3/13/2012 Update Antibiotics-เวชศาสตร ครอบคร ว. First. Cefazolin. Cephalexin Cefadroxil. Cefaclor. 3/13/2012 Update Antibiotics-เวชศาสตร ครอบคร ว

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1 Therapeutic eview of Cephalosporins ole of Cephalosporins in Multi Drug esistance(md) Era. Panpit Suwangool Chulalongkorn University Problem of Bacterial esistance in Thailand 1.Multi-drug-resistant GNB (MD-GNB) [ esist > classes antibiotics ] - Acinetobacter sp. - Pseudomonas aeruginosa - Klebsiella,E.coli. Enterobacter.MD-GPB -MSA(methicillin resistant S.aureus) -DSP( drug resist S.pneumoniae ) /1/1 Update Antibiotics-เวชศาสตร 1 /1/1 Update Antibiotics-เวชศาสตร MD-Gm-Neg Infections 1. Nosocomial Infections. Infection In Cancer Patient. Septic Patient with ecent-/frequent antibiotic Use /1/1 Update Antibiotics-เวชศาสตร First Cephalosporins : 5. Generations Cefazolin Cephalexin Cefadroxil Cefaclor Second Cefuroxime Cefamandole Cefoxitin Third Cefotaxime Ceftriaxone Ceftazidime Cefoperazone Cefixime Ceftibuten Cefdinir Cefditoren Cefpodoxime /1/1 Update Antibiotics-เวชศาสตร Fourth Cefpirome Cefepime Fifth Gen ceftobiprole ceftaroline Vitro-activity of parenteral cephalosporins Cephalosporin generation First Second Third Fourth Fifth /1/1 Update Antibiotics-เวชศาสตร Bacterial activity Gram positive Gram negative & MSA Antibacterial activity of parenteral cephalosporins Cephalosporins Cefazolin Cefuroxime Cefamandole Cefoxitin Cefotaxime Ceftriaxone Ceftazidime Cefpirome Gram positive Strep Stap Cefepime /1/1 Update Antibiotics-เวชศาสตร Gram negative Enterobacteriaceae P. aeug

2 6 year old female, HT, DM, admitted because of fever, diagnosed acute pyelonephritis. She was given Antibiotic IV., Day rd. Better.. Urine and blood culture grew E.coli, How long to give antibiotic?? Parenteral days Oral?? 7 8 IDSA Uncomplicated UTI Treatment Guidelines She became afebrile on day th What is your plan for antibiotic? 1. Duration of antibiotic?. Should IV ceftriaxone be continued?.1 yes?. No : what agent should be switched to? ecommendation Acute uncomplicated cystitis Single-dose therapy is generally less effective than the same antimicrobial used for longer durations Most antimicrobials given for -5 days are as effective as the same antimicrobial given for a longer duration TMP-SMX for d should be considered the current standard therapy TMP alone is equivalent to TMP-SMX Ofloxacin is equivalent to TMP-SMX Other fluoroquinolones, such as, ciprofloxacin, and fleroxacin are probably of similar effectiveness Nitrofurantoin and fosfomycin may become more useful as resistance to TMP-SMX and TMP increase Fluoroquinolones are not recommended as initial empirical therapy except in communities with high rates of resistance (ie, >1%-%) to TMP-SMX or TMP among uropathogens Category or grade of recommendation A, I A, I A, I A, II A, I A, II B, I Not rated 9 1 Clin Infect Dis 11 IDSA Uncomplicated UTI Treatment Guidelines ecommendation Acute uncomplicated pyelonephritis 1 d of antimicrobial therapy is appropriate Courses of highly active agents as short as 7 d may e sufficient for mild or moderate cases Mild cases can be managed with oral medications An oral fluoroquinolone is recommended or If the organism is known to be susceptible, TMP-SMX Patients with more severe cases of acute pyelonephriits should be shospitalized and treated with a parenteral fluoroquinolone, an aminoglycoside+ ampicillin, or an extended-spectrum cephalosporin+an aminoglycoside or With improvement, can change to an oral antimicrobial to which the organsims is susceptible to complete the couse of therapy Category or grade of recommendation A, I B, I A, II A, II B, II A, II B, III B, II 11 Bacterial etiology of urinary tract infection Gram-negative E.coli P mirabilis Klebsiella sp Citrobacter sp Enterobacter sp P aeruginosa Other Gram-positive Coagulase-negative staphylococci Enterococci Group B streptococci S. aureus Other % Uncomplicated b 1- a Data from Nicolle LE. A practical guide to the management of complicated urinary Tract infection. Drugs 1997; b S saprophyticus %Complicated a

3 Management of Urinary Tract Infections Acute Uncomplicated Cystitis Women yrs, non pregnant Urinalysis Evidence - based Clinical Practice Guideline To promote best practice linked to OUTCOME and COST EFFECTIVENESS 1 1st UTI No recent antibiotic * Ciproflox, Ofloxacin,Levoflox x days FU-Urinalysis * NO UINE CULTUE ecurrent UTI, Previous UTI due to pathogen ecent Antibiotic + Urine culture then Ciprofloxacin, Ofloxacin or Levoflox or rd cephalosporins 1 Why - No Urine Culture in Cystitis?? Are Majority of Uropathogen in Cystitis susceptible? LUTI in non Pregnant Women age yrs can be treated with antibiotic without any testing Identifying Barriers and Tailoring Intervention to improve the management of UTI : a pragmatic study using qualitative methods BMC Health Service esearch ; BMJ ;5:67 15 *No need for Urine culture in 1st episode acute uncomplicated cystitis in women 16 Why not TMP-SMX (Co-trimoxazole) (gold standard antibiotic in many countries) Uropathogen in Thailand TMP-SMX esistance >% (Many Guideline, US, EU. If, esistance > 1 - % not appropriate) Why?? Aim / Objective of LUTI Management 1) Prompt relieve of Symptoms ) Cure as LUTI So is Norfloxacin appropriate as 1st line empiric in 1st episode Cystitis 17 18

4 Impact of esistance on the treatment of UTI PK : High Urine Concentration esistant Uropathogen - < 5 % Cure Susceptible Uropathogen > 9% Cure Acute Pyelonephritis : Moderate to Severe High fever, severe flank pain CVA tenderness Systemic S/S Sepsis Nausea - vomiting Hospitalization UA - Urine C/S Blood Culture Clin Therapeutic ;:88 Urology 1997; Parenteal 8-7 hr. (ต อ) Improving Parenteral Ceftriaxone 1- g Once daily 8-7 hr. Oral Switch (IB) Ciprofloxacin Ofloxacin,Levofloxacin 1-1 days (Total antibiotic days) Not improve pathogen Change antibiotic S pathogen Investigation 1 Uropathogen in Community-acquired UTI in Thailand: Increasing nd generation Quinolone - esistant - E.coli (esistant to Oflox / Ciproflox) More common in UUIT than LUTI Severity of UUTI > LUTI What is antibiotic of choice in case with resistance 1 : rd or advanced generation cephalosporins : rd and th generation Quinolones ESBL producing Bacteria (extended spectrum beta lactamase) Found in complicated UTIs,healthcare asso-infections Klebsiella spp esp K. pneumoniae E. coli Therefore do not test ESBL in others Bacteria When to suspect ESBL producing Klebsiella & E.coli Ceftazidime-resistant Klebsiella or E.coli esp with co-resistant to gentamicin/amikacin may be resistant to Fluoroquinolone Problems of ESBL even in Klebsiella or E. coli Clinical dilemma Frequently resistant to many agents Mostly treated with carbapenems..resulted in more MD-GNB /1/1 Update Antibiotics-เวชศาสตร Chen & Livemore 199, Sirot 1995, Sazbo 1,Paterson 8 /1/1 Update Antibiotics-เวชศาสตร

5 Problems posed by ESBLs Treatment options for infections Caused by ESBL-producing organism Clinical dilemma Serious infections Carbapenem always recommended Combination of β-lactam/β-lactamase Carbapenems,Tigecycline UTI,not serious/severe β-lactam/β-lactamase inhibitor inhibitors may be useful Cefoperazone/sulbactam,pip/tazobactam ( cefoperazone-sulbactam ) th Cephalosporin+Aminglycoside Sazbo 1,Paterson 8 /1/1 Update Antibiotics-เวชศาสตร 5 /1/1 Update Antibiotics-เวชศาสตร 6 Implication for Antimicrobial Dosing α PK/PD Principles Bacterial-killing activities of antibiotics : B-lactams Carbapenems T > MIC (% of dosing interval) MIC MIC Normal, mild-moderate Severe infections Neutropenic host P.aeruginosa infections -6 > Hr. /1/1 Update Antibiotics-เวชศาสตร 7 Turnidge J:CID 1998, McNabb BL: Pharmacokynamics /1/1 Update Antibiotics-เวชศาสตร 8 Advantage of cephalosporins? 1. Broad spectrum. Stability to β-lactamase. Oral and parenteral preparations. High safety profile similar to amoxicillin 5. easonable costs 9 Cost Of Treatment Direct Cost Drug Cost Drug Administration - Monitoring Indirect Cost Hospitalization Investigation. etc. Intangible Cost Time - Income Cost Family Visit evisit /1/1 etc Update Antibiotics-เวชศาสตร 5

6 Good oral antibiotics Why Oral Beta-lactams? 1. Optimal PK-PD properties (excellent oral absorption, good penetration to infection sites, When amoxicillin? long terminal disposition half-life, and stability in serum) When Amoxici-clavulanate?. Low adverse effect. Convenience (OD or BID dosing) When Cephalosporins? 1 Classification Of Oral Cephalosporins: I. 1st generation Cefphalexin Cefadroxil Cefaclor II. nd generation Cefuroxime axetil Cefprozil III. rd generation - Cefixime - Ceftibuten - Cefpodoxime proxetil - Cefdinir - Cefditoren elative Acitivities Of Oral Cephalosporins (PK/PD based) Generation 1st nd rd Gram+ cocci Gram rod 1 MIC 9 (µg/ml) of oral cephalosporins against Some gram positive species* The Comparative MIC 9 (µg/ml) between Gram Negative For Oral Third and Advanced Generation Cephalosporins Antibiotics Cephalexin <8 Cefuroxime < Cefpodoxime < Cefdinir Cefixime S.pneumoniae PSSP PS - 16-> Staphylococcus aureus MSSA MSA S. pyogens Drug Organism Escherichia coli Klebsiella pneumoniae Klebsiella oxytoca Proteus mirabilis Proteus vulgalis Cefditoren Cefdinir Cefixime Cefpodoxime Cefditoren ** <.6 + Morganella morganii * Adapted from Felmingham D. Infectious Diseases Strategy In Clinical To Practice Deliver 1998,;7(Suppl Antibiotic with ): s75-8, **Drug ;6():5-1 5 Kazumitsu Strategy Sano To et Deliver al, Antibiotic with 6

7 Cefdinir mg q 1 hr Cefditoren mg q 1 hr Cefdinir mg q 1 hr % T > MIC % T > MIC 9 PSSP H. Influenzae ole of Oral Cephalosporins In x of infection Community acquired infections Cefpodoxime p. / mg q 1 hr Cefixime mg qd Ceftibuten mg qd 98/ / Novel Otolaryngol Drug Head Neck Surg ;17:S1-S16 8 Clinical Use of oral cephalosporins 1. Skin and Skin Structure Infections ; cellulitis,abscess. UTI (Urinary Tract Infection) Pyelonephritis, Cystitis. Switch Therapy after parenteral cephalosporins Some TIs; sinusitis,otitis media,bronchitis community-acquire pneumonia Need For Novel Antibiotics 1.For resistant pathogen.better PK-PD amoxicillin > pen V / ampicillin azithromycin/ clarithro > erythromycin cefdinir > cephalexin 9 Approaches to minimize cost of treatment is to know the real cost of treatment Total Cost of treatment Direct Cost Drug Drug monitoring Indirect Cost Investigation Hospitalization Cost Intangiable Cost Cost of evisit Lose of / from work Family visit 1 Approaches to minimize cost of treatment eg. with moderate to severe infection Therapy are Switch Therapy or Out patient Antibiotic Therapy or IPD Antibiotic Therapy Oral antibiotic (Switch Therapy) Parenteral antibiotic (OPAT) OPD Day Care Home OPD Therapy 7

8 The single most important step in reducing hospital antibiotic costs is to initiate an outpatient-antibiotic therapy. Conventional belief to the contrary, many infections can be treated orally or parenterally-opd with the same therapeutic effectiveness amirez 199 A Tice BA Cunha 1997 Williams DN, Tice AD, Craig WA: Practice guideline CID 1997,5 To start with oral antibiotic Localized infection eg. some CAP, UUTI Mild-Moderate severeity systemic infection Enteric fever, Ac.pyelonephritis Sequential, Step down from parenteral antibiotic After (During) improvement Good Oral Antibiotics Good Bioavailability vs pathogen (PK-PD based) OD - BID (For Good Compliance) Tolerable Good Oral Antibiotics: Amoxicillin Amoxicillin Clavulanate, ampi-sulbactam Co-trimoxazole Advanced Macrolides (oxithromycin, Azithromycin, Clarithro) Metronidazole Some Cephalosporin 1st Generation: Cefadroxil nd Generation: Cefuroxime rd or advanced generation: Cefdinir, Cefditoren, Cefixime Fluoroquinolones nd - Ofloxacin, Ciprofloxacin. rd - Levofloxacin,Gatiflox th - Moxifloxacin, Gemiflox 5 Doxycycline, Minocycline Clinical Experience with Switch Therapy INFECTIONS Community-acquired pneumonia (CAP) Acute Pyelonephritis, Complicated UTI Skin/Soft-tissue infection Septic arthritis Osteomyelitis Pyogenic liver abscess Melioidosis 6 Switch Therapy/Out Patient Parenteral Therapy General ules of Guidelines Should be applied wisely with respect to Individual variations Type of infections Antimicrobial susceptibility pattern Underlying disease 7 6 y/o female HT, DM, admitted because of septic arthritis of right knee joint, treated with cefazolin gm daily and became afebrile on day 6 th. She was continued on cefazolin for one more week. What should be her choice? 1. continue on IV cefazolin for total of weeks. discharge on.1 oral dicloxacillin 5 mg QID. oral amoxi-clavulanate 1 g TID. oral cephalexin 5 mg QID. oral cefdinir mg BID.5 oral cefditoren mg BID 8 8

9 Switch Therapy For Septic Arthritis I. Parenteral antibiotic 1-1 days: Cloxacillin or Cefazolin (Strep, Stap) or PGS (if culture grew streptococci) II. After D 1 or 1 oral antibiotic: Dicloxacillin Cefadroxil or Cefdinir Penicillin allergic : Clindamycin 9 Outpatient Antibiotic Therapy For Osteomyelitis Pioneer or First treated OPAT Ceftriaxone gm OD Hospital-based OPD programmed (popular in Europe) Doctor office-based programmed (popular in USA) Home-based programmed CID ;:5 5 Outpatient Therapy for Soft Tissue Infection Uncomplicated Cellulitis Mostly Oral Antibiotic or One dose of IM Cefazolin or Clindamycin then Oral antibiotic Underlying Disease Evaluate Patients Complicated severe Hospitalize 51 Streptococci : Staphylococci: Good Oral Antibiotic For Soft Tissue Infection Bioavailability > 7% OD or BID dosing Tolerable Amoxicillin Cefadroxil, Cefdinir, Clindamycin Dicloxacillin Mixed Streptococci + Staphylococci ~ Amoxicillin clavulanate + Anaerobes Clindamycin + oral rd Ceph or Quinolone 5 6 y/o male admitted with diagnosis of AECOPD Community acquired pneumonia Treated with ceftriaxone, with improvement sputum No Commorbidity With Comorbidity or Sever CAP Grew S. pneumoniae, resist to penicillin, sensitive Ceftriaxone. He asked for discharge what would be Oral antibiotic of choice Oral antibiotic rd Ceph 1. Amoxicillin/Advanced macrolide. Amoxy-clavulanate (failed 1). rd. Gen. cephalosporin Improved switch to Oral antibiotic 1st Amoxy-clavulanate+macrolide nd Choice rd-th gen Quinolone 5 5 9

10 Antibiotic In Pyogenic Liver Abscess: Common Pathogen: GNB > 7% Anaerobes 1-% Initial Empiric Antibiotic I. Not Severe Ceftriaxone+Metronidazole or B-lactamase Inhibitor II. Severe sepsis - Add Gentamicin or Metronidazole+Cefazidime (Northeast) Oral Antibiotic In Pyogenic Liver Abscess: 1st: BL-BI nd : rd Ceph* + Metronidazole or Clindamycin 1-1 Days then switch to oral Antibiotic * Any oral rd ceph year old female came in because of dysuria & burning for 1 day. No fever,not sick. Urinalysis : numerous WBC, Appropriate antibiotic should be. 1. Co-trimoxazole. Norfloxacin. Ciprofloxacin. Cefdinir 58 5 yo female,dm,ht.,came in due to fever. BT 7.8 c. 1 yo male c cellulitis lt. foot,no fever. Urinalysis: WBC > /HPF Apropriate antibiotic should be. Appropriate antibiotic should be; 1. IV Cloxacillin 1.Oral cefixime or cefdinir. Oral dicloxacillin. Oral levofloxacin. Ceftazidime. Ceftriaxone. Oral cefdinir.oral cefixime

11 Ceftriaxone for UTI should be given; 1.Once daily.twice daily. Thrice daily Dose of cefdinir for UTI should be mg tid. mg bid. mg od. mg bid. QID