Antibiotics II
Glycopeptides
Aminoglycosides
Macrolides
“The Mycins”
Margaret K. Hostetter, M.D.
Vancomycin +
+ requires addition
of an aminoglycoside
THE GLYCOPEPTIDES
B. fragilis
Gut
GRAM NEGATIVES
Mouth
Ps.aerug
Pseud spp
Serratia
Enterobacter
Klebsiella
E. coli
H. flu
Meningococcus
Grp A strep
Pneumo
Enterococcus
Grp B strep
Listeria
St. aureus
St. epi
GRAM POSITIVES
ANAEROBES
B. fragilis
Gut
Mouth
Ps.aerug
ANAEROBES
Pseud spp
Serratia
Enterobacter
Klebsiella
E. coli
H. flu
Meningococcus
Grp A strep
GRAM NEGATIVES
Pneumo
Enterococcus
Grp B strep
Listeria
St. aureus
St. epi
GRAM POSITIVES
SIDE EFFECTS of VANCOMYCIN
VANCOMYCIN-RESISTANT
ENTE ROCOCCI
HISTAMINE-RELEASE
Infusion in < 1 hour
• flushed skin
• angioneurotic edema
• hypotension
NEPHROTOXICITY or
OTOTOXICITY RARE
Risk Factors for Health Care
Acquired MRSA
• MRSA252
• Hospitalized on antibiotics or frequently
hospitalized (e.g. cystic fibrosis)
• Previous colonization - patient or family
• Long-term care facility - patient or family
• Respiratory therapy - patient or family
• Dialysis - patient or family
• Serious infections susceptible only to Vancomycin,
Daptomycin, Linezolid
Emerg Infect Dis 11(6) 2005
Risk Factors for Community
Acquired MRSA (CA-MRSA)
•
•
•
•
USA300 >> USA400
~5% of children are carriers
NO RISK FACTORS
Crowding, sharing of personal items: sports teams,
military facilities, correctional facilities, child care
• Skin condition (e.g. eczema)
• Differing susceptibilities: TMP-SMX,
clindamycin, doxycycline
D-Test for Inducible
Clindamycin Resistance
E
E
C
C
Resistant Organisms in YNHH
40%
35%
30%
25%
20%
15%
10%
5%
0%
*3/91- *3/92- '93
2/92 2/93
VRE*
'94
'95
MRSA
'96
'97
'98
CipR Pseudomonas
'99
'00
'01
'02
CeftazR Klebsiella
'03
'04
'05
Treatment of MRSA
Drug
CSF
Blood
Lungs
Bones/
Joints
Nafcillin
Cephs
Vanco
√ at 60/kg
Clinda
Bactrim
√
+
If susceptible If susceptible If susceptible
but not
ABE, SBE
Linezolid
√
√ but not
ABE, SBE
Daptomycin
√
√
√
√
√
Penicillin Resistance in
Pneumococci
Drug
Susceptible Intermediate
µg/ml
µg/ml
Resistant
µg/ml
PO penicillin
<0.06
0.12-1.0
>2.0
IV penicillin
non-meningeal
<2.0
4.0
>8.0
IV penicillin
meningeal
<0.06
None
>0.12
3˚ cephs
non-meningeal
<1.0
2.0
>4.0
3˚ cephs
meningeal
<0.5
1.0
>2.0
Treatment of Penicillin
Resistant Pneumococci
Drug
CSF
Blood
Lungs
PO
√
√
Amox
Immunocompetent
Immunocompetent
√
√
Immunocompetent
Immunocompetent
√
√
PCN (all)
Ceph
2˚, 3˚
Clinda
Except endocarditis
Vanco
√
+ rifampin
√
Increase dose to 60 mg/kg/day
√
±
Ceftin
Clinda
Case Study
A 60-day-old female infant presents with temperature to
39.5˚ C rectally, poor feeding, and lethargy. Physical
exam is normal except for lethargy and fever. Blood
culture is drawn. Urinalysis and CXR are normal. CSF
shows 100 WBC’s (90% PMN’s, 10% lymphs), glucose
40/90, protein 175.
• Differential diagnosis?
• Possible causative organisms?
• Antibiotic regimens?
Antibiogram for Meningitis
in Infants 2 -36 mos
Possible
Cause
Penicillin
Group B
strep
PCN,
ampicillin
Strep
pneumoniae
All
unless resist.
Cephalosporin
3˚
3˚
unless resist.
Aminoglycoside
Other
---
Vanco
---
Vanco
H. influenzae Ampicillin
type b
(only ~75%)
3˚
---
---
Meningococcus
3˚
---
---
PCN,
ampicillin
Therefore, the regimen for meningitis in any child
2 months of age or older is
Vancomycin
PLUS
Cefotaxime or Ceftriaxone
Vancomycin Levels
• Not generally indicated (Clin ID 1994;18:533-43)
• Used for patients with fluctuating renal
function or chronic renal failure
• PEAK 20-40 µg/ml; now shoot for 40µg/ml
• TROUGH 10-15 µg/ml
Vancomycin: Not a Wonder Drug
• Very confined spectrum
• Poorer anti-staphylococcal activity than Nafcillin in
endocarditis (AAC 1990; 33:1227-1231)
• Very poor penetration into lung and bone (AAC 1988;
32:1320-1322)
• Advantages
– Staphylococcus epidermidis or MRSA
– Penicillin-allergic patients
– Acceptable penetration into CSF (shunts,
meningitis 2˚ penicillin resistant pneumococci)
but at higher dosage (60 mg/kg/day)
Case Study
Administration of IV Vancomycin (plus other agents where necessary)
is required for which of the following scenarios?
• antibiotic-associated colitis that has failed to respond to
metronidazole
√ • initial therapy of meningitis in a 10-year-old
• routine surgical prophylaxis for line insertion
√ • prophylaxis for urethral dilatation in a 13 month-old infant
with corrected tetralogy of Fallot
• initial therapy of pneumococcal otitis media in a vomiting
patient
√ • initial therapy of a respiratory decompensation in a 6 monthold tracheotomized child known to carry MRSA
Case Study
A 6-year old boy who did not receive varicella vaccine is
hospitalized with an area of erythema and induration
extending for a diameter of 5 cm. around a pox. Aspirate
of the advancing border grows group A streptococci and
Staph aureus. The empiric therapy of choice is
• aqueous penicillin G
• aqueous penicillin G plus Vancomycin
√ • Vancomycin
• Clindamycin
• Imipenem
Case Study
A 6-year old boy who did not receive varicella vaccine is
hospitalized with an area of erythema and induration
extending for a diameter of 5 cm. around a pox. Aspirate
of the advancing border grows group A streptococci and
Staph epidermidis. The therapy of choice is
√ • aqueous penicillin G alone
• aqueous penicillin G plus Vancomycin
• Vancomycin alone
• Imipenem
When Is Staph epi a Pathogen?
Blood cultures of neonates with lines in place Confirm with culture of peripheral blood before Abx
Blood cultures of other patients with lines in place Confirm with culture of peripheral blood before Abx
Cultures of CSF in symptomatic patients with ventricular
shunts
Blood cultures of patients with prosthetic valves or
patches in the heart
Cultures of implants in patients with prosthetic joints
The Aminoglycosides
• Gentamicin
• Tobramycin
• Amikacin
of a peniclllin
+ - requires addition
Amikacin
+
Gentamicin
+
Tobramycin
B. fragilis
Gut
GRAM NEGATIVES
Mouth
Ps.aerug
Pseud spp
Serratia
Enterobacter
Klebsiella
E. coli
H. flu
Meningococcus
Grp A strep
Pneumo
Enterococcus
Grp B strep
Listeria
St. aureus
St. epi
GRAM POSITIVES
ANAEROBES
B. fragilis
Gut
Mouth
Ps.aerug
ANAEROBES
Pseud spp
Serratia
Enterobacter
Klebsiella
E. coli
H. flu
Meningococcus
Grp A strep
GRAM NEGATIVES
Pneumo
Enterococcus
Grp B strep
Listeria
St. aureus
St. epi
GRAM POSITIVES
SIDE EFFECTS of the AMINOGLYCOSIDES
TRUE ALLERGY RARE
NEPHROTOXICITY
OTOTOXICITY
RESPIRATORY
Associated with
• Hypotension
• Loop diuretics
• Vancomycin
• Liver disease
High-tone frequencies
Curare-like effects
with IV push
Treat with calcium
HIGH TROUGH
Vestibular
HIGH PEAK
Aminoglycoside Levels
• Gentamicin/Tobramycin
– PEAK 5-10 µg/ml
– TROUGH < 2 µg/ml
• Amikacin
– PEAK 20-30 µg/ml
– TROUGH <10 µg/ml
Aminoglycoside Levels
• Patients at risk for nephrotoxicity
– Fluctuating renal function, usually 2˚ BP
instability
– Other nephrotoxic agents -e.g. Vancomycin
– Liver disease
•
•
•
•
When to do trough: just before third dose
When to do peak: 1 hour after third dose
PEAK - correlates with efficacy, ototoxicity
TROUGH - correlates with nephrotoxicity
How to Adjust
• Adjust the dosage interval, not the
individual dose, in order to retain the peak
• Rough rule of thumb
– If pt’s creatinine is 2X normal, increase the
dosing interval 2-fold (e.g. from 8 to 16 hours)
– If pt’s creatinine is 3X normal, increase the
dosing interval 3-fold (e.g. from 8 to 24 hours)
Case Study
A three-year old girl with a neurogenic bladder has a history of recurrent
urinary tract infections. Six weeks ago she was treated with Cefotaxime for
a resistant E. coli. She now presents with fever and blood and urine
cultures growing Pseudomonas aeruginosa, sensitive to Ticarcillin and
Gentamicin. On a dose of Ticarcillin of 300 mg/kg/day and Tobramycin,
2.5 mg/kg/dose, her Tobramycin levels are as follows:
• Tobra peak of 8.0 and trough of 3.0
• Tobra peak of 3.0 and trough of 0.4
• Tobra peak of 13.0 and trough of 1.0
• Discuss the implications of each of these levels in terms of adequacy of
treatment, risk for nephrotoxity or ototoxicity, and changes in management.
Case Study
A 16-year-old boy under treatment for ALL
presents to the ED with 6 hours of fever, onset
about 7 days after his last chemotherapy.
Physical exam shows a Broviac catheter and
an enlarging black lesion on his thigh. His
WBC count is 2,000 with <10% PMN’s.
• Possible causative organisms?
• Antibiotic regimens?
Antibiogram for Sepsis in the
Immunocompromised Host
Possible Causes
Penicillins
Cephalosporins
Penicillin Allergy
Gram +
Nafcillin
1˚, 2˚, 3˚ except
Ceftaz
Bactrim?
Clindamycin
Vancomycin
Gram –
E. coli, Klebsiella
Enterobacter,
Ps aeruginosa
Ticar/clav
(Timentin)
Pip/tazo
(Zosyn)
1˚, 2˚, 3˚
Aminoglycoside
Fungi
---
---
---
St epi/aureus, GAS, oral
strep, Enterococci
When Do You Need “Double
Coverage” for Gram Negatives?
• When treating Pseudomonas aeruginosa with
Ticarcillin or Piperacillin---requires Gent or Tobra
for synergy
• When choosing empiric therapy for a patient with
fever and neutropenia/neutrophil dysfunction and
shock
• As an empiric regimen for an immunocompromised
patient possibly infected with GNR (CSF, blood,
lungs, urine, other sterile sites)
When Don’t You Need “Double
Coverage” for Gram Negatives?
• When treating an uncomplicated nonpseudomonal infection in a normal host (e.g. UTI,
pyelo, osteo, cellulitis)
–
–
–
–
Cefotaxime
Ceftazidime
Aminoglycoside
Fluoroquinolone
• N.B. When treating Pseudomonas aeruginosa
with Ticarcillin or Piperacillin in a normal host,
it’s advisable to add an aminoglycoside
Azithromycin
Chlamydia
Clinda
Mycoplasma,
B. fragilis
Gut
GRAM NEGATIVES
Mouth
Ps.aerug
Pseud spp
Serratia
Enterobacter
Klebsiella
E. coli
H. flu
Meningococcus
Grp A strep
Pneumo
Enterococcus
Grp B strep
Listeria
St. aureus
St. epi
GRAM POSITIVES
ANAEROBES
C. difficile
Case Study
An 18-month-old unvaccinated male infant presents with
two days of fever, cough, and increasing work of
breathing. CBC shows a WBC count of 35,000 with 80%
PMN’s. CXR shows a lobar infiltrate in the left lower
lobe. A blood culture is drawn and the child is admitted.
• Possible causative organisms?
• Antibiotic regimens?
• Antibiotic regimens if he has anaphylaxis to
penicillin?
Antibiogram for Community
Pneumonia in Child < 6 years
Organism
Penicillins
Cephalosporins
Aminoglyco
side
Other
MSSA
Nafcillin
1˚, 2˚, 3˚ except
Ceftaz
---
Clindamycin
Linezolid
Vancomycin
MRSA
---
---
---
Bactrim
Clindamycin
Linezolid
Vancomycin
Strep
pneumoniae
Penicillin, 1˚, 2˚, 3˚ except
Ampicillin, Ceftaz
Nafcillin
---
Linezolid
Vancomycin
Azithromycin
Group A strep
All PCN
1˚, 2˚, 3˚ except
Ceftaz
---
Clindamycin
Linezolid
H flu type B
Ampicillin
2˚, 3˚ except
Ceftaz
---
Aztreonam
Case Study
A 10-year-old girl presents with two days of fever, cough,
and increased work of breathing. CBC shows a WBC
count of 35,000 with 80% PMN’s. CXR shows a
segmental infiltrate in the left lower lobe. A blood culture
is drawn and the child is admitted.
• Possible causative organisms?
• Antibiotic regimens?
• Antibiotic regimens if she has anaphylaxis to
penicillin?
Antibiogram fro Community
Pneumonia in a Child > 6 years
Possible
Cause
Penicillin
Strep
pneumoniae
All
1˚, 2˚, 3˚
even if resist.
Mycoplasma --pneumoniae
Cephalosporin
---
Aminoglycoside
Other
---
Clinda,Eryth,
Azithro
---
Eryth,
Azithro
Case Study
An 11-day-old female infant presents with temperature to
39.5˚ C rectally, poor feeding, and lethargy. No source for
the fever is found on physical exam. Blood culture is
drawn. Urinalysis and CXR are normal. CSF shows 400
WBC’s (90% PMN’s), glucose 25/90, protein 175.
• Differential diagnosis?
• Possible causative organisms?
• Antibiotic regimens?
Antibiogram for Late Onset
Neonatal Meningitis
Possible
Cause
Penicillin
Cephalosporin
Aminoglycoside
[St. aureus]
Other
Vanco
Listeria
Ampicillin
or other PCN
Gent, Tobra
as adjunct
---
Group B
strep
Ampicillin
1˚, 2˚, 3˚
or other PCN
Gent, Tobra
as adjunct
---
GNR
Ampicillin
(only ~50%)
Gent, Tobra
---
1˚, 2˚, 3˚