1

Antibiotic Algorithm & Trends in

Antimicrobial Resistance

Elizabeth Race, MD, MPH Infectious Diseases / Internal Medicine

Medical City Dallas

Gram Stain

Strep pneumoniae Gpc’s in pairs

Staph aureus Gpc’s in clusters

PCN→ Mouth Strep, oral anaerobes ↓

_____________________________________________________

↓ ↓ ↓ Anti-Staphylococcal: Anti- Pseudomonal:

AMPICILLIN OXACILLIN / NAFCILLIN TICARCILLIN (hepatitis) (neutropenia) PIPERACILLIN

MEZLOCILLIN PO= DICLOXACILLIN

Anti-Staphylococcal: Anti-Pseudomonal: AMPICILLIN OXACILLIN / NAFCILLIN TICARCILLIN (hepatitis) (neutropenia) PIPERACILLIN MEZLOCILLIN

↓ ↓ ↓ Some community-acq. E.coli Staph. aureus (MSSA) Pseudomonas aerug.

po Dicloxacillin 500 qid + ↑ anaerobic coverage + H.influenzae + Sensitive Enterococcus strains + Listeria

PCN→ Mouth Strep, oral anaerobes

↓

Anti-Staphylococcal: Anti-Pseudomonal: AMPICILLIN OXACILLIN / NAFCILLIN TICARCILLIN

(hepatitis) (neutropenia) PIPERACILLIN MEZLOCILLIN

↓ ↓ ↓ MSSA

To pick up Staph. aureus and To pick up Staph. aureus & anaerobic coverage: anaerobic coverage: UNASYN (amp/sulbactam) TIMENTIN (ticar/clavulanate) ZOSYN (pip/tazobactam) (po = AUGMENTIN (amox/clavulanate) Note: Augmentin = CIDAL but poor po absorption; Vs. Clindamycin = STATIC but excellent po absorption

PCN→ Mouth Strep, oral anaerobes

↓

CEFAZOLIN IV (Ancef, Kefzol) = equivalent to AMP + OXACILLIN + PCN coverage i.e. covers Strep, oral anaerobes, community-acquired E.coli & Proteus mirabilis & Staph. aureus po = Cephalexin (Keflex); poor po absorption; major gap in coverage is Pasturella in dog and cat bites - use Amoxicillin/clavulanic acid (Augmentin) instead

1st GENERATION CEPHALOSPORINS:

2

Respiratory Type: Anaerobic Types: CEFUROXIME CEFOTETAN /

CEFOXITIN Covers: Covers:

S. pneumo B. fragilis & GC

H. influenzae Moraxella

Po: Cefuroxime axetil, Cefaclor (Ceclor); Ceprozil (Cefzil); Loracarbef (Lorabid)

2nd GENERATION:

GNR Types: Anti-Pseudomonals: CEFTRIAXONE (Rocephin) CEFTAZIDIME

CEFOTAXIME CEFOPERAZONE

Covers: Covers: (As for 2nd gen. + Serratia, Citrobacter, (as for 2nd gen. + Serratia,

Proteus vulgaris, resistant Klebsiella, Citrobacter, Proteus vulgaris, Enterobacter, GC) resistant Klebsiella,

Enterobacter, GC, Pseudomonas

And some Staph. aureus coverage BUT NO STAPH.AUREUS COVERAGE

Po = Cefpodoxime (Vantin); also Cefixime (Suprax) - good for single-dose GC tx; NO Staph. aureus coverage

3rd GENERATION:

CEFEPIME Covers: Resistant Pseudomonas, Serratia, Citrobacter, Enterobacter, Klebsiella, Proteus; GOOD Staph. aureus coverage Regarding Cephalosporins: DOC for: Staph. aureus = Cefazolin Pseudomonas = Ceftazidime or Cefepime

4th GENERATION: BUT FOR: Enterococcus: NO ORAL CEPHALOSPORINS ARE EFFECTIVE Listeria - NO ORAL CEPHALOSPORINS ARE EFFECTIVE Pasturella multocida – CEPHALEXIN (KEFLEX )IS INEFFECTIVE (For dog & cat bites - must use Augmentin; or, in the case of PCN-allergic pts; a combo of clinda (for Staph and Strep) + doxycycline or levofloxacin (Levaquin) (for Pasturella)

AMINOGLYCOSIDES: Two Groups

I. GENT = TOBRA against most GNR's ( except that Tobra is more effective against Pseudomonas); Gent is more effective vs. gram positives (Staph – Ox/Gent, Vanc/Gent; Enterococcus, - Amp/Gent or Vanc/Gent; Strep – PCN/Gent)

Examples: -Suspected Staph aureus endocarditis gets Vanc/Gent; -Strep endocarditis gets PCN/Gent -Enterococcal endocarditis gets Amp/Gent (or Vanc/Gent) -Neutropenic fever with Pseudomonas gets Zosyn/Tobra

AMIKACIN has increased activity against resistant GNR's (and mycobacteria). Used for MDR Acinetobacter (with Tigecycline, or sulbactam, or colistin). Also used for M. chelonae/acbscessus infections and historically, M.avium complex (MAC) infections II. STREPTOMYCIN - primarily used for TB (Also PAROMOMYCIN (Humantin) is an oral aminoglycoside; NOT ABSORBED SIGNIFICANTLY FROM THE GI TRACT; which has some efficacy against Cryptosporidiosis in AIDS, although now we use nitazoxanide)

AMINOGLYCOSIDES: Two Groups

3

I.  Synergy for severe GNR Infections: (want high peaks)

Pseudomonas, Serratia, Enterobacter, Proteus vulgaris II. Synergy for Enterococcal Infections: (want low peaks) Note that "low-

level" resistance to gent is still associated with successful synergy with Amp or Vanc; while "high-level" gent resistance indicates that gent will not add any Enterococcal coverage to the Amp or Vanc. Call Micro to get the additional "low-level" or "high-level" report - it does not usually come up in the computer.

INDICATIONS FOR AMINOGLYCOSIDES:

Metronidazole (Flagyl) - all GNR anaerobes; most importantly the DOC for B. fragilis infections

(Note: P. acnes, a GPR, is flagyl-resistant) Clindamycin - all gram-positive anaerobes and a few GNR anaerobes (will NOT cover all strains of Bacteroides) Combo Drugs: Unasyn, Timentin, Zosyn - excellent B.frag as well as gram + anaerobic coverage; no need to add metronidazole/clindamycin to these drugs

ANAEROBIC DRUGS:

Imipenem, Meropenem - excellent broad anaerobic coverage; cover MSSA, Strep, GNR’s, anaerobes; Imipenemem has more gram-positive shifted coverage - better for Enterococcus; Meropenem/Doripenem more GNR - better for Pseudomonas Note that a once daily carbapenem (Ertapenem, Invanz) 1 gm/day IV covers ESBL GNR’s (resistant E.coli/Klebsiella) and anaerobes BUT LACKS PSEUDOMONAL COVERAGE; so use meropenem for Pseudomonas Cefotetan, Cefoxitin (mainly used by OB-GYN for anaerobic & GC coverage in PID) Chloramphenicol; remember that β-lactams cover gram-pos. anaerobes

ANAEROBIC DRUGS:

All Fluoroquinolones are not the same

Bactericidal Activity of Fluoroquinolones

Zhanel, JAC Apr 2001; 47:435-440. Klepser, AAC 2001;45:673-678; Karlowsky, IJAA 2002;19:21-31. Milatovic, AAC 2000;44:1102-1107)

LEVOFLOXACIN CIPROFLOXACIN

MOXIFLOXACIN (Avelox) GEMIFLOXACIN (Factive)

GPC GNR

S. pneumo Other GPC Other GNR Pseudomonas

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GNR’s-Resistance Patterns

v  Gram-Negative Bacteria have potential to acquire resistance in ICUs.

v  Spread thru devices, hands, water, plants. v  Periodically cause outbreaks: May be single or

group of antibiotic-resistant GNR’s. v  Extended-Spectrum B-Lactamases (ESBL)

responsible for latest outbreaks (Klebsiella, E.coli’s)

• Ampicillin

• First-gen Ceph (Keflex)

• TMP/SMZ (Bactrim)

Adapted from Stamm WE. In: Gorbach SL, et al., eds. Infectious Diseases. 1st ed. 1992;788-798.

Emerging Bacterial Resistance in Complicated UTI

% of Resistant Pathogens in

Complicated UTI

• 70

• 49

• 37

38.0 38.4 38.3

17.5 17.6 17.8

2.7 3.1 3.7 0

5

10

15

20

25

30

35

40

00 99 98

% o

f Iso

late

s

USA Database: % Resistance in E. coli UTI

TSN Database - USA, Focus Technologies, Focus Technologies

Ampicillin 00 99 98

Trimeth/Sulfa 00 99 98

Quinolones

6.0

12.317.3 19.3

20.3

27.1

0

5

10

15

20

25

1989 1991 1993 1995 1997 1999 (2289) (6183) (60,162) (31,161) (3455) (831)

% R

esis

tanc

e

Pseudomonas aeruginosa Ciprofloxacin Resistance Trends

Source: The Surveillance Network (TSN), Focus Technologies

Susceptibility of Gram-Negative Isolates: TRUST 12 Surveillance Study

GN Pathogen N LVX CIP AMP CRO CAZ DOR IPM PTZ GEN SXT

S marcescens 441 95.7 93.2 10.4 95.9 97.1 98.9 99.5 97.3 96.8 97.7

Citrobacter spp 369 94.6 93.0 36.6 84.6 84.0 99.2 99.7 88.3 93.5 83.5

K pneumoniae 1540 89.9 89.6 5.1 91.9 91.0 97.0 97.5 91.9 93.5 85.9

E cloacae 455 91.9 91.4 18.9 76.0 78.5 98.9 99.8 82.6 94.7 88.1

E coli 1723 75.0 75.0 51.6 94.9 96.3 99.8 99.8 96.1 89.4 73.0

P mirabilis 814 75.8 72.4 77.6 98.6 99.6 95.1 100 99.9 90.8 76.4

P aeruginosa 1533 67.3 69.1 –* –* 86.0 86.0 81.0 90.0 86.0 –*

In TRUST 12 , a total of 9551 isolates, of which 7464 were GN, were tested from 56 geographically distributed sites in the US. Moxifloxacin was not tested against Enterobacteriaceae as there are no CLSI breakpoints for moxifloxacin. *Ampicillin, ceftriaxone, trimethoprim-sulfa are not indicated for P aeruginosa.

Implications of Antimicrobial Resistance in Treatment of

Community Acquired Pneumonia

5

Consider Pneumococcal resistance trends when selecting empiric abx

therapy

TRUST 12 Antibiogram: % Susc. of S. pneumo (TX, OK, LA, AK)

Levoflox, Moxiflox 100% Ceftriaxone 93%

Amox/clav (Augmentin) 82% Ciprofloxacin 82% Cefuroxime (oral) 77% Trimeth-sulfa 64% Azithromycin 54% Clarithromycin 54% Penicillin 53%

Cipro not rec’d as 1st line drug for → Pneumococcal infection

Macrolide Susceptibility Has Decreased Over Time

*In vitro activity does not necessarily correlate with clinical results. 1. Data on file. Ortho-McNeil Pharmaceutical, Inc.; 2. Karlowsky JA, et al. Clin Infect Dis. 2003;36:963-970; 3. Gay K, et al. J Infect Dis. 2000;182:1417-1424; 4. Thornsberry C, et al. Diagn Microbiol Infect Dis. 1997;29:249-257; 5. Thornsberry C, et al. J Antimicrob Chemother. 1999;44:749-759; 6. Barry AL, Fuchs PC. Antimicrob Agents Chemother. 1995;39:238-240.

% S. pneumoniae susceptibility vs usage*1-6

% S

usce

ptib

ility

Tot

al U

S R

xs

(mill

ions

)— C

umul

ativ

e

0

100

70

0

50

100

150

200

250

300 95

90 85

80

75

‘92– ‘93

‘94 ‘99– ‘00

‘98– ‘99

‘97– ‘98

‘96– ‘97

‘95 ‘00– ‘01

‘01– ‘02

‘02– ‘03

‘03– ‘04

Macrolides Against Strep. pneumoniae: Pharmacokinetics & Potency

MIC 90 mcg/mL

T ½

Hours Relative Potency

Clarithro 4 6 hr 24X

Erythro 8 3 hr 4X

Azithro 16 68 hr 1X

Gerbino PP, et al. Managed Care Interface 2005;18(12):41-8; Doern, et al. Antimicrob Agents Chemother 2001; 45:1721-9.

Estimates place Strep pneumo macrolide resistance in Texas & Oklahoma at between 50-60%

Some recent improvement in resistance rates

Perc

ent o

f iso

late

s

1998 TRUST 2

2000 TRUST 4

2001 TRUST 5

1999 TRUST 3

Multidrug-Resistant S. pneumoniae

The most common MDR phenotype were PEN-AZI-SXT.

Sensitivity to levo/moxi/gati still >99% in 2003.

Selman LJ, et al. 40th ICAAC, 2000, abstract 1789. Selman LJ, et al. 38th IDSA, 2000, abstract 96. Kelly LJ, et al. 41st ICAAC, 2001, abstract 2109.

0

5

10

15

20

25

30

35

MDR PCN AZIT

2002 TRUST 6

2003 TRUST 7

6

Penicillin-Resistant S. pneumoniae Is Often Resistant to Other Antimicrobials

0

20

40

60

80

100

Azithromycin Clarithromycin Cefuroxime TMP/SMX Amox/clav Gatifloxacin Levofloxacin

% R

esis

tant

Doern GV, et al. Antimicrob Agents Chemother. 2001;45:1721-1729.

N=329 PRSP strains.

Therapy for CAP

IDSA / ATS Guidelines

Mandell LA, Bartlett JG, File TM, et al.Clin Inf Dis2003;37:1405-33.

CAP Guidelines: Out-Patients • AMOXICILLIN 3000-4000 mg/day (Augmentin: TWO 1000 mg XR tabs BID

(for Strep pneumo) PLUS

azithromycin or doxycycline (for atypical pathogens Mycoplasma. Chlamydia pneumoniae, Legionella)

OR • Anti-Pneumococcal Fluoroquinolone Levofloxacin or Moxifloxacin

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IDSA/ATS Guidelines for CAP in Adults: Outpatient Therapy

Previously healthy and no risk factors for DRSP infections •  Level I: Macrolide - azithromycin, clarithromycin, erythro •  Level III: Doxycycline (weak recommendation). Presence of comorbidities, recent use of antimicrobials, other

risks for DRSP infection •  Level I: Respiratory fluoroquinolone: levofloxacin (750 mg qd),

moxifloxacin, gemifloxacin •  Level I: β-lactam plus a macrolide (or doxycycline): β-

lactams:high dose amoxicillin (1 g q8h) or amox/clav (2 g q12h); alternatives – ceftriaxone, cefpodoxime, cefuroxime (500 mg q12)

Regions with high rate (>25%) macrolide-R SP •  Respiratory FQ or β-lactam plus doxycycline

Mandell et al. Clin Inf Dis. 2007;44:S27-72.

CAP Guidelines: Hospitalized Patients

•  Beta lactam (usually cefotaxime 2gm iv q 6 to 8 hours or ceftriaxone 2 gm iv q day PLUS azithromycin OR

•  Anti-Pneumococcal Fluoroquinolone

Levofloxacin Moxifloxicin

Staphylococcus aureus

Update on MRSA

Clinical Syndromes & Treatment Options

Types of Community Acquired MRSA Infections

•  Furuncles •  Impetigo •  Scalded Skin Syndrome •  Necrotizing soft tissue infections •  Septic Arthritis / Osteomyelitis •  Pneumonia •  Endocarditis •  Toxic Shock Syndrome •  Pyomyositis PVL+/SEC+

Kravitz GR, et al. Purpura fulminans due to Staphylococcus aureus. Clin Infec Dis 2005 ;40:941-7.

8

TSST-1+

Kravitz GR, et al.

Community Acquired MRSA Emerging Clinical Syndromes

Skin & Soft Tissue Infections

“Spider Bites”

CA-MRSA Syndromes •  Furunculosis: PVL assoc. with cutaneous necrosis,

leukocytoclasis, vascular necrosis; also with ↑ lesions, ↑ erythema

•  Toxic Shock Syndrome: 4 pts in Chicago with shock; DIC, pneumonia & desquamation; no TSST-1 detected, but all pts had at least 2 genes associated with TSS: SEB, SEC,SEH (2 had CA-MRSA with PVL; 2 with MSSA)

•  Necrotizing Fasciitis/Myositis: 14 cases in LA; all had ST8 USA300 strain; PVL+; 79% required radical debridement

Yamasaki O, et al. CID 2005 ;40:381-5; Miller LG, et al. N EJM 2005;352:1445-53; Mongkolrattanothai K, et al. CID 2003;37:

1050-8.

Therapy for Mild to Moderate to CA-MRSA Infections

Skin & Soft Tissue

Oral Antibiotic Selection: MSSA (only 40%) vs. MSSA (approx. 60%)

MSSA •  Dicloxacillin •  Cephalexin •  Amoxi/Clav.

CA-MRSA •  TMP-SMZ •  Doxycycline, Minocycline •  Clindamycin •  Rifampin •  Respiratory Quinolones •  Linezolid (FDA-approved for MRSA)

File TM Jr, Tan JS. Am J Surg. 1995;169(Suppl 5A):27S-33S.

Estimated Susceptibility of CA MRSA •  FDA Approved: 100% to linezolid, daptomycin, vanco •  Off-Label: •  95 – 100%: TMP-SMZ, doxycycline, minocycline (but

CA-MRSA TMP-SMZ resistance 30% in Europe) •  91-99%: Rifampin •  80-95%: Clindamycin (only 43% susc. in Boston area) •  60-85%: Quinolones - avoid ciproflox; use levoflox 750

mg; moxiflox 400 Ellis MW, et al. Clin Infec Dis 2004; 39:971-79; Focus: MRSA in the Community (CMRSA); Vol.21 (2); 2003; Fokas S, et al. 14th European Congress of Clin Microbiol & Infec Dis May 1-4, 2004; Prague; . Naimi TS, LeDell KH, Como-Sabetti K, et al. “Comparison of community and health care-associated methicillin-resistant Staphylococcus aureus infection.” JAMA, 2003; 290:2976-84; Internal Medicine News 2004; 37 (16): 45-46; Laibl VR. Sheffield JS, Wendel GD, et al. Obstet Gynecol 2005;106:461-5; Moran GJ, et al. MRSA infections among patients in the ED. NEJM 2006; 355:666-74.

9

Updated List of Anti-Staphylococcal Agents

• Doxy/minocycline (static) • TMP/SMX (inferior to vancomycin); recent report of

30% CA-MRSA TMP-SMZ resistance in Europe • Levofloxacin 750 / rifampin for MRSA osteomyelitis • Clindamycin-inducible cross-resistance in 20%-26%;

related to macrolide resistance • New report of CA-MRSA clinda resistance rate

approaching 60% in Boston area Fokas S, et al. 14th European Congress of Clin Microbiol & Infec Dis May 1-4, 2004; Prague; Schrenzel, et al. CID 2004; 39:1285-92; Shopsin B, Zhao X, Kreiswirth BN, et al. “Are the new quinolones appropriate treatment for community-acquired methicillin-resistant Staphylococcus aureus?” Int J Antimicrob Agents, 2004; 24:32-4; .Firsov AA, Vostrov SN, Lubenko IY, et al. “Prevention of the selection of resistant Staphylococcus aureus by moxifloxacin plus doxycycline in an in vitro dynamic model: an additive effect of the combination.” Int J Antimicrob Agents, 2004; 23:451-6; Voorn GP, et al. J Antimicrob Agents and Chemotherapy 1994;33:785-94; Kaatz GW, et al. AAC 1987 ;31:527-30.; Chambers HT, et al. AAC 1999;43:2742-6.Internal Medicine News 2004; 37 (16): 45-46.

Inducible Clindamycin resistance: D-Test +

TMP-SMZ (Bactrim) in CA-MRSA •  In a rabbit model of MSSA endocarditis, TMP-SMZ was no

better than placebo •  In a rabbit model of MRSA, TMP-SMZ was better than

placebo but not as effective as vancomycin •  Markowitz published pivotal randomized, double-blind study

of vancomycin vs. TMP-SMZ in IDU (1992); 47% of pts had MRSA; 65% of all pts bactermic

•  Cure rates significantly higher on vancomycin, P<0.02 •  Adra & Lawrence reviewed subject in 2004; concluded that

TMP-SMZ was sufficient for “low bacterial burden infections”

de Gorgolas M, Aviles P, Verdejo C, Fernandez Guerrero ML. “Treatment of experimental endocarditis due to methicillin-susceptible or methicillin-resistant Staphylococcus aureus with Trimethoprim-Sulfamethoxazole and antibiotics that inhibit cell wall synthesis.” Antimicrob Agents Chemother, 1995; 39:953-7.Markowitz N, Quinn EL, Saravolatz LD. “Trimethoprim-sulfamethoxazole compared with Vancomycin for the treatment of Staphylococcus aureus infection.” Ann Intern Med, 1992; 117:390-98; Adra M, Lawrence KR. “Trimethoprim /Sulfamethoxazole for treatment of severe Staphylococcus aureus infections.” Ann Pharmacother, 2004; 38:338-41.

Tetracyclines and CA-MRSA

•  CA-MRSA is most susceptible in vitro to minocycline; then to doxycycline – least susceptible to tetracycline

•  Two resistance mechanisms: 1) tetK & tetL genes encoding efflux pumps; and 2) tetM & tetO – encoding ribosomal mutations

•  If only tetK is present, an isolate should be resistant to TCN but susceptible to minocycline

•  However, if tetM or tetKM are present, the isolate should be resistant to the entire class

Ruhe JJ, et al. Use of Long-Acting Tetracyclines for MRSA infection: Case series and review of the literature. Clin Infec Dis 2005;40:1429-34. Klein NC and Cunha BA. Tetracyclines. Med Clin North Am 1995;79:789-801;Minuth JN, et al. Activity of tetracycline, doxycycline and minocycline against methicillin-susceptible and – resistant Staphylococci. Antimicrob Agenents Chemother 1974;6:411-4; Trzcinski K, Cooper BS, Hyrniewicz W, Dowson CG. “Expression of resistance to tetracyclines in strains of methicillin-resistant Staphylococcus aureus.” J Antimicrob Chemother, 2000; 45:763-70.

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Therapy for Moderate to Severe CA-MRSA Infections

CA MRSA necrotizing post viral pneumonia

Gillet Y, et al. Association between Staph aureus strains carrying the gene for PVL and highly lethal necrotizing pneumonia in young, immunocompetent patients. Lancet 2002; 359:753-59.

Current FDA-Approved Drug Treatments for Health Care-Associated MRSA

• Linezolid (IV, PO) • Vancomycin (IV)

• Linezolid (IV, PO) • Vancomycin (IV) • Daptomycin (IV) • Tigecycline (IV)

cSSSI=complicated skin and skin structure infection.

PNEUMONIA COMP. SKIN / SOFT TISSUE

Drug Penetration (% Tissue/Serum)

Tissue Vanco Linezolid Lung (ELF) 11-17%4,5 450%13

1. Graziani 1988; 2. Matzke 1986; 3. Albanese 2000; 4. Georges 1997; 5. Lamer 1993; 6. Daschner 1987; 7. Blevins 1984; 8. Wilson 2000; 9. Stahl 1987; 10. Wise 1986; 11. Frank 1997; 12. Lovering 2002; 13. Conte 2002; 14. Gee 2001; 15. Gendjar 2001.

Comparison of Adult & Pediatric Doses

→

→

→

→

Pedi- Approv.

11

Emerging issues with FQ’s

C.difficile Colitis

Both the Rate and the Severity of C.difficile Colitis May Be Increasing

•  NNIS data collection noted an upsurge in the in CDAD rates from the late 1980’s through 2001

•  Between 2000 & 2001, a 26% increase was noted in the proportion of pts d/c’d from non-federal US hospitals with CDAD

•  Also between 2000 & 2001, institutions such as the Univ. of Pittsburgh noted a doubling of the rate of CDAD as compared to the prior 10 years

McDonald CL, et al. An epidemic, toxin gene-variant strain of C.difficile. NEJM 2005;353:2433-41.

Both the Rate and the Severity of C.difficile Colitis May Be Increasing

•  Between 2000 & 2001, a 26% increase was noted in the proportion of pts d/c’d from non-federal US hospitals with CDAD

•  Also between 2000 & 2001, institutions such as the Univ. of Pittsburgh noted a doubling of the rate of CDAD as compared to the prior 10 years

McDonald CL, et al. An epidemic, toxin gene-variant strain of C.difficile. NEJM 2005;353:2433-41.

A New, Epidemic, Multiple-Toxin-Positive Strain of C.difficile

•  McDonald examined 187 C.dif strains from 6 states (GA, IL, ME, NJ, OR, PA) obtained during the 2000-3 outbreaks

•  Compared them with a database of over 6000 isolates from previous years

•  Described the dominant strain: Restriction Endonuclease Analysis (REA) Group BI; North American PFGE type 1 (NAP1); toxinotype III; pos. for binary toxin CDT; with an 18bp tcdC deletion

McDonald CL, et al. An epidemic, toxin gene-variant strain of C.difficile. NEJM 2005;353:2433-41.

Epidemic, Multiple-Toxin-Positive Strain of C.difficile

REA BI/NAP1 Toxinotype III

Binary Toxin CDT+ Quinolone-Resistant

McDonald CL, et al. An epidemic, toxin gene-variant strain of C.difficile. NEJM 2005;353:2433-41.

12

DC

PR AK

HI

States with the North American Pulsed Field Type 1 strain of C. difficile confirmed by CDC as of November 15, 2005 (N=16)

Normal Inhabitants of the Healthy GI Tract

13

Normal Colonic Flora

Mandell Infectious Diseases

Novel RiskFactors for CDAD

•  Impact of Antibiotics on Risk for CDAD:

•  > 7 days Vanco – OR 1.9 •  > 7 days FQ – OR 2.5 •  > 7 days 1st-gen ceph – OR 5.6 (Cefazolin/Ancef, Kefzol) •  > 7 days 3rd-gen ceph – OR 9.2 (Cetriaxone/Rocephin, Cefotaxime/

Claforan) •  > 7 days 4th-gen ceph – OR 3.3 (Cefepime/Maxipime) •  Metronidazole use – OR 0.5

Dubberke,et al. Clin Infec Dis 2007;45:1543-9.

Recent C. diff Treatment Guidelines Recommend Oral Vancomycin (125 mg po QID) for moderate to severe disease

Metronidazole failures reported

Agents with Activity Against C.difficile

Preventing Recurrent C.difficile with Rifaximin

•  Rifaximin is a rifamycin with excellent in vitro activity vs.

C.dif & low intestinal absorption •  Clinical trial of 8 women (43-88yo) with h/o 4 to 8 C.dif

recurrences; received vancomycin followed by 400-800 mg of rifaximin divided q 8-12 hrs

•  7/8 pts remained C.dif negative by cx & toxin assay and asymptomatic (F/U 51-431 days); rifaximin was well-tolerated

•  1 pt required a second course of rifaximin & was asymptomatic thereafter (but stool grew a rifaximin-resistant strain, MIC > 256mcg/mL

Johnson S, et al. Clin Infec Dis 2007;44:846-8.

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Combination Therapy for C.difficile?

•  Single-blind randomized clinical trial •  39 inpatients with a primary episode of CDAD were

randomized to receive 10 days of metronidazole vs. 10 days of metronidazole + rifampin

•  65% of pts on monotherapy had improved by day 10; vs. 63% of pts on combination therapy (P=NS)

•  Proportion of pts who relapsed was also similar between the two treatment arms

Lagrotteria D, et al. Clin Infec Dis 2006;43:547-552.

Nitazoxanide for CDAD •  Nitazoxanide is FDA-approved for tx of giardiasis &

cryptosporidiosis; has in vitro activity vs. C.dif at conc. well below those achieved in the colon after po dosing

•  Prospective, double-blind clinical trial •  142 pts with CDAD randomized to receive metronidazole X

10 d vs. nitazoxanide (1gm total daily dose) x 7 or 10 days •  Response rates:

• Metronidazole: 82.4%; 4 recurrences • Nitazoxanide X 7d: 90%; 9 recurrences • Nitazoxanide X 10d: 88.9%; 4 recurrences

•  Nitazoxanide not inferior to metronidazole

Musher DM, et al. Clin Infec Dis 2006;43:421-7.

Probiotics for Abx-Associated Diarrhea

•  Incidence of Abx-associated diarrhea is 5-25%, depending on the series; C.dif is responsible for approx. 24% of abx-assoc. diarrhea (and for 90% of cases of pseudomembranous colitis)

•  Placebo-controlled, double-blind clinical trial of 193 pts given Saccharomyces boulardii within 72 hrs of ß-lactam abx to prevent diarrhea

•  Diarrhea developed in only 7.2% of pts given S.boulardii; vs. 14.6% of pts given placebo

McFarland LV, et al. Am J Gastroenterology 1995;90:439

Guidelines for Probiotic Use in Abx-Assoc. Diarrhea & CDAD

•  Prevention of Abx-Associated Diarrhea: • Adults: S.boulardii 1 gm/d- Strength of Evidence: Good • Children: LGG* 1-2 X 1010 cfu/d-Strength of Evidence:

Good •  Prevention of CDAD:

• No evidence to support primary prevention of CDAD • Recurrent CDAD: • Adults: S. boulardii 1gm/d–Strength of

Evidence:Moderate • Children: Insufficient evidence

•  AVOID IN IMMUNOCOMPROMISED PATIENTS Katz J, et al. J Clin Gastroenterology 2006;40:249; LGG + Lactobacillus GG

PREVENT INFECTION 1. Vaccinate 2. Get the catheters out

DIAGNOSE AND TREAT INFECTION EFFECTIVELY 3. Target the pathogen 4. Access the experts

USE ANTIMICROBIALS WISELY 5. Practice antimicrobial control 6. Use local data 7. Treat infection, not contamination 8. Treat infection, not colonization 9. Know when to say “no” to vanco 10. Stop treatment when infection is cured

PREVENT TRANSMISSION 11. Isolate the pathogen 12. Break the chain of contagion

12 Steps to Prevent Antimicrobial Resistance in Hospitalized Adults

CDC. Available at: www.cdc.gov/drugresistance /healthcare.