sign in sign up
<<
Home , Mezlocillin

Algorithm & Trends in Gram Stain Antimicrobial Resistance

Elizabeth Race, MD, MPH Infectious Diseases / Internal Medicine Medical City Dallas Strep pneumoniae Staph aureus Gpc’s in pairs Gpc’s in clusters

PCN→ Mouth Strep, oral anaerobes ↓ Anti-Staphylococcal: Anti-Pseudomonal: PCN→ Mouth Strep, oral anaerobes / ↓ (hepatitis) (neutropenia) MEZLOCILLIN ______↓ ↓ ↓ Some community-acq. E.coli Staph. aureus (MSSA) aerug. ↓ ↓ ↓ po 500 qid + Anti-Staphylococcal: Anti- Pseudomonal: ↑ anaerobic coverage AMPICILLIN OXACILLIN / NAFCILLIN TICARCILLIN + (hepatitis) (neutropenia) PIPERACILLIN H.influenzae MEZLOCILLIN + PO= DICLOXACILLIN Sensitive Enterococcus strains + Listeria

PCN→ Mouth Strep, oral anaerobes 1st GENERATION : ↓ Anti-Staphylococcal: Anti-Pseudomonal: AMPICILLIN OXACILLIN / NAFCILLIN TICARCILLIN (hepatitis) (neutropenia) PIPERACILLIN IV (Ancef, Kefzol) = equivalent to AMP + MEZLOCILLIN OXACILLIN + PCN coverage ↓ ↓ ↓ MSSA i.e. covers Strep, oral anaerobes, community-acquired E.coli & To pick up Staph. aureus and To pick up Staph. aureus & & Staph. aureus anaerobic coverage: anaerobic coverage: UNASYN (amp/) TIMENTIN (ticar/clavulanate) ZOSYN (pip/)

po = Cephalexin (Keflex); poor po absorption; major gap in coverage is Pasturella in dog and cat bites - use / (po = AUGMENTIN (amox/clavulanate) (Augmentin) instead Note: Augmentin = CIDAL but poor po absorption; Vs. Clindamycin = STATIC but excellent po absorption

1 2nd GENERATION: 3rd GENERATION:

GNR Types: Anti-Pseudomonals: Respiratory Type: Anaerobic Types: (Rocephin) /

CEFOXITIN Covers: Covers: Covers: Covers: (As for 2nd gen. + Serratia, Citrobacter, (as for 2nd gen. + Serratia, S. pneumo B. fragilis & , resistant Klebsiella, Citrobacter, Proteus vulgaris, GC , GC) resistant Klebsiella, H. influenzae Enterobacter, GC, Pseudomonas

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

Po: , (Ceclor); Ceprozil (Cefzil); Po = (Vantin); also (Lorabid) (Suprax) - good for single-dose GC tx; NO Staph. aureus coverage

4th GENERATION: BUT FOR:

CEFEPIME Enterococcus: NO ORAL CEPHALOSPORINS ARE EFFECTIVE Covers: Listeria - NO ORAL CEPHALOSPORINS ARE EFFECTIVE Resistant Pseudomonas, Serratia, Citrobacter, Enterobacter, Klebsiella, Proteus; Pasturella multocida – CEPHALEXIN (KEFLEX )IS GOOD Staph. aureus coverage INEFFECTIVE (For dog & cat bites - must use Augmentin; or, in the case of PCN-allergic pts; a combo of clinda (for Staph Regarding Cephalosporins: and Strep) + doxycycline or levofloxacin (Levaquin) (for DOC for: Pasturella)

Staph. aureus = Cefazolin Pseudomonas = Ceftazidime or

AMINOGLYCOSIDES: AMINOGLYCOSIDES: Two Groups Two Groups

AMIKACIN has increased activity against resistant GNR's (and I. GENT = TOBRA against most GNR's ( except that Tobra is mycobacteria). Used for MDR Acinetobacter (with Tigecycline, more effective against Pseudomonas); Gent is more effective or sulbactam, or ). Also used for M. chelonae/ vs. gram positives (Staph – Ox/Gent, Vanc/Gent; acbscessus infections and historically, M.avium complex Enterococcus, - Amp/Gent or Vanc/Gent; Strep – PCN/Gent) (MAC) infections

Examples: II. STREPTOMYCIN - primarily used for TB

-Suspected Staph aureus endocarditis gets Vanc/Gent; (Also PAROMOMYCIN (Humantin) is an oral aminoglycoside; -Strep endocarditis gets PCN/Gent NOT ABSORBED SIGNIFICANTLY FROM THE GI TRACT; -Enterococcal endocarditis gets Amp/Gent (or Vanc/Gent) which has some efficacy against Cryptosporidiosis in AIDS, -Neutropenic fever with Pseudomonas gets Zosyn/Tobra although now we use nitazoxanide)

2 INDICATIONS FOR AMINOGLYCOSIDES: ANAEROBIC DRUGS:

Metronidazole (Flagyl) - all GNR anaerobes; most importantly I. Synergy for severe GNR Infections: (want high peaks) the DOC for B. fragilis infections (Note: P. acnes, a GPR, is flagyl-resistant) Pseudomonas, Serratia, Enterobacter, Proteus vulgaris Clindamycin - all gram-positive anaerobes and a few GNR II. Synergy for Enterococcal Infections: (want low peaks) Note that "low- anaerobes (will NOT cover all strains of ) 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. Combo Drugs: Unasyn, Timentin, Zosyn - excellent B.frag as Call Micro to get the additional "low-level" or "high-level" report - it well as gram + anaerobic coverage; no need to add does not usually come up in the computer. metronidazole/clindamycin to these drugs

ANAEROBIC DRUGS:

Imipenem, - excellent broad anaerobic coverage; cover MSSA, Strep, GNR’s, anaerobes; Imipenemem has more gram-positive shifted coverage - better for Enterococcus; Meropenem/ more GNR - better for Pseudomonas

Note that a once daily (, 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, (mainly used by OB-GYN for anaerobic & GC coverage in PID)

Chloramphenicol; remember that β-lactams cover gram-pos. anaerobes

Bactericidal Activity of Fluoroquinolones

All Fluoroquinolones GPC GNR are not the same S. pneumo Other GPC Other GNR Pseudomonas LEVOFLOXACIN CIPROFLOXACIN MOXIFLOXACIN (Avelox) GEMIFLOXACIN (Factive)

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)

3 GNR’s-Resistance Patterns Emerging Bacterial Resistance in Complicated UTI

v Gram-Negative have potential to acquire % of Resistant resistance in ICUs. Pathogens in Complicated UTI v Spread thru devices, hands, water, plants. v Periodically cause outbreaks: May be single or •Ampicillin •70 group of antibiotic-resistant GNR’s. •First-gen Ceph (Keflex) •49 v Extended-Spectrum B-Lactamases (ESBL) responsible for latest outbreaks (Klebsiella, E.coli’s) •TMP/SMZ (Bactrim) •37

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

USA Database: % Resistance in E. coli UTI Ciprofloxacin Resistance Trends 40 25 35

30 20

25 27.1 15 20 38.0 38.4 38.3 20.3 19.3 15 10 17.3 % of Isolates %of 12.3 10 17.5 17.6 17.8 5 5 %Resistance 6.0 3.1 3.7 0 2.7 0 98 99 00 98 99 00 98 99 00 1989 1991 1993 1995 1997 1999 Ampicillin Trimeth/Sulfa Quinolones (831) (3455) (2289) (6183) (31,161) (60,162)

TSN Database - USA, Focus Technologies, Focus Technologies 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 Implications of Antimicrobial K pneumoniae 1540 89.9 89.6 5.1 91.9 91.0 97.0 97.5 91.9 93.5 85.9 Resistance in Treatment of 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 Community Acquired Pneumonia 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.

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

Levoflox, Moxiflox 100% Ceftriaxone 93% Consider Pneumococcal resistance trends when selecting empiric abx Amox/clav (Augmentin) 82% Cipro not rec’d as therapy 1st line drug for → Ciprofloxacin 82% Pneumococcal Cefuroxime (oral) 77% infection Trimeth-sulfa 64% Azithromycin 54% Clarithromycin 54% 53%

Macrolide Susceptibility Has Macrolides Against Strep. pneumoniae: Decreased Over Time & Potency 100 300 % S. pneumoniae susceptibility vs usage*1-6 95 MIC 90 T Relative 250 ½ 90 Potency 85 200 mcg/mL Hours 80 150 Cumulative

75 — Clarithro 4 6 hr 24X 70 100 Total US Rxs US Rxs Total % Susceptibility % Susceptibility 50 (millions) 0 0 Erythro 8 3 hr 4X ‘92– ‘94 ‘95 ‘96– ‘97– ‘98– ‘99– ‘00– ‘01– ‘02– ‘03– ‘93 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04

*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; Azithro 16 68 hr 1X 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.

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

Multidrug-Resistant S. pneumoniae

MDR PCN AZIT Estimates place Strep pneumo 35 30 macrolide resistance in Texas & 25 Oklahoma at between 50-60% 20 15

Percent of isolates of isolates Percent 10 Some recent improvement in 5 0 resistance rates 1998 1999 2000 2001 2002 2003 TRUST 2 TRUST 3 TRUST 4 TRUST 5 TRUST 6 TRUST 7 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.

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

100 80 Therapy for CAP 60

40 % Resistant% IDSA / ATS Guidelines 20

0 Azithromycin Clarithromycin Cefuroxime TMP/SMX Amox/clav Gatifloxacin Levofloxacin

N=329 PRSP strains.

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

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

6 IDSA/ATS Guidelines for CAP in Adults: CAP Guidelines: Outpatient Therapy Hospitalized Patients Previously healthy and no risk factors for DRSP infections • Level I: Macrolide - azithromycin, clarithromycin, erythro • Beta lactam (usually cefotaxime 2gm iv q 6 to 8 • Level III: Doxycycline (weak recommendation). hours or ceftriaxone 2 gm iv q day Presence of comorbidities, recent use of antimicrobials, other PLUS azithromycin risks for DRSP infection OR • Level I: Respiratory fluoroquinolone: levofloxacin (750 mg qd), moxifloxacin, gemifloxacin • Level I: β-lactam plus a macrolide (or doxycycline): β- • Anti-Pneumococcal Fluoroquinolone 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 Levofloxacin • Respiratory FQ or β-lactam plus doxycycline Moxifloxicin Mandell et al. Clin Inf Dis. 2007;44:S27-72.

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.

7 Community Acquired MRSA Emerging Clinical Syndromes

Skin & Soft Tissue Infections TSST-1+ “Spider Bites”

Kravitz GR, et al.

CA-MRSA Syndromes

• Furunculosis: PVL assoc. with cutaneous necrosis, leukocytoclasis, vascular necrosis; also with ↑ lesions, ↑ erythema Therapy for Mild to Moderate to CA-MRSA Infections • 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 Skin & Soft Tissue (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.

Oral Antibiotic Selection: MSSA (only 40%) vs. MSSA (approx. 60%) Estimated Susceptibility of CA MRSA

• FDA Approved: 100% to linezolid, , vanco MSSA CA-MRSA • Off-Label: • Dicloxacillin • TMP-SMZ • 95 – 100%: TMP-SMZ, doxycycline, minocycline (but • Cephalexin • Doxycycline, Minocycline CA-MRSA TMP-SMZ resistance 30% in Europe) • Amoxi/Clav. • Clindamycin • 91-99%: Rifampin Rifampin • • 80-95%: Clindamycin (only 43% susc. in Boston area) • Respiratory Quinolones • 60-85%: Quinolones - avoid ciproflox; use levoflox 750 • Linezolid mg; moxiflox 400 (FDA-approved for MRSA) 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. File TM Jr, Tan JS. Am J Surg. 1995;169(Suppl 5A):27S-33S. “Comparison of community and health care-associated -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.

8 Inducible Clindamycin resistance: Updated List of D-Test + Anti-Staphylococcal Agents • Doxy/minocycline (static) • TMP/SMX (inferior to ); 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.

TMP-SMZ (Bactrim) in CA-MRSA Tetracyclines and CA-MRSA

• In a rabbit model of MSSA endocarditis, TMP-SMZ was no better than placebo • CA-MRSA is most susceptible in vitro to minocycline; then to • In a rabbit model of MRSA, TMP-SMZ was better than doxycycline – least susceptible to tetracycline placebo but not as effective as vancomycin • Two resistance mechanisms: 1) tetK & tetL genes encoding • Markowitz published pivotal randomized, double-blind study efflux pumps; and 2) tetM & tetO – encoding ribosomal of vancomycin vs. TMP-SMZ in IDU (1992); 47% of pts had mutations MRSA; 65% of all pts bactermic • If only tetK is present, an isolate should be resistant to TCN Cure rates significantly higher on vancomycin, P<0.02 • but susceptible to minocycline • Adra & Lawrence reviewed subject in 2004; concluded that TMP-SMZ was sufficient for “low bacterial burden • However, if tetM or tetKM are present, the isolate should be infections” 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. de Gorgolas M, Aviles P, Verdejo C, Fernandez Guerrero ML. “Treatment of experimental endocarditis due to methicillin-susceptible or methicillin-resistant Staphylococcus Klein NC and Cunha BA. Tetracyclines. Med Clin North Am 1995;79:789-801;Minuth JN, et al. Activity of tetracycline, doxycycline and minocycline aureus with Trimethoprim-Sulfamethoxazole and that inhibit synthesis.” Antimicrob Agents Chemother, 1995; 39:953-7.Markowitz N, Quinn EL, Saravolatz against methicillin-susceptible and – resistant Staphylococci. Antimicrob Agenents Chemother 1974;6:411-4; Trzcinski K, Cooper BS, Hyrniewicz LD. “Trimethoprim-sulfamethoxazole compared with Vancomycin for the treatment of Staphylococcus aureus infection.” Ann Intern Med, 1992; 117:390-98; Adra M, Lawrence W, Dowson CG. “Expression of resistance to tetracyclines in strains of methicillin-resistant Staphylococcus aureus.” J Antimicrob Chemother, KR. “Trimethoprim /Sulfamethoxazole for treatment of severe Staphylococcus aureus infections.” Ann Pharmacother, 2004; 38:338-41. 2000; 45:763-70.

9 CA MRSA necrotizing post viral pneumonia

Therapy for Moderate to Severe CA-MRSA Infections

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 Drug Penetration for Health Care-Associated MRSA (% Tissue/Serum)

PNEUMONIA COMP. SKIN / SOFT TISSUE Tissue Vanco Linezolid • Linezolid (IV, PO) • Linezolid (IV, PO) Lung (ELF) 11-17%4,5 450%13 • Vancomycin (IV) • Vancomycin (IV) • Daptomycin (IV) • Tigecycline (IV)

cSSSI=complicated skin and skin structure 1. Graziani 1988; 2. Matzke 1986; 3. Albanese 2000; 4. Georges 1997; 5. Lamer 1993; 6. Daschner 1987; 7. Blevins infection. 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.

Pedi- Approv. → Comparison of

Adult & Pediatric Doses →

→

→

10 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 Emerging issues with FQ’s • Between 2000 & 2001, a 26% increase was noted in the proportion of pts d/c’d from non-federal US hospitals with CDAD C.difficile Colitis • 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 Epidemic, Multiple-Toxin-Positive (GA, IL, ME, NJ, OR, PA) obtained during the Strain of C.difficile 2000-3 outbreaks • Compared them with a database of over 6000 REA BI/NAP1 isolates from previous years Toxinotype III • Described the dominant strain: Restriction Binary Toxin CDT+ Endonuclease Analysis (REA) Group BI; North Quinolone-Resistant 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. McDonald CL, et al. An epidemic, toxin gene-variant strain of C.difficile. NEJM 2005;353:2433-41.

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

DC

HI PR AK

Normal Inhabitants of the Healthy GI Tract

12 Normal Colonic Flora 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 Mandell Infectious Diseases

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

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

Metronidazole failures reported

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.

13 Combination Therapy for C.difficile? Nitazoxanide for CDAD

• Nitazoxanide is FDA-approved for tx of giardiasis & • Single-blind randomized clinical trial cryptosporidiosis; has in vitro activity vs. C.dif at conc. well • 39 inpatients with a primary episode of CDAD were below those achieved in the colon after po dosing randomized to receive 10 days of metronidazole vs. • Prospective, double-blind clinical trial 10 days of metronidazole + rifampin • 142 pts with CDAD randomized to receive metronidazole X 10 d vs. nitazoxanide (1gm total daily dose) x 7 or 10 days • 65% of pts on monotherapy had improved by day 10; vs. 63% of pts on combination therapy (P=NS) • Response rates: Metronidazole: 82.4%; 4 recurrences • Proportion of pts who relapsed was also similar • between the two treatment arms • Nitazoxanide X 7d: 90%; 9 recurrences • Nitazoxanide X 10d: 88.9%; 4 recurrences Lagrotteria D, et al. Clin Infec Dis 2006;43:547-552. • 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 12 Steps to Prevent Antimicrobial Abx-Assoc. Diarrhea & CDAD Resistance in Hospitalized Adults DIAGNOSE AND TREAT • Prevention of Abx-Associated Diarrhea: PREVENT INFECTION INFECTION EFFECTIVELY 1. Vaccinate 3. Target the pathogen • Adults: S.boulardii 1 gm/d- Strength of Evidence: Good 2. Get the catheters out 4. Access the experts • 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 USE ANTIMICROBIALS WISELY PREVENT TRANSMISSION Evidence:Moderate 5. Practice antimicrobial control 11. Isolate the pathogen 6. Use local data 12. Break the chain of contagion 7. Treat infection, not contamination • Children: Insufficient evidence 8. Treat infection, not colonization 9. Know when to say “no” to vanco • AVOID IN IMMUNOCOMPROMISED PATIENTS 10. Stop treatment when infection is cured CDC. Available at: www.cdc.gov/drugresistance / Katz J, et al. J Clin Gastroenterology 2006;40:249; LGG + Lactobacillus GG healthcare.

14