New Antibiotics for Old Problems

1
New Antibiotics for Old Problems

• David A. Pegues, M.D.
• Division of Infectious Diseases
• David Geffen School of Medicine at UCLA

2
Vancomycin for MRSA pneumonia is it obsolete?
3
Most Common Isolates All ICU HAP vs VAP
20
18
18
18
18
17
16
All HAP

14
VAP

12
12
11
10
8
7
7
6
5
5
4
4
4
4
4
2
0
S aureus
Pseudomonas
Enterobacter spp
Klebsiella
Candida albicans
Escherichia coli
Haemophilus
aeruginosa
pneumoniae
influenzae
January 1992-May 1999. 1990-1995.
NNIS. Am J Infect Control. 199927520-532.
Fridkin SK et al. Infect Dis Clin North Am.
199711479-496.
4
Necrotizing CA-MRSA Pneumonia
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Vancomycin

• Gold standard of therapy for MRSA
• Poor concentration in lung and CSF
• Nephrotoxicity 1.4, ototoxicity uncommon
• Emerging concerns
• VRSA, VISA
• heteroresistant strains
• vancomycin MIC creep1
• UCLA 2004--MIC 1 (70.4) or 2 ( 0.4)
• agr mutations

1 Wang G, et al. J Clin Microbiol 2006443883-6.
6
Drug Concentration in epithelial Lining Fluid
Drug at 4 hrs
Stevens DL. Clin Infect Dis 200642S51.
7
Vancomycin PK and Treatment of MRSA HCAP

• 102 patients BAL MRSA HCAP
• Examined vancomycin PK and correlated PK with
  mortality
• Neither Trough 15 mcg/ml or AUC 400 mcg hr/ml
  were associated with survival benefit

Jeffres MN, et al. Chest 2006 130947.
8
Vancomycin Nephrotoxicity
25 reduction in GFR
Jeffres MN, et al. ClinTher 2007
9
High-Dose Vancomycin Therapy for MRSA Infections
Efficacy and Toxicity
Initial response (72 hrs) Final
response (end of Rx)
Hidayat LK, et al. Arch Intern Med
20061662138-44.
10
Linezolid vs Vancomycin in VAP by MRSA
Linezolid
Vancomycin
100
90
80
84.1
70
60
Clinical cure ( of patients)
62.2
61.7
60.5
50
53.7
37.7
48.9
36.7
35.2
40
45.4
30
20
22.9
21.2
10
P 0.07
P 0.02
P 0.06
P 0.001
P 0.02
P 0001
0
VAP
Gram VAP
S. aureus
MRSA VAP
Survival
Eradication
VAP
(N434) (N214) (N179) (N70)
Kollef MH, et al. Intensive Care Med
200430388-94.
11
Linezolid vs. Vancomycin for VAP

• Linezolid is an alternative to vancomycin for the
  treatment of MRSA VAP and may be preferred on the
  basis of a subset analysis of two prospective
  randomized trials (Level II)
• Linezolid may also be preferred if patients have
  renal insufficiency or are receiving other
  nephrotoxic agents, but more data are needed
  (Level III).

Niederman MS, et al. Am J Respir Crit Care Med.
2005171402.
12
Metronidazole for Clostridium difficile
associated disease is it okay for mom?
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Increasing Severity and Costs of CDAD

• Boston, 19981
• Very low attributable mortality
• Average of 3,600 excess costs per case
• Average of 3.6 extra hospital days
• Pittsburgh, 20002
• Life-threatening disease from 1.6 to 3.2
• 44 colectomies and 20 deaths

1 Kyne L, et al. Clin Infect Dis.
200234346-353. 2 Dallal RM, et al. Ann Surg.
2002235363-372.
14
Toxin production by an emerging strain of C.
difficile associated with outbreaks of severe
disease
Growth Curve
Toxin Production
Warny M, et al. Lancet 20053661079.
15
Studies of Metronidazole Treatment in CDAD
Treatment Failure and Recurrences
Studies Rx failures Recurrences F/U (d) FR
() Cherry et al, 1982 0/13 2/13 (15) 30
15 Teasley et al, 1983 2/42 (5) 2/39 (5)
21 10 Olson et al, 1994 14/632 (2)
39/632 (6) 30 8 Wenisch et al, 1996 2/31
(6) 5/31 (16) 30 22 Kyne et al,
2001 .. 22/44 (50) 60 .. Fernandez et al,
2004 38/99 (38) .. .. .. Musher et al,
2005 46/207 (22) 58/207 (28) 90 50 Pepin
et al, 2005 178/1123 (16) 243/845 (29) 60
45
Aslam D, et al. Lancet Infect Dis 20055549-57.
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Studies of Vancomycin Treatment in CDAD
Treatment Failure and Recurrences
Studies Rx failures Recurrences F/U (d) FR
()
Bartlett et al, 1980 3/79 (4) 11/79 (14) 30
18 Silva et al, 1981 0/16 2/16 (13) 42
13 Teasley et al, 1983 0/52 6/51 (12) 21
12 Bartlett, 1984 6/189 (3) 46/189 (24)
25 27 Young et al, 1985 8/42 (19) 11/30
(37) 30 56 Dudley et al, 1986 0/15 3/15
(20) 60 20 de Lalla et al, 1989 2/25 (8)
3/25 (12) 30 20 Fekety et al, 1989 0/46
9/46 (20) 42 20 de Lalla et al, 1992 0/20
4/20 (20) 30 20 Olson et al, 1994 1/122
(1) 12/122 (10) 30 11 Wenisch et al,
1996 2/31 (6) 5/31 (16) 30 22 Pepin et al,
2005 .. 31/112 (28) 60 ..
Aslam D, et al. Lancet Infect Dis 20055549-57.
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Other Therapies for CDAD

• Bacitracin
• Teicoplanin and fusidic acid
• Nitazoxanide
• blocks anaerobic metabolic pathways
• MIC90 0.060.5 µg/mL
• Open-label study cured 75 of patients who had
  failed metronidazole therapy1/3 relapsed
• Rifampin, rifaximin

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Vancomycin vs. Metronidazole for the Treatment of
CDAD

• Methods Oct. 1994 Jun. 2002, patients with
  CDAD stratified as having mild or severe disease
  based on clinical criteria
• Intervention oral metronidazole (250 mg 4 times
  per day) or oral vancomycin (125 mg 4 times per
  day) for 10 days

Zar FA, et al. Clin Infect Dis 200745302-7.
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Patient Characteristics and Response to
Metronidazole (MTZ)
Zar FA, et al. Clin Infect Dis 200745302-7.
20
Echinocandin or fluconazole for treatment of
candidemia?
21
Species Distribution and Crude Mortality for 1890
Cases of Candida BSI, 1995-2002
Wisplinghoff H, et al. Clin Infect Dis
2003361103-10
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Spectrum of Activity Echinocandins
Species
Activity
C. krusei C. kefyr P. jiroveci
C. albicans C. glabrata C. tropicalis
Highly Active Low MIC, with fungicidal activity
and good in-vivo activity
A. fumigatusA. flavusA. terreus
C. parapsilosisC. gulliermondiiC. lusitaniae
Very Active Low MIC, but without fungicidal
activity in most instances
P. variotiiH. capsulatum
C. immitisB. dermatididisScedosporium spp
Some Activity Detectable activity, which might
have therapeutic potential for man (in some cases
in combination with other drugs).
Fusarium spp Trichosporon spp
Zygomycetes Cryptococcus neoformans
Inactive No intrisic activity
Denning DW, Lancet 2003 (Oct 4)1142-51.
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Anidulafungin versus Fluconazole for Invasive
Candidiasis

• Design DB, R, MC non-inferiority trial
  comparing
• Anidulafungin 200 mg once then 100 mg QD x 14
  days
• Fluconazole 800 mg once then 400 mg QD x 14 days
• Could switch to fluconazole 400 mg PO QD after 10
  days
• Setting 33 sites in US, 8 in Canada, 6 in Europe
• Patients 261 enrolled, 245 in MITT analysis
• Results
• Candida albicans--62 of episodes in vitro FLU
  resistance uncommon
• Treatment success at end of IV therapy 75.6 ANF
  vs. 60.2 FLU
• All cause death rate 23 ANF vs. 31 FLU
  (P0.13)
• Conclusion Anidulafungin was noninferior to
  fluconazole in the treatment of invasive
  candidiasis

Reboli AC, et al. N Engl J Med 2007 3562472-82.
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Baseline Patient Characteristics
Reboli AC, et al. N Engl J Med 2007 3562472-82.
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Global Response to Treatment for MITT Population
Reboli AC, et al. N Engl J Med 2007 3562472-82.
26
Risk of Hospital Mortality and Timing of
Antifungal Therapy for Candidemia

• Retrospective cohort analysis
• 151 episodes of Candidemia over 4-yr period BJH
• 50 (31.8) patients died during hospitalization
• Risk factors for hospital mortality
• APACHE II OR1.24
• Prior antibiotics OR4.05
• Delay in Rx 12 hr OR-2.09

Morrell M, et al. Antimicrob Agents Chemother
2005493640-45
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How should asymptomatic candiduria be managed?
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Ranking of Fungal Infection
NNIS System Report 1990 - 1999
Candida spp.
S. aureus
E. coli
Other isolates
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Management of Candiduria

• Acquisition GI or GU tract hematogenous
• Risk factors indwelling urinary catheters,
  antimicrobial therapy
• Differentiating infection from colonization is
  difficult
• Infection is commonly asymptomatic
• Pyuria is very common in catheterized patients
• Presence of pseudohype or colony counts do not
  help
• Ascending infection obstruction or
  instrumentation
• Candidemia usually brief and low grade

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• Sobel JD, et al. Clin Infect Dis 20003019-24.
• R, DB trial compared fluconazole to placebo
• 316 patients with candiduria and minimal or no
  symptoms
• Rate of eradication FLU vs. placebo
• Overall 50 vs. 29
• 14 days of Rx and no catheter 78 vs. 47
• Candiduria 14 days after Rx 32 vs. 35
• Kaufman CA, et al. Clin Infect Dis 20003014-8.
• Prospective, MC, observational study
• 861 patients with funguria, almost all
  asymptomatic
• Resolution of funguria
• No antifungal Rx 76
• Catheter removal 35
• FLU or AMB bladder wash 50

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Management of Asymptomatic Candiduria

• Asymptomatic candiduria rarely requires
  antifungal therapy
• Should not be treated unless neutropenia,
  low-birth weight, or urinary manipulation are
  present
• Antifungal Rx is associated with rapid recurrence
  
• No survival benefit
• Same probability of clearing Candida as catheter
  removal
• Focus on reducing the risk of Candida acquisition
• Remove catheters and prosthetic stents
• Limit antibacterial therapy
• Treat whenever symptomatic, upper tract
  involvement, or hematogenous dissemination