Transcript The New Antibiotics

The New Antibiotics
DR MS REZAI
Pediatric Infectious Disease Subspecialist
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The New Antibiotics
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Synercid
Linezolid
Cefipime
Imipenem-Meropenem
Tazocin
Synercid
• Quinupristin/dalfopristin
• Streptogramin antibiotic (isolated from
Streptomyces sp.)
• Weak individual activity, but synergistic
together
Synercid
• Mechanism of Action
– inhibits bacterial protein synthesis by
irreversibly binding to different sites on the 50S
bacterial ribosomal subunit
– quinupristin inhibits peptide chain elongation
– dalfopristin interferes with peptidyl transferase
Synercid
• Mechanism of resistance
– plasmid-mediated target modification
• confers resistance to macrolides, lincosamides and
quinupristin by methylation of their common
binding site
– drug-modifying enzymes or efflux
Synercid
• Antimicrobial activity
– E. faecium (not E. faecalis)
• bacteriostatic or slowly bactericidal
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S. aureus (including MRSA)
CNS
S. pneumoniae (including PCN resistant)
viridans strep and Group A Strep
Legionella, M. pneumoniae
Synercid
• Administration
– 6 mg/kg IV every 12 hours, single dose IM
• Distribution
– does not penetrate CNS
– eliminated primarily in bile
• Toxicities
– phlebitis (75% when given through peripheral IV)
– arthralgias/myalgias
– hyperbilirubinemia (primarily conjugated)
Synercid
• Drug interactions
– cyclosporin
– antihistamines
– NNRTIs and PIs
– benzodiazepines
– calcium channel blockers
– HMG-CoA reductase inhibitors
– cisapride
– methylprednisolone, carbamazepine
Synercid
• Major uses
– primarily multiple-drug-resistant gram-positive
pathogens (VRE, MRSA)
– VRE
• 90% clearance of bacteremia
• 52% overall efficacy (clinical success and
eradication of initial pathogen)
– Complicated skin and skin structure infections
• equal to oxacillin and cefazolin
Linezolid
• Unique class of synthetic antibacterial
agents: oxazolidinones
• Mechanism of Action
– inhibit protein synthesis (bacteriostatic)
– bind to the 50S ribosome near the 30S
ribosome interface
– prevents initiation of protein synthesis
Linezolid
• Gram-positive organisms
– VRE, MRSA, PCN-resistant S. pneumo
– Significant gram-positive anaerobic effect
• Pharmacology
– Can be given orally or IV
• Side-effects
– tongue discoloration
– HA (6.5%), diarrhea (8.3%), nausea (6.2%)
– weak inhibitor of MAOI (not clinically
relevant)
Linezolid
• Efficacy
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Community-acquired pneumonia
Skin and soft-tissue infections
MRSA infections
Hospital-acquired pneumonia (with aztreonam
or an aminoglycoside)
– VRE infections
Fourth generation
Prototype drugs
• Cefepime
• Cefpirome
Spectrum
Gm (+) =Excellent activity
Gm (–) = Expanded activity
Anaerobes = Excellent activity
Gen.
Gm (+)
Gm (-)
Anaerobes
I
+++
+
-
II
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+
III
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IV
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+++
+++
Pharmacological class
• Cefepime is a
– Semi-synthetic
– Broad-spectrum cephalosporin
– Fourth generation class.
Cefepime’s superior activity is
attributed to
1.
2.
3.
4.
More rapid penetration into bacteria: Allows for the higher
concentration of the antibiotic in the periplasmic space of
Gram negative bacteria; this ultimately increases the access
to PBPs
Targeting of multiple penicillin-binding proteins
Lower affinity for several β-lactamases and is stable against
many of the common plasmid- and chromosome-mediated
beta-lactamases. As a result, it retains activity against
Enterobacteriaceae that are resistant to third-generation
cephalosporins, such as derepressed mutants of Enterobacter
spp
Decreased propensity to induce beta-lactamases compared
with other beta-lactam antibiotics.
Pharmacokinetics
• Absorption: Bioavailability 82.3%
• Protein Binding: 16% to 20%
• Distribution: Aqueous humor, Appendix tissue,
bile, bronchial mucosa, gallbladder, Interstitial
Fluid, Peritoneal fluid Prostate tissue, sputum,
Urine
• Volume of Distribution: 14 to 20 Liters
• Plasma half-life: 2 hours.
Pharmacokinetics
• Metabolism : Cefepime is excreted
primarily as unchanged drug (85%).
• Renal Excretion (Major): About 70% is
recovered unchanged in the urine within 4
hours, and 99% within 8 hours
Antimicrobial spectrum
• Gram-positive bacteria, including
meticillin-sensitive Staphylococcus aureus
and Streptococcus pneumoniae.
• Gram-negative bacteria that produce
extended spectrum β-lactamase.
• Anaerobes
Indication
Cefepime is approved for the treatment of:
FDA Approved:
• Skin and soft-tissue infections
• Intra-abdominal infections
• Community acquired pneumonia,
• Uncomplicated and complicated urinary tract infections
• Febrile Neutropenia
Off- label:
• Meningitis
• Infective endocarditis
• Osteomyelitis
Contraindication
• Hypersensitivity
• Precautions
• renal dysfunction
• hypersensitivity to penicillins
• patients with history of colitis
Adverse reactions
• Hematologic effects: eosinophilia
• CNS effects: headache
• Gastrointestinal effects: pseudomembranous
colitis
• Genitourinary effects: Vaginitis
• Hepatotoxicity: Mild elevations in liver enzymes
• Dermatologic effects: Skin rash
• Local reactions - phlebitis
• Other: Cross-sensitivity with penicillins
Drug interactions
• Aminoglycosides: additive nephrotoxicity
• Furosemide: additive nephrotoxicity
Pediatric Patients (2 months up to 16 years)
The usual recommended dosage in pediatric patients
up to 40 kg in weight is 50 mg/kg/dose for
durations as given for adults
• Administered every 12 h:
– Uncomplicated and Complicated urinary tract
infections (including pyelonephritis)
– Uncomplicated skin and skin structure infections
– Pneumonia
• Administered every 8 h:
– Febrile neutropenic patients
CARBAPENEMS
e.g. Imipenem / Cilastatin
Meropenem
Imipenem / Cilastatin, i.v
Mechanism of action
Similar to other B. lactams
Antibacterial spectrum
Aerobic & anaerobic G+ & G- bacteria, including
pseudomonads and most enterobacter.
MRSA is less sucebtible
IMIPENEM / CILASTATIN ( CONT. )
Pharmacokinetics
Not absorbed orally ( i.v infusion )
Partly broken down by dehydropeptidase in the proximal tubulegiven with cilastatin ( dihydropeptidase inhibitor )
Excreted primarily by the kidney
Doses must be reduced in renal failure
Half- life about 1 hr
Clinical uses of imipenem / cilastatin
Infections require multiple antibiotics ( useful in nosocomial
infections )
Not used alone for serious pseud.infections
Not used for MRSA infections
Side effects
Similar to those seen with B- lactams
Nausea & vomiting are frequent
Excessive levels with renal failure may lead to seizures
Pts allergic to penicillins may be allergic to imipenem
Disadvantages of Imipenem / cilastatin vs Meropenem
High incidence of seizures, whereas meropenem is not.
A 1g of imip./cilas require 200 ml saline to dissolve, whereas
A 1g of meropenem dissolves in only 20 ml saline.
Hence, meropenem can be given either by i.v bolus or i.v infusion
Whereas, Imip./cilas should be given only by i.v infusion, so:
Less suitable for fluid restricted pts
Not suitable for outpatients- need hospitalization
Meropenem
• Carbapenem
• Excellent penetration into bacteria, high
affinity for PBPs and stability to Blactamases
• Slightly more active that imipenem against
gram-negative organisms
• Slightly less active than imipenem against
gram-positive organisms
Meropenem
• Less epileptogenic and nephrotoxic than
imipenem
• Clinical use:
– nosocomial pathogens where imipenem would
be used, but risk of seizures or nephrotoxicity is
a concern
MONOBACTAMS
AZTREONAM
Mechanism of action
Similar to other B- lactams
Antibacterial spectrum
Active only against G- aerobic bacteria (pseudomonads, N.
gonorrhea, N. meningitidis, H. influenzae and
enterobacteriaceae )
Inactive against G+ and anaerobic bacteria
AZTREONAM ( CONT. )
Pharmacokinetics
Poorly absorbed orally( i.v / 8 hr )
Limited penetration into the CSF
Excreted primarily by the kidney
Half- life 2 hr
Side effects
Similar to other B- lactams.
Pts allergic to penicillins and cephalosporins can
receive aztreonam
Clinical uses of aztreonam
Active against G- aerobes only
Alternative for penicillins ( piperacillin ) and cephalosporins (
ceftazidime ) allergic pts for G- infections
Safe alternative to aminoglycosides, esp. in pts with renal
impairements
Piperacillin vs. Tazocin
• Tazobactam in Tazocin®
– Tazobactam is a beta-lactamase inhibitor
– Renders the combination of Tazocin® more
active against
• Gram positive: MSSA
• Gram negative: Haemophilus influenzae and others
• Anaerobe: Bacteroides fragilis
Piperacillin vs. Tazocin
• Tazobactam in Tazocin®
– For Pseudomonas aeruginosa susceptible to
piperacillin, Tazocin Piperacillin \are
equivalent
Case Scenario
• 17 year old male with PMH cystic fibrosis
complicated with chronic renal failure requiring
kidney transplantation X2 that failed and placed
on chronic dialysis, patient acquired HBV
• Admitted on January 17, 2010 with:
– Fulminant hepatitis secondary to HBV
– Acute liver failure
– Coagulopathy
– Hepatic encephalopathy
Management
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ICU monitoring
Dialysis continued
Vitamin K
Lactulose
Not candidate for liver transplantation
January 21, 2010
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Respiratory distress
Fever
Developed bilateral pulmonary infiltrates
Intubated
FiO2 50%, pO2: 65 mm Hg
Yellowish endotracheal aspirate
WBC: 12.400
Which of the following
organisms is unlikely in this
situation?
A. Pseudomonas aerugniosa
B. Escherichia coli
C. Staphylococcus aureus
D. Klebsiella pneumoniae
E. Haemophillus influenza
Tracheal Aspirate Gram Stain
What empiric antibiotics would
you choose at this time?
A. Ceftriaxone + metronidazole
B. Ceftazidime + vancomycin
C. Pipercillin/tazobactam + vancomycin
D. Meropenem + vancomycin
E. Ciprofloxacin + amikacin + vancomycin
Hospital Acquired Aspiration Pneumonia
Antibiotic Selection
Pseudomonas aeruginosa GPC/MRSA
•Piperacillin / tazobactam
•Ceftazidime
•Cefepime
•Ceftobiprole
•Carbapenems
•Aztreonam
•Ciprofloxacin
•± aminoglycoside
• Vancomycin
• Ticoplanin
• Telavancin
• Daptomycin
• Linezolid
• Qunupristin/Dalfopistin
• Tigecycline
• Clindamycin
Enterobacteriacae
Anaerobes
• Amoxicillin/clavulanate
• Piperacillin/tazobactam
• Third- and fourth-generation
cephalosporins
• Carbapenems
• Fluoroquinolones
• Tigecycline
• Metronidazole
• Clindamycin
• Amoxicillin /
clavulanate
• Piperacillin /
tazobactam
• Cefoxitin
• Carbapenems
• Moxifloxacin
• Tigecycline
Antibiotic Course
Pip/Taz
Vancomycin
January 31, 2010
• Developed acute abdominal pain
• Distended abdomen with tenderness and
decreased bowel sounds
Perforated Viscus
• Managed conservatively secondary to high
risk surgery
Which of the following
organisms is least likely in this
situation?
A. Bacteroides fragilis
B. Pseudomonas aerugniosa
C. Escherichia coli
D. Klebsiella pneumoniae
E. Enterococcus
Microbiology of Peritonitis
Primary
(Monomicrobial)
Secondary
(Polymicrobial)
B. fragilis group
E. coli
Klebsiella spp.
E. coli
Streptococcus spp.
Clostridium spp.
Enterococcus spp.
Klebsiella spp.
S. anginosus
Other gram-negative Streptococcus spp.
bacilli
Enterococcus spp.
E. coli
B. fragilis
Pseudomonas
spp.
©Copyright 2005 cmsp.com / All rights reserved
Tertiary
(Polymicrobial)
Enterococci
Pseudomonas
S. epidermidis
Candida
S. epidermidis
©Copyright 2005 cmsp.com / All rights reserved
©Copyright 2005 gbf.de / All rights reserved
Barie PS. J Chemother. 1999;11:464-477.
LaRoche M, Harding G. Eur J Clin Microbiol Infect Dis. 1998;17:542-550.
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What empiric antibiotics would
you choose at this time?
A. Ceftriaxone + metronidazole
B. Pipercillin/tazobactam
C. Imipenem
D. Tigecycline
E. Ciprofloxicin + metronidazole
Secondary Peritonitis
(Antibiotic Selection)
B. Fragilis Group
Enterobacteriacea
Enterococcus
Amoxicillin / clavulanate
Metronidazole
Ampicillin
Piperacillin / tazobactam
Clindamycin
Vancomycin
Carbapenems
Amoxicillin / clavulanate
Ticoplanin
3rd gen cephalosporins
Piperacillin / tazobactam
Telavancin
4rd gen cephalosporins
Cefoxitin
±Aminoglycosides
Aztreonam
Carbapenems
Daptomycin
Fluoroquinolones
Moxifloxacin
Linezolid
± aminoglycoside
Tigecycline
Qunupristin/Dalfopistin
Tigecycline
Tigecycline
Risk factors for ESBL, AmpC or MDR?
Antibiotic Course
Pip/Taz
Vancomycin
Meroppenem
Vancomycin
Fluconazole
Feb 6, 2010
• No improvement with concervative
approach
• CT scan abdomen
CT Scan Report
• Significant wall thickening involving the large and small
bowel loops with patent abdominal vessels, probably
representing nonocclusive bowel ischemia with differential
diagnosis inflammatory bowel disease.
• Interval progression of ascites with interval regression of
pneumoperitoneum.
• Interval progression of bilateral pleural effusion with
passive basal atelectatic changes. The rest of the
examination is unchanged compared with the recent
previous study done on 1 February 2010.
ICU Course
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Laporatomy revealed peritonitis
No clear perforation site
Washing and drains placed
Improved over the next days
Discharged to floor
February 19, 20010
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Fever: T: 39
Hypotension: SBP 70
Tachypnea: RR 32
Tachycardia: 130/min
WBC: 28.4
pO2: 56 on FiO2 60%
Thrombocytopenia: 87,000
Anuric
Lactic acid: 4.2
Sepsis Continuum
Infection
Microorganism
invading
sterile tissue
SIRS
Sepsis
 A clinical response
arising from a
nonspecific insult,
with 2 of the
following:
 T >38oC or
<36oC
 HR >90
beats/min
 RR >20/min
 WBC
>12,000/mm3 or
<4,000/mm3 or
>10% bands
Severe Sepsis
SIRS with a
presumed
or confirmed
infectious
process
Sepsis with
organ failure
Vascular collapse
Renal
Hemostasis
Lung
LA
Septic Shock
Refractory
hypotension
Chest 1992;101:1644
Sepsis Syndromes
1992: SCCM/ACCP
Parasite
Virus
Severe
Sepsis
Infection
Fungus
Shock
Sepsis
SIRS
Trauma
BSI
Bacteria
Burns
What is the likely source of
sepsis?
A.
B.
C.
D.
E.
F.
Line infection?
Nosocomial pneumonia?
abscesses?
Urinary catheter-related infection?
C-diff colitis
Any of the above
Urinalysis
Severe Sepsis Management
Source Control
Early Goal
Directed Therapy
Appropriate and
Adequate Empiric
Antibiotics
Which of the following
organisms is least likely in this
situation?
A. Bacteroides fragilis
B. Pseudomonas aerugniosa
C. Proteus mirabilis
D. Candida albicans
E. Enterococcus
CR-UTI
(Antibiotic Selection)
Candida
Pseudomonas
Enterococcus
Piperacillin / tazobactam
Ampho B
Ampicillin
Carbapenems
Azoles
Vancomycin
Ceftazidime
Ticoplanin
Cefepime
Telavancin
Ceftobiprole
±Aminoglycosides
Aztreonam
Daptomycin
Ciprofloxacin
Linezolid
± aminoglycoside
Qunupristin/Dalfopistin
Tigecycline
Risk factors for ESBL, AmpC or MDR?
What empiric antibiotics would
you choose at this time?
A. Ceftazidime
B. Pipercillin/tazobactam
C. Imipenem
D. Tigecycline
E. Ciprofloxicin
Antibiotic Course
Pip/Taz
Vancomycin
Meroppenem
Vancomycin
Fluconazole
Pip/Taz
Vancomycin
February 25, 2010
• Wound dehiscence
• Surgically reduced
• Complicated with intra-abdominal bleed
which was surgically and medically
controlled
March 1, 2010
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Distended abdomen
Decreased bowel sounds
Fever
WBC 2.5
Abdominal fluids: >1200 WBC,
85%PMN’s
Which of the following
organisms is least likely in this
situation?
A. Bacteroides fragilis
B. Pseudomonas aerugniosa
C. Proteus mirabilis
D. Candida albicans
E. Enterococcus
Which of the following resistant
mechanism is likely in this
situation?
A. ESBL
B. AmpC
C. KPC
D. Capabemases
E. Any of the above
What empiric antibiotics would
you choose at this time?
A. Tigecycline + anidulafungin
B. Colistin + anidulafungin
C. Meropinem + anidulafungin
D. Colistin+ Ceftazidime + anidulafungin
E. Piperacillin/tazobactam + anidulafungin
Tertiary Peritonitis
(Antibiotic Selection)
MDR Pseudomonas
Candida
Enterococcus
Meropenem
Ampho B
Ampicillin
Doripenem
Anidulafungin
Vancomycin
Imipenm
Caspofungin
Ticoplanin
Colistin
Micafungin
Telavancin
Cefepime
Fluconazole
±Aminoglycosides
Ceftobiprole
Voriconazole
Daptomycin
Aztreonam
Linezolid
Ciprofloxacin
Qunupristin/Dalfopistin
± aminoglycoside
Tigecycline
Risk factors for ESBL, AmpC or MDR?
Antibiotic Course
Pip/Taz
Vancomycin
Meroppenem
Vancomycin
Fluconazole
Pip/Taz
Vancomycin
Meropenem
Colistin
Caspofungin
Vancomycin
March 13, 2010
• Tertiary peritonitis
• Not responding
• Bacteremia
Antibiotic Course
Pip/Taz
Vancomycin
Meroppenem
Vancomycin
Fluconazole
Pip/Taz
Vancomycin
Meropenem
Colistin
Caspofungin
Amikacin
Tigecycline
Findings
Quite large amounts of pleural effusion seen on the right side with
adjacent atelectasis and spread opacifications seen in the visualized
lower part of the lung. The amount of pleural effusion on the right side
is essentially unchanged compared to previous examination dated
February 6, 2010. On the left side, the pleural effusion seen previously
has resolved and there is now atelectasis seen in the lower part of the
left lung.
No free air intraabdominally. Nasogastric tube with its tip in the
duodenum. Double abdominal drains, one on each side. There are
dilated bowel loops, both small and large bowel, but there is gas seen
all the way to the rectum. There is some free fluid intraabdominally
with variable attenuation. No certain collection though. The variability
of the free fluid density is of uncertain cause, contrast leak? though no
free air. Blood/clotted blood? Kidney transplants seen to the left and
right in the pelvis. Splenomegaly. Previous examination revealed
extensive wall thickening of both small and large bowel. Today, there
is remaining wall thickness of small bowel loops.
March 21, 2010
• Right pleural effusion
What persistent pseudomonas
bacteremia indicate?
A. Persistent intra-abdominal infection
B. Persistent pneumonia
C. Catheter related blood stream infection
D. Enterovesicular fistula
E. Endocarditis
April 17, 2010
• Fever
• Increasing FiO2
What Organisms?
Stenotrophomonas maltophilia
Pseudomonas aeruginosa
Flavobacterium
What antibiotics would you add?
A. Bactrim
B. Doxyclycline
C. Tigecycline
D. Imipenem
E. Chramphenicole