat listed.
PMeropenem
No specific caveat listed.
PMetronidazole
No specific caveat listed.
PPip-tazo
No specific caveat listed.
ATigecycline/Eravacycline
No specific caveat listed.
XClindamycin
Resistance is common; not reliable for B. fragilis group.
-Aztreonam
No specific caveat listed.
-Cefepime
No reliable anaerobic coverage without metronidazole.
-Ceftazidime
No specific caveat listed.
-Ceftriaxone
No reliable anaerobic coverage without metronidazole.
Anaerobes
Oral anaerobes / Fusobacterium
Oral anaerobes are covered by beta-lactam/beta-lactamase inhibitors, carbapenems, and metronidazole-containing combinations.
Metronidazole has no aerobic streptococcal coverage, so pair it when mixed oral flora are suspected.
PAmox-clav
No specific caveat listed.
PAmp-sulbactam
No specific caveat listed.
PErtapenem
No specific caveat listed.
PMeropenem
No specific caveat listed.
PPip-tazo
No specific caveat listed.
AMetronidazole
Add aerobic streptococcal coverage for mixed oral flora.
VClindamycin
Resistance varies; no gram-negative aerobic coverage.
VPenicillin G
Some oral anaerobes susceptible; beta-lactamase production varies.
Anaerobes
Clostridioides difficile
CDI treatment uses enteral lumen-active agents; systemic susceptibility tables are the wrong frame.
Oral vancomycin and fidaxomicin are not systemic antibiotics.
Metronidazole is no longer preferred for most adult CDI.
PFidaxomicin
Preferred for initial and recurrent CDI when feasible.
AVancomycin PO
Acceptable alternative; required backbone for fulminant CDI.
VMetronidazole
Alternative only in selected nonsevere situations when preferred agents unavailable; IV adjunct in fulminant CDI.
-Cefepime
No specific caveat listed.
-Ceftriaxone
No specific caveat listed.
-Meropenem
No specific caveat listed.
-Vancomycin IV
IV vancomycin does not treat luminal CDI.
Atypical / intracellular
Legionella pneumophila
Legionella requires intracellular-active therapy; beta-lactams do not work clinically.
Use azithromycin or a respiratory fluoroquinolone for pneumonia.
PAzithromycin
No specific caveat listed.
PLevofloxacin
No specific caveat listed.
ACiprofloxacin
No specific caveat listed.
ADoxycycline
No specific caveat listed.
-Cefepime
No specific caveat listed.
-Ceftriaxone
Beta-lactams do not treat Legionella.
-Meropenem
No specific caveat listed.
-Pip-tazo
No specific caveat listed.
Atypical / intracellular
Mycoplasma / Chlamydophila pneumoniae
Atypical respiratory pathogens lack classic beta-lactam targets or require intracellular-active agents.
Beta-lactams do not cover Mycoplasma.
PAzithromycin
No specific caveat listed.
PDoxycycline
No specific caveat listed.
ACiprofloxacin
No specific caveat listed.
ALevofloxacin
No specific caveat listed.
-Cefepime
No specific caveat listed.
-Ceftriaxone
No specific caveat listed.
-Meropenem
No specific caveat listed.
-Pip-tazo
No specific caveat listed.
-Vancomycin IV
No specific caveat listed.
Atypical / intracellular
Rickettsiae / Coxiella burnetii
Doxycycline is the key empiric therapy for rickettsial disease and Q fever.
Do not delay doxycycline for suspected RMSF.
PDoxycycline
No specific caveat listed.
VAzithromycin
Alternative only in selected scenarios.
VLevofloxacin
No specific caveat listed.
-Cefepime
No specific caveat listed.
-Ceftriaxone
No specific caveat listed.
-Meropenem
No specific caveat listed.
-Pip-tazo
No specific caveat listed.
-Vancomycin IV
No specific caveat listed.
GI / water / zoonotic
Pasteurella multocida
Pasteurella is a key cat/dog bite pathogen; dicloxacillin, cephalexin, and clindamycin alone are unreliable.
Bite wounds require polymicrobial coverage, not just Pasteurella coverage.
PAmox-clav
Preferred oral bite-wound agent.
PAmp-sulbactam
Preferred IV bite-wound agent.
ACeftriaxone
Pair with anaerobic coverage for bite wounds.
ACiprofloxacin
Pair with anaerobic coverage for bite wounds.
ADoxycycline
No specific caveat listed.
ALevofloxacin
Pair with anaerobic coverage for bite wounds.
APip-tazo
No specific caveat listed.
XCephalexin
Unreliable for Pasteurella.
-Clindamycin
No Pasteurella coverage.
-Nafcillin/Oxacillin
No specific caveat listed.
GI / water / zoonotic
Vibrio vulnificus / Aeromonas
Water-associated gram-negative wound infections require exposure-specific coverage.
Vibrio vulnificus severe infection classically uses doxycycline plus a third-generation cephalosporin or fluoroquinolone-based therapy.
PDoxycycline
Part of classic Vibrio vulnificus combination therapy.
ACefepime
No specific caveat listed.
ACeftazidime
Often paired with doxycycline for Vibrio vulnificus.
ACeftriaxone
Often paired with doxycycline for Vibrio vulnificus.
ACiprofloxacin
No specific caveat listed.
ALevofloxacin
No specific caveat listed.
VTMP-SMX
No specific caveat listed.
XAmox-clav
Unreliable for Aeromonas and severe water-associated infections.
-Cephalexin
No specific caveat listed.