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

• 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 micro-
organisms
• 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
• Pseudomonal coverage
• Good gram-negative coverage
• Less gram-positive coverage
• Ceftriaxone and cefotaxime
• 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)
• 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 (penicillin-
resistant 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
• 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 multi-
drug 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 MDR-
Pseudomonas 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-beta-
lactamases
• 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 beta-
lactams
• 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?