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Antimicrobials
Making sense of them
W. Sligl
Infectious Diseases/Critical Care
Outline
General considerations when
prescribing antimicrobials
Review of antibacterial classes
Mechanisms of resistance
Empiric Therapy
Initiation of treatment for a clinical
syndrome before the specific
microbiology known
‘Best guess’
Requires some understanding of
infectious disease epidemiology
Case Examples
Case #1: 17 yo M, previously healthy, with 2
day hx of fever, sore throat, cough.
 Diagnostic possibilities?
 Can he wait or should be be treated?
 What would you treat him with?
Case #2: 17 yo M with advanced HIV and 2
day hx of fever, sore throat, cough.
 Diagnostic possibilities?
 Can he wait or should he be treated?
 What should he be treated with?
Factors to Consider when
Prescribing Antimicrobials
Host Factors
Microbial Factors
Antimicrobial Factors
Host Factors
Age
Immune adequacy
Underlying diseases
Renal/hepatic impairment
Presence of prosthetic materials
Ethnicity
Pregnancy/nursing
Age
Can help to narrow the diagnosis with certain
infections
Examples:

Meningitis
 What bugs would you consider in a neonate? In an adult?

EBV infection
 In what age group would you consider this diagnosis?

UTI
 How does age affect your interpretation of laboratory
results?
Immune Adequacy
Immune status important
May be at increased risk of specific
infections

Asplenia
 Encapsulated bacterial infections

HIV/AIDS
 Opportunistic infections

Transplantation
 Variety of infections depending on net degree
of immunosuppression
Underlying Diseases
Increased risk of infection in pts with

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
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
Diabetes mellitus
HIV/AIDS
Malignancies
Renal impairment
Autoimmune diseases
Renal/Hepatic Impairment
Implications for treatment



Dose adjustments may be needed
Avoid concomitant nephro- or hepato-toxic drugs
May require fluid boluses prior to administration
 E.g. amphotericin B, acyclovir
Implications for monitoring


Monitor renal/liver function
Consider monitoring drug levels if available (i.e.
therapeutic drug monitoring; TDM)
Presence of Prostheses
Implications for diagnosis

What bug(s) are more pathogenic in
artificial joints/valves?
Implications for treatment


Infected hardware needs to be removed
– antibiotics alone don’t usually work
May add rifampin in certain situations
(biofilm penetration)
Ethnicity
Consider diseases endemic in country of
origin
Examples:



TB in patients from TB endemic areas as
well as First Nations patients
Strongyloides in patients from tropical
countries
Also consider malaria, trypanosomiasis,
leptospirosis, leishmaniasis, leprosy
Geographic Factors
Need to know common microbial
causes of infection in your area
 Example: Recent emergence of CA-MRSA in
outpatient skin and skin structure infections
Travel history is important
 Example: Fever in traveler returning from
Sudan vs. person who has never left
Edmonton
Pregnancy and Nursing
Safety of antibiotic use in pregnancy and
nursing has to be considered
 Generally SAFE




Beta-lactams
Macrolides
Clindamycin
Conventional dosing AG
 NOT SAFE




Fluoroquinolones
TMP/SMX
Extended interval AG
Tetracyclines
Microbial Factors
Probable microorganisms
Microbial susceptibility patterns
Natural history of infections
Likelihood of obtaining microbiologic
data
Site of Infection
Probable Microorganisms
Have to know most likely organisms for
various common infections






CAP, HAP, VAP
Intra-abdominal infections
Catheter-related UTIs
Line infections
Endocarditis
Meningitis
Microbial Susceptibilities
Know general microbial susceptibilities as well
as those which are geographically specific:

S. pneumoniae
 ~15% resistant to erythromycin, ~3% to penicillin


P. aeruginosa
 ~30-40% resistant to ciprofloxacin
 Higher in ICU pts; ~50-70%
MRSA
 MRSA made up 6% of S. aureus isolates in Capital Health Region
2005
 Huge increase in 2007-2008; up to 50% of isolates in OPAT
setting (CA-MRSA)
 Vs. up to 70% in some US centers
 Know your local epidemiology!
And don’t forget to ask about recent Abx use!
Natural History of Infection
Rapidly fatal vs. slow growing


Meningococcemia – can be rapidly fatal
TB meningitis often more indolent course
Know what to expect

Pyelonephritis – expect fever for up to 72
hours, image if still febrile after 72 hours to
r/o perinephric abscess
Likelihood of Obtaining
Microbiologic Data
May be difficult to get specimen(s)

E.g. brain abscess
If patient has been on antibiotics, will
affect culture results
May need to treat empirically, and
follow clinical response/imaging
Site of Infection
Susceptibility testing is geared to attainable
serum levels
Does not account for host factors or
conditions that alter antimicrobial access
Diffusion into CSF is limited in many drugs
Abscesses
 Difficult to penetrate abscess wall
 High bacterial burden
 Low pH and low oxygen tension can affect antimicrobial
activity
Antimicrobial Factors
Route of Administration
Bactericidal vs. bacteristatic
Combination vs. monotherapy
Route of Administration
Many options exist





Enteral
Parenteral
Nebulization
Intrathecal
Topical
Enteral Administration
Check drug oral bioavailability
Must be resistant to breakdown by
gastric acid


Some drugs must be given with buffer
Some require acidity for absorption
Other drugs cannot be given in high
enough doses orally (usually d/t side
effects/intolerance)
Bactericidal vs. Bacteristatic
Antibiotics work by either killing (cidal)
vs. halting growth (static) of microorganisms
Cidal: beta-lactams, aminoglycosides,
fluoroquinolones, glycopeptides,
daptomycin, metronidazole
Static: tetracyclines, macrolides,
clindamycin, linezolid
Combination Therapy
Three main reasons:

Broader coverage
 May be necessary for empiric treatment of certain
infections
 E.g. intra-abdominal sepsis, VAP

Synergistic activity
 E.g. amp + gent for serious enterococcal infections

Prevent resistance
 E.g. TB, pseudomonal infection
Disadvantages:


Antagonism (e.g. linezolid and vancomycin)
Potential for increased toxicity
Adjunctive Approaches
Don’t forget to do all the other stuff:
Septic shock: EGDT, steroids, rhAPC
Bacterial meningitis: steroids

Benefit in S. pneumoniae in adults and H.
influenzae in children
Drainage and debridement of abscesses
Removal of prosthetic materials
Correction of malnutrition
Assisted organ function

Mechanical ventilation, CRRT/IHD, hemodynamic
support with inotropes/vasopressors
Monitoring Response to
Therapy
Monitor infectious parameters



Fever
WBC
ESR etc.
Know natural history
Serial imaging may be useful
Repeat cultures

E.g. bacteremia, endocarditis
Duration of Therapy
Very few studies to establish minimum
durations of therapy

Duration usually based on anecdote
Most uncomplicated bacterial infections
should be treated for 7–14 days
10-14 days: bacteremia
4-6 weeks: endocarditis, empyema, septic
arthritis, osteomyelitis
6-12 months: mycobacterial diseases,
nocardia, endemic mycoses
*VAP: used to recommend 14-21 days!; recent studies suggest 7-8 days is
adequate but depends on microorganism, severity of disease, and pt
comorbidities (e.g. may want to Rx immunosuppressed pts or those
with Pseudomonas orS. aureus a little longer)
Pharmacoeconomics
Cost of illness includes




Medications
Provider visits
Administration of medications
Loss of productivity
*Cost is a tertiary consideration after
effectiveness and safety
Antibacterials
Beta-Lactams
Includes

Penicillins, cephalosporins, carbapenems,
monobactams
Mechanism of Action

Inhibit cell wall synthesis by binding to PBP
and preventing formation of peptidoglycan cross
linkage
Toxicity


Hypersensitivity reactions
Cross-reactivity with penicillin allergy
 10-20% with carbapenems (50% if skin test +)
 10% with 1st gen. cephalosporins
 1% with 3rd gen. cephalosporins
Beta-Lactams
Natural Penicillins
Includes

Pen G, Pen V, benzathine penicillin
Spectrum of activity

Streptococci
 Viridans group strep, beta-hemolytic strep, many S.
pneumoniae


Most N. meningiditis
Oral anaerobes
 Peptostreptococcus

Other: Listeria monocytogenes, Pasteurella
multocida, Treponema pallidum, Actinomyces
israelii
Aminopenicillins
Prototypes: Ampicillin, Amoxicillin
Spectrum of activity

Streptococcus spp.

Enterococcus faecalis (not faecium)
Spectrum extended to include
some GNB

E. coli, Proteus mirabilis, Salmonella spp.,
Shigella, Moraxella, Hemophilus spp.
Penicillinase Resistant
Penicillins
Prototype: Cloxacillin
Spectrum of activity

Staphylococci
 MSSA, 1/3 of CoNS

Streptococcus spp.
No enterococcal coverage
No gram-negative or anaerobic
coverage
Carboxypenicillins
Prototype: Ticarcillin
Broad spectrum activity including
Stenotrophomonas and Pseudomonas
Problems with hypernatremia,
hypokalemia, platelet dysfunction
If clavulanate added – MSSA coverage,
improved gram-negative and anaerobic
coverage
Ureidopenicillins
Prototype: Piperacillin
Spectrum of activity





Streptococcus spp. (less than earlier generations)
Enterococcus faecalis (NOT faecium)
Anaerobic organisms
Pseudomonas
Broad Enterobacteraciae coverage
If tazobactam added – MSSA coverage,
improved gram-negative and anaerobic
coverage
Cephalosporins
Divided into 4 generations
In general: ↑ gram-negative coverage
and ↓ gram-positive coverage with ↑
generation
Enterococci not covered by any
generation!
1st Generation
Prototype: Cefazolin (Ancef®)
Spectrum of activity

MSSA
Streptococcus spp.

E. coli, Klebsiella, Proteus mirabilis

No anaerobic activity
2nd Generation
Prototype: Cefuroxime
Spectrum of activity



Gram positives (MSSA, Streptococcus)
H. influenzae
M. catarrhalis
3rd Generation
Divided into two main groups:

Ceftazidime
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Ceftriaxone and cefotaxime

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Pseudomonal coverage
Good gram-negative coverage
Less gram-positive coverage
Less reliable MSSA coverage
Good gram-negative coverage
No anti-pseudomonal activity
No anaerobic activity
Good CSF penetration – used in meningitis
Toxicity includes biliary sludging
Cefixime – oral equivalent

No anti-pseudomonal activity
4th Generation
Cefepime




Maintains gram positive activity, better
MSSA coverage than with 3rd generation
cephalosporins
Active against Pseudomonas
? Activity against SPICEM organisms
Lower potential for resistance
The Next Generation
“Fifth Generation”; “Extended-spectrum”
Ceftobiprole (Zeftera)

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Recently approved by Health Canada (June 2008)
Available via special access
First broad-spectrum anti-MRSA cephalosporin
Broad-spectrum activity including MRSA,
Pseudomonas, and E. faecalis
Reduced activity against cephalosporin-resistant
SPICEM and ESBLs organisms
Binds to PBP2a (MRSA) and PBP2x (penicillinresistant S. pneumoniae)
The Next Generation
“Fifth Generation”; “Extended-spectrum”
Ceftobiprole (Zeftera)




Caramel taste during infusion (diacetyl formed
during conversion from prodrug to active
metabolite)
Statistically non-inferior to vancomycin and
vancomycin/ceftazidime for the treatment of skin
and soft tissue infections
 STRAUSS 1 and 2 trials
Current indications: complicated skin and skin
structure infections (cSSSI), DM foot infections,
?nosocomial pneumonia (awaiting further trials)
Dose: 500mg IV q12h for GP, 500mg IV q8h for
GN
Carbapenems
Imipenem/Meropenem


MSSA, Streptococcus
Broad-spectrum gram-negative coverage including
SPICEM organisms

Pseudomonas
Enterococcus faecalis but NOT faecium

Anaerobic activity

Ertapenem


Allows once a day dosing
Does not cover Pseudomonas or
Enterococcus
Monobactam
Prototype: Aztreonam

Aerobic GNB
 Including Pseudomonas

No gram-positive or anaerobic coverage
Similar spectrum to aminoglycosides without
renal toxicity
Cross reactivity to penicillin rare (may use in
pen-allergic pts)

Some cross-reactivity with ceftazidime
(same side-chains)
Aminoglycosides
Includes




Gentamicin
Tobramycin
Amikacin
Streptomycin
Mechanism of action


Bind to 30S/50S ribosomal subunit
Inhibit protein synthesis
Toxicity



CN VIII - irreversible
Renal toxicity – reversible
Rarely hypersensitivity reactions
Aminoglycosides
Spectrum of activity

Aerobic GNB including Pseudomonas
Mycobacteria (mainly streptomycin)
Brucella, Fransicella (tularemia)

Nocardia



Synergistic with beta-lactams (Enterococci,
Staphylococci)
Fluoroquinolones
Includes





Ciprofloxacin
Ofloxacin
Levofloxacin
Gatifloxicin
Moxifloxacin
Mechanism of Action

DNA gyrase inhibitors
Toxicity

GI symptoms, QTc prolongation
Fluoroquinolones
All cover

Atypicals: Mycoplasma, Legionella, Chlamydia

Fransicella, Rickettsia, Bartonella

Atypical mycobacteria
Ciprofloxacin

Good gram-negative coverage

N. gonorrhea, H. influenzae


Good for UTI, infectious diarrhea
May be used in combination for Pseudomonas
Fluoroquinolones
Levofloxacin



L-enantomer of ofloxacin
Better gram-positive coverage (mainly
Streptococcus) than ciprofloxacin
Used for LRTI
Moxifloxacin

Quite broad-spectrum
 Activity against Strep/Staph plus gram-negatives
 Anaerobic coverage

Minimal to no anti-pseudomonal activity
Macrolides
Includes



Erythromycin
Clarithromycin
Azithromycin
Mechanism of Action



Bind to ribosomal subunit
Block protein synthesis
***Static, not cidal
Toxicity

GI upset (especially with erythromycin)
Erythromycin
Active against Streptococcal spp.
Also effective against


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Legionella
Mycoplasma
Campylobacter
Chlamydia
Neisseria gonorrheae
Poor for H. influenzae
Used infrequently due to GI upset
Lots of safety data in children/pregnancy
Clarithromycin
Spectrum of activity

Streptococci including S. pneumoniae

Moraxella, Legionella, Chlamydia



Atypical mycobacteria
More active against H. influenzae
Used in combination against H. pylori
Less GI side effects
Azithromycin
Spectrum of activity



Mycoplasma, Legionella, Chlamydia
H. influenzae
Streptococcus spp.
Long half-life

5 day course is adequate
Less GI side effects
Anti-inflammatory properties in addition to
antimicrobial action?

Some evidence of improved outcomes when
added to beta-lactam in bacteremic pneumococcal
CAP
Telithromycin
Ketolide, similar to macrolides
Macrolide resistant S. pneumoniae usually the result
of a point mutation altering ribosomal target site
binding

Telithromycin binds to two independent sites on 50S and is a
poor substrate for efflux – potent against macrolide-R
pneumococcus
Bewrare serious side effects: hepatic necrosis, GI
upset, arrhythmias, rash
*P450 inhibitor – multiple drug interactions
Used only for mild-moderate CAP due to multidrug resistant S. pneumoniae
Clindamycin
Mechanism of Action


Blocks protein synthesis by binding to ribosomal
subunits
***Static, not cidal
Toxicity



Rash
GI symptoms
C. difficile colitis in 1-10%
Covers MSSA, Streptococcus, and anaerobes
No gram-negative or Enterococcal coverage
Tetracyclines
Includes




Tetracycline
Doxycycline
Minocycline
Tigecycline (glycylcycline)
Mechanism of Action



Bind to 30S ribosomal subunit
Block protein synthesis
***Static, not cidal
Toxicity

Rash, photosensitivity, impairs bone growth and
stains teeth of children, increased uremia
Tetracyclines
Spectrum includes unusual organisms






Rickettsia
Chlamydia
Mycoplasma
Vibrio cholera
Brucella
Borreila burgdorferii (Lyme disease)
Minocycline
 Active against Stenotrophomonas and P. acnes
 May be active against MRSA
Doxycycline
 Used in uncomplicated CAP and for prophylaxis against
malaria
Tigecycline
Tygacil®
Novel broad-spectrum
Glycylcyline
Biliary/fecal excretion
Active against gram-positives including MSSA
and MRSA (not VRE), Enterobacteraciae
including ESBLs, MDR-Acinetobacter, and
anerobes
No anti-pseudomonal activity
For complicated intra-abdominal and skin/soft
tissue infections
Not approved for bacteremia or pneumonia
Glycopeptides
Prototype: Vancomycin
Mechanism of Action
 Inhibits cell wall synthesis
Toxicity
 Ototoxicity – rare
 Can induce histamine release – red man
syndrome

Usually with rapid infusion
Glycopeptides
Spectrum of activity
 Gram-positives: S. aureus (incl. MRSA), CoNS,
Streptococcus, Enterococcus
 Gram-positive anaerobes
 Exceptions: VRE, Leuconostoc, Lactobacillis
Inferior to beta-lactams in terms of cure rates
for beta-lactam sensitive organisms
Big, bulky molecule – poor CSF penetration in
the absence of meningeal inflammation
(including those treated with corticosteroids)
Lipopeptides
Daptomycin or Cubicin®
Bactericidal
Disrupts bacterial membrane function

Binds to cell membrane, forms ion channel,
K+ efflux, depolarization, cell death
In vitro activity against gram-positive
organisms including MSSA, MRSA,
VRSA, VRE, PRSP
Daptomycin
Approved for use in MSSA/MRSA and other
selected gram-positives (not VRE, yet):


Complicated skin and soft tissue infections
S. aureus bacteremia/R. IE
Cannot be used to treat pneumonia


Does not achieve sufficiently high concentrations
in the respiratory tract
Inactivated by surfactant
Side effects: myopathy; monitor CK
Metronidazole
Mechanism not well understood

Interferes with DNA synthesis via toxic intermediates
Spectrum of activity


Most anaerobes except Peptostreptococcus,
Actinomyces, Propionibacterium acnes
Parasites: Giardia lamblia, Entamoeba histolytica
Toxicity



Disulfuram reaction
Neuropathy
Potentiation of warfarin
Sulfa drugs
Includes: TMP/SMX
Mechanism of Action
 Folate reductase inhibitor
Toxicity
 Hypersensitivity reactions
 Thrombocytopenia
 Rash
 Hyperkalemia
Sulfa drugs
Broad-spectrum coverage








Streptococcus, Staphylococcus
H. influenza
L. monocytogenes
Many Enterobacteraciae (E. coli, Klebsiella)
Stenotrophomonas maltophila
PJP
Nocardia
Isospora belli
Frequent allergic rxns
Used in special circumstances (e.g. PJP,
nocardia, Stenotrophomonas)
Chloramphenicol
Broad-spectrum activity




GPC, GNB
Meningitis organisms
Rickettsia spp.
No activity against Klebsiella, Enterobacter,
Serratia, Proteus, Pseudomonas
Toxicity



Dose related marrow toxicity
Idiosyncratic aplastic anemia
Gray baby syndrome
Linezolid
Oxazolidinone
Binds to ribosomal subunit inhibiting protein
synthesis
Static, not cidal
Excellent oral bioavailability
Active against
 MSSA, MRSA, enterococci including VRE, S.
pneumoniae

No activity against gram-negatives
Linezolid
No cross-resistance with other drugs
Approved for use in nosocomial pneumonia
and skin/soft tissue infections
Major side effect:


Reversible myelosuppression
Monitor CBCD
Resistance reported, but rare
Very expensive ($140/day) and currently not
covered (used mainly in WCB cases)
Quinupristin/dalfopristin
Synercid®
Combined stretogramin A and B
Bactericidal
Approved for use in skin and soft tissue
infections only
Active against a wide variety of gram-positive
bacteria

MSSA, MRSA, CoNS, Streptococci, VRE (E. faecium not E.
faecalis)
Major side effect: phlebitis, hyperbilirubinemia
Resistance, although rare, has been reported
Colistin
Polymyxin E
Older drug, recently has come into re-use
Binds to phospholipids in cell membrane
causing disruption
Most commonly used in salvage Rx in MDRPseudomonas or Acinetobacter infections
Bactericidal
Nephrotoxic, neurotoxic
*Needs to be renally adjusted
Nitrofurantoin
Synthetic nitrofuran
Inhibits bacterial acetylcoenzyme A –
disrupts carbohydrate metabolism
Cidal at high concentrations, static at
lower
Concentrated in urine with normal renal
function

Contraindicated in renal insufficiency
Nitrofurantoin
Effective against:
 E. coli, Enterococcus, S. aureus, some strains

Klebsiella and Enterobacter
Proteus, Serratia, and Pseudomonas are resistant!
*Only indication is Rx or prophylaxis of
lower UTIs

Should not be used for systemic infection
Adverse effects: n/v, hypersensitivity
pneumonitis, pulmonary fibrosis, hemolytic
anemia in G6PD deficiency, hepatitis
Mechanisms of Action Summary I
Mechanisms of Action Summary II
Mechanisms of Resistance
Mechanisms of Resistance
Enzymatic inactivation of antimicrobial
Target site binding
Efflux
Decreased permeability
Others
Enzymatic Inactivation
Beta-lactamases


Penicillinases, ampCs, ESBLs, metallo-betalactamases
Seen in S. aureus, H. influenzae, N. meningitidis,
SPICEM, E. coli, Klebsiella spp., P. aeruginosa
Enzymatic Inactivation
AG-modifying enzymes


n-acetylation, o-nucleotidylation, o-phosphorylation
Seen in Enterobacteriaceae, Pseudomonas, and
Enterococci
Macrolide, lincosamide, and streptogramin
inactivating enzymes (esterases)

Uncommon
Altered Target Site Binding
Cell wall precursor targets

D-ala-D-ala changed to D-ala-D-lac in VRE
Target enzymes

PBP2a in MRSA; low affinity for betalactams
Ribosomal target sites

Methylase enzymes
 Seen in tetracyclines, macrolides, lincosamides,
aminoglycosides
 erm gene confers MLSB phenotype in S. aureus
which may be constitutive or inducible
Efflux
Seen with tetracyclines, macrolides,
streptogramins, beta-lactams,
fluoroquinolones, and carbapenems
Macrolide resistance in

S. pneumoniae (mef)

Staphylococci (msr)
Beta-lactam resistance in Pseudomonas
Fluoroquinolone resistance in
Enterobacteriaceae
Clindamycin Resistance
ERYTHRO
CLINDA
Decreased Permeability
Porin channels determine rate of
diffusion of Abx – mainly a problem in
GN organisms
Causes


Fluoroquinolones resistance in:
 P. aeruginosa and S. marsecans
Aminoglycoside resistance in:
 E. coli, S. aureus, and Salmonella spp.
Others
Target site protection


DNA gyrase protection and fluoroquinolone-R
Ribosomal protection and tetracycline-R
Overproduction of target


Sulfonamides compete with enzyme DHFR and
halt nucleic acid production
Overproduction of DHFR may overwhelm sulfa
inhibition
Bypass of antimicrobial inhibition

Development of different growth factor
requirements and subsequent evasion of
inhibition
 E.g. trimethoprim/sulfamethoxazole
Questions?