Antibiotic Update

Antibiotic Update

Contents

Emerging and reemerging infectious diseases, antibiotic resistance, novel agents and their clinical uses

Reducing bacterial resistance with IMPACT

Antibiotic Stewardship Program (ASP)

Conventional antibiotics

Penicillins Cephalosporins Carbapenems Quinolones Aminoglycosides Macrolides Tetracyclines

Nitrofurantoin, metronidazole, clindamycin, vancomycin, teicoplanin, cotrimoxazole, fusidic acid, etc

Isoniazid, pyrazinamide, ethambutol, rifampin, cycloserine, etc

Penicillins

Penicillin G Still useful for a number of diseases (e.g. meningitis, syphilis)

Cloxacillin For MSSA infections

Ampicillin, amoxicillin Active vs. Gram-positive (not MSSA), Gram-negative

organisms Augmentin, Unasyn

Broad spectrum, covers Gram-positive, Gram-negative and anaerobes

Piperacillin, Tazocin, Timentin Are active vs. Pseudomonas

Cephalosporins

Cefazolin, cephalexin Active vs. Gram-positive organisms including

MSSA Cefuroxime, Cefaclor

Covers some Gram-negative organisms Cefotaxime, Ceftriaxone

Broad spectrum, enhanced activity towards Gram-negative organisms

Ceftazidime, Cefepime, Sulperazon Additive Pseudomonas coverage

Carbapenems

Imipenem Broad spectrum, covers Gram-positive, Gram-

negative (including ESBL-producing strains), Pseudomonas and anaerobes

Meropenem Less seizure-inducing potential, can be used to

treat CNS infections Ertapenem

Lacks activity vs. Acinetobacter and Pseudomonas Has limited activity against penicillin-resistant

pneumococci

Quinolones

Ciprofloxacin Active vs. MSSA, Gram-negative and

Pseudomonas

Levofloxacin Has activity vs. Streptococcus pneumoniae, but

slightly less active towards Pseudomonas compared to ciprofloxacin

Moxifloxacin Has activity vs. anaerobes but less active towards

Pseudomonas

Aminoglycosides

Active vs. some Gram-positive and Gram-negative organisms

Gentamicin Active vs. Pseudomonas

Tobramycin More active vs. Pseudomonas than gentamicin Shows less activity against certain other Gram-negative

bacteria Amikacin

More stable to enzymes, used in severe infections by gentamicin-resistant organisms

Streptomycin Used for tuberculosis

Macrolides

Erythromycin Active vs. Gram-positive organisms, atypicals GI side effects

Clarithromycin Slightly greater activity than erythromycin

Azithromycin Slightly less active than erythromycin vs. Gram-

positive but enhanced activity vs. some Gram-negative organisms

Tetracyclines

Drug of choice in infections caused by Chlamydia, Rickettsia, Brucella and Lyme disease

Value has decreased due to increasing bacterial resistance

Tetracycline Role in Helicobacter pylori eradication (less

frequently used than other antibiotics) Doxycycline

Once daily Minocycline

Broader spectrum

Other antibiotics

Clindamycin Vs. Gram-positive cocci and anaerobes

Metronidazole Vs. anaerobes Preferred therapy in antibiotic associated diarrhoea

(Clostridium difficile) than oral vancomycin, although unlicenced

Vancomycin, teicoplanin For Gram-positive organisms (including MRSA)

Other antibiotics

Cotrimoxazole Role in uncomplicated UTI, UTI prophylaxis, acute

exacerbations of chronic bronchitis Pneumocystis carinii (now jiroveci) infections

Nitrofurantoin For UTI, prophylaxis vs. UTI

Fusidic acid, rifampin For penicillin-resistant staphylococci Not for monotherapy due to risk of emergence of

resistance

Good news vs. bad news

Good news A few novel antibiotics have shown promising results / are

undergoing clinical studies

Bad news As immunosuppressive diseases and use of

immunosuppressive agents become more prevalent, opportunistic infections becomes more common, esp. by organisms rarely encountered previously

Diseases: e.g. HIV, leukemia Drugs: e.g. in solid organ transplants, bone marrow transplants,

rheumatoid disorders Development of bacterial resistance to antibiotics is much

faster than research and development of new antibiotics

Emerging and reemerging infectious diseasesAntibiotic resistanceNovel agents and their clinical uses

Part 1

Gram-positive superbugs

Gram-positive superbugs

Resistant Gram-positive bacteria terminology

PRSP Penicillin resistant Streptococcus pneumoniae

MDRSP Multidrug resistant Streptococcus pneumoniae

MRSA Methicillin resistant Staphylococcus aureus

VRSA Vancomycin resistant Staphylococcus aureus

VISA (GISA) Vancomycin (Glycopeptide) intermediate Staphylococcus aureus

VRE (GRE) Vancomycin (Glycopeptide) resistant Enterococcus

Case 1

F/74, DM on oral hypoglycemic drugs Presented with fever and malaise, cough with sputum,

tachypnea; chest X-ray revealed bilateral infiltrates Travel history, occupation, contact and clustering non-

remarkable Received a course of amoxicillin for urinary tract

infection 10 weeks ago Diagnosis: Community-acquired pneumonia

Question What is the empirical treatment for CAP?

Community-acquired pneumonia (CAP)

Microbiology “Typical” organisms

Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis

“Atypical” organisms Chlamydia pneumoniae Mycoplasma pneumoniae Legionella pneumophilia

Empirical therapy Beta-lactams to cover typical organisms Doxycycline / macrolides to cover atypical organisms Respiratory fluoroquinolones (levo, moxi) for beta-lactam

allergy


Empirical therapy (as per IMPACT) CAP, out-patient

Augmentin/Unasyn PO ± macrolide PO Amoxicillin PO + clarithromycin / azithromycin PO

CAP, hospitalized in general ward Augmentin / Unasyn IV/PO ± macrolide Cefotaxime / ceftriaxone IV ± macrolide

CAP, hospitalized in ICU for serious disease Add cover to Gram-negative enterics Tazocin / cefotaxime / ceftriaxone IV + macrolide Cefepime IV + macrolide


Empirical therapy Modifying factors

Allergy to beta-lactams Fluoroquinolone (levofloxacin / moxifloxacin)

Aspiration likely: anaerobes should be covered Augmentin / Unasyn / Tazocin already provide coverage Cephalosporins (except Sulperazon) is inactive Moxifloxacin

Bronchiectasis: Pseudomonas cover essential Tazocin / Timentin / cefepime + macrolide Fluoroquinolone + aminoglycoside

Case 1

Patient was started on Augmentin + clarithromycin empirically

3 days later, fever persisted, chest X-ray showed progressive pneumonia

Endotracheal aspirate (WBC +++, few epithelial cells) grew heavy Streptococcus pneumoniae, with penicillin MIC > 4mcg/ml

Questions Risk factors for penicillin-resistant S. pneumoniae? Appropriate management in this case?

Penicillin resistant Streptococcus pneumoniae(PRSP)

Risk factorsAge > 65 yearsBeta-lactam therapy in past 3 monthsAlcoholismMultiple medical comorbidities (e.g.

immunosuppressive illness or medications)Exposure to a child in a day care centre


If susceptible, penicillin group is the drug of choice for Streptococcus pneumoniae

Check susceptibility and MIC if resistant to penicillin

Penicillin susceptible (MIC 0.1 mcg/ml) Penicillin G, amoxicillin

Penicillin resistant (0.1< MIC 1.0 mcg/ml) High dose penicillin G or ampicillin, cefotaxime /

ceftriaxone


Penicillin resistant (MIC > 2.0 mcg/ml) Vancomycin rifampin High dose cefotaxime tried in meningitis Non-meningeal infection: cefotaxime / ceftriaxone,

high dose ampicillin, carbapenems, or fluoroquinolone (levofloxacin, moxifloxacin)

Multidrug resistant (MDRSP, resistant to any 2 of the following: penicillins, erythromycin, tetracycline, macrolides, cotrimoxazole) Vancomycin rifampin Clindamycin, levofloxacin, moxifloxacin could be

tried


Any alternative for PRSP / MDRSP in respiratory tract infection?

Newer agentsTelithromycin (Ketek®)Linezolid (Zyvox®)

Telithromycin (Ketek®)

A ketolide (structurally related to macrolides) Spectrum of activity

Group A, B, C and G Streptococci, Streptococcus pneumoniae (including multidrug resistant strains), MSSA

Listeria monocytogenes, Neisseria meningitidis, Moraxella catarrhalis, Haemophilus influenzae

Legionella, Chlamydia, Mycoplasma No activity vs. MRSA, GRE, or any enteric gram-

negative bacteria Indications

Mild to moderate community acquired pneumonia

Linezolid (Zyvox®)

An oxazolidinedione Spectrum of activity and indications

Vancomycin-Resistant Enterococcus faecium infections, including cases with concurrent bacteremia

Nosocomial pneumonia caused by MSSA or MRSA or Strep pneumoniae (including MDRSP)

Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by MSSA or MRSA, Strep pyogenes, or Strep agalactiae

Uncomplicated skin and skin structure infections caused by MSSA or Strep pyogenes.

Community-acquired pneumonia caused by Strep pneumoniae (including MDRSP), including cases with concurrent bacteremia, or MSSA

Case 2

M/56Presented with skin redness, warmth,

swelling, tenderness on his right lower limb, a pocket of fluid palpated

Diagnosis: cellulitis with pus formation

QuestionEmpirical treatment?

Skin and soft tissue infection

CellulitisMicrobiology

Staphylococcus, StreptococciStreptococci more likely when cellulitis is

well demarcated and there are no pockets of pus or evidence of vein thrombosis

Staphylococcus aureus

If susceptible, penicillinase-resistant penicillins are the drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA)

Drug of choice Cloxacillin, flucloxacillin Cefazolin, cephalexin (penicillin allergic but tolerate cephs) With beta-lactamase inhibitor

As two-agent combination in Augmentin, Unasyn Erythromycin, clindamycin (if penicillin allergic)

The above antibiotics also have good activity vs. Streptococci

Case 2

Skin tenderness and redness did not appear to improve despite Augmentin has been given

Pus grew MRSA after 2 days R to methicillin, cephalothin, erythromycin S to clindamycin, vancomycin, gentamicin,

cotrimoxazole Patient is clinically stable

Questions What is the drug of choice in MRSA infection? Can clindamycin be used in this case?

Methicillin resistant Staphylococcus aureus(MRSA)

Healthcare-associated Endemic in hospitals, old

age homes Risk factors

Hospitalization in previous 1 year

Recent surgery Old age home residence Renal dialysis Exposure to invasive

devices Employment in a

healthcare institute

Community-associated Do not have usual risk

factors associated with HA-MRSA

More common in the following in overseas countries

Children with chronic skin condition

Prisoners Military personnel Aboriginals Injection drug users The homeless Contact sports athletes


Healthcare-associated Multiresistant to

Clindamycin Aminoglycosides Tetracyclines Fluoroquinolones

Community-associated Often remains

susceptible to Clindamycin Aminoglycosides Tetracyclines Fluoroquinolones

More associated with skin/soft tissue infections and severe necrotizing pneumonia


Obtain culture for susceptibility testing right before empirical antibiotics!

Treatment (as per Sanford Guide 37th ed) Community-associated

Mild to moderate infections Abscess, afebrile, immunocompetent, outpatient

Cotrimoxazole / doxycycline / minocycline rifampin Clindamycin (do not use if R to erythromycin due to

inducible resistance) Abscess with fever, outpatient

Cotrimoxazole-DS + rifampin or linezolid


Clinical guideline for management of suspected CA-MRSA infections (15 March 2007) Most CA-MRSA isolates in HKSAR are susceptible

to: Cotrimoxazole Doxycycline, minocycline Clindamycin Moxifloxacin

Out-patient oral therapy available for uncomplicated CA-MRSA skin and soft tissue infection


Antimicrobials for outpatient therapy of uncomplicated skin and soft tissue infections (Clinical guideline for management of suspected CA-MRSA infections,15 March 2007)

Agent Potential advantage

Precautions Usual adult dose (oral)

Cotrimoxazole Oral Not for patient with sulfa allergy / G6PD

960mg bd

Doxycycline High skin concentration

Not for children <12 yo or pregnant women

200mg once, then 100mg bd

Minocycline As above As above 100mg bd

Clindamycin Inhibit toxin production

Inducible resistance if erythromycin resistant

300-450mg tds

Moxifloxacin Oral Resistance may develop during therapy

400mg qd


Appropriate treatment in uncomplicated skin and soft tissue infectionCotrimoxazole, doxycycline, minocycline or

moxifloxacinClindamycin is not reliable in this case

Inducible clindamycin resistance due to erythromycin resistance

Case 2

What to do if the organism is resistant to agents listed

above and vancomycin, and Infection is complicated (unstable patient,

extensive involvement, severe sepsis, etc)?

VISA and VRSA

VISA: vancomycin-intermediate Staph aureus VRSA: vancomycin-resistant Staph aureus Classified based on minimum inhibitory

concentration (MIC) (CDC definition)

VISA: vancomycin MIC is 4-8 µg/ml VRSA: vancomycin MIC is >16 µg/ml

(HA Central Committee on Infectious Diseases) Susceptible: vancomycin MIC is ≤ 4µg/ml VISA: vancomycin MIC is 8-16 µg/ml VRSA: vancomycin MIC is >32 µg/ml

VISA and VRSA

More likely to develop among patients with Underlying conditions (including renal failure) which

predispose the patient to MRSA colonization; Indwelling medical devices; and/or MRSA infection requiring treatment with

vancomycin for a prolonged period

Usually isolated during vancomycin (or teicoplanin) therapy for MRSA infections which fail to respond

VISA and VRSA

Linezolid (Zyvox®) (discussed in PRSP session)

Quinupristin/dalfopristin (Synercid®)Dalbavancin (Zeven®)

Still under investigationDaptomycin (Cubicin®)Tigecycline (Tygacil®)

Linezolid (Zyvox®)

Demonstrate bacteriostatic action vs. VISA and VRSA

Indications Complicated skin and skin structure infections,

including diabetic foot infections, without concomitant osteomyelitis, caused by MSSA or MRSA, Strep pyogenes, or Strep agalactiae

Uncomplicated skin and skin structure infections caused by MSSA or Strep pyogenes

Quinupristin/dalfopristin (Synercid®)

Intravenous streptogramins (combination results in synergy) In vitro activity has been demonstrated against VISA and VRSA Spectrum of activity

Vancomycin-resistant Enterococcus faecium Penicillin-resistant Streptococcus pneumoniae Methicillin-resistant Staphylococci Vancomycin-resistant Enterococcus faecalis is relatively resistant to

quinopristin/dalfopristin Anaerobes and some gram-negative pathogens (e.g., Haemophilus

influenzae) have also been susceptible Indications

Bacteremia - Vancomycin-resistant Enterococcus faecium infection Infection of skin and/or subcutaneous tissue, Complicated, caused

by Staphylococcus aureus and Streptococcus pyogenes

Dalbavancin (Zeven®)

Second generation glycopeptide First generation: vancomycin, teicoplanin

Spectrum of activity Staphylococci and Streptococci, including resistant

isolates Clostridium spp., Peptostreptococcus spp.,

Actiniomyces spp., Corynebacterium spp. and Bacillus subtilis

No activity vs. most gram-negative bacteria No activity vs. vancomycin-resistant enterococci

with Van A gene

Dalbavancin (Zeven®)

Demonstrated favorable in vitro activity against MSSA, MRSA,VISA, VRSA, and linezolid-resistant S. aureus

Also, methicillin-susceptible, methicillin-resistant, and vancomycin-intermediate Coagulase negative Staphylococci strains have had favorable in vitro results

Place of therapy (no FDA approved indication at the moment) Currently in phase III trials for treatment of resistant gram-

positive organisms Published efficacy and safety data from 2 clinical trials are

available for treatment of skin and soft-tissue infections and catheter-related bloodstream infections

Daptomycin (Cubicin®)

Cyclic lipoglycopeptide Spectrum of activity

MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and

Enterococcus faecalis (vancomycin-susceptible isolates only) Indications

Complicated skin and skin structure infections caused by susceptible Gram-positive microorganisms

Staphylococcus aureus bloodstream infections including those with right-sided infective endocarditis (methicillin-susceptible and methicillin-resistant) (native valve)

Tigecycline (Tygacil®)

A glycylcycline Derived from minocycline

A very broad spectrum antibiotic Covers many resistant strains of Gram-positive,

Gram-negative, and anaerobic organisms Note active vs. Pseudomonas

Both in vitro and in vivo activities have been demonstrated against MSSA, MRSA, and VISA

Tigecycline (Tygacil®)

Indications Complicated skin and skin

structure infections by Escherichia coli Enterococcus faecalis

(vancomycin-susceptible isolates only)

Staphylococcus aureus (Methi-S or Methi-R)

Streptococcus agalactiae Streptococcus anginosus

grp. Streptococcus pyogenes Bacteroides fragilis

Complicated intra-abdominal infections by

Citrobacter freundii Enterobacter cloacae E. coli, K. oxytoca, K.

pneumoniae Enterococcus faecalis

(Vanco-S isolates only) Staphylococcus aureus

(Methi-S or Methi-R) Streptococcus anginosus

group Bacteriodes fragilis Clostridium perfringens Peptostreptococcus

micros

Emerging and reemerging infectious diseasesAntibiotic resistanceNovel agents and their clinical uses

Part 2

Gram-negative superbugs

Gram-negative superbugs

Resistant Gram-negative bacteria terminology

ESBL-producing Enterobacteriaceae

Extended spectrum beta-lactamases producing Enterobacteriaceae, e.g. Escherichia coli, Klebsiella pneumoniae

MRPA (MDR-PA) Multidrug resistant Pseudomonas aeruginosa

MRAB (MDR-AB) Multidrug resistant Acinetobacter baumannii

Pan-resistant Pseudomonas aeruginosa / Acinetobacter baumannii

Case 3

M/59 Presented with 2-day history of right upper quadrant

pain, fever, jaundice Emesis x 2 past 24 hours, dark color urine Elevated LFT Radiologic finding: dilated common bile duct, no

increase in gallbladder size Diagnosis: acute cholangitis

Question What is the empirical therapy?

Acute cholangitis/cholecystitis

MicrobiologyGram negative enterics

E. coli, Klebsiella spp., Proteus spp.Anerobes

Bacteriodes fragilis, Clostridium spp.Enterococcus

Acute cholangitis/cholecystitis

Adequate drainage is essentialEmpirical treatment complementary to

drainageAugmentin/Unasyn ± aminoglycosideTimentinCefuroxime + metronidazoleCiprofloxacin (if beta-lactam allergic)

Case 3

Biliary drainage performed with cefuroxime + metronidazole pre- and post-operation

Became septic (with high fever, tachycardia, WBC > 12 x 109/L) 2 days post-op

Blood culture grew E. coli (ESBL-producing), moderately sensitive to Augmentin, sensitive to Sulperazon and imipenem

Question What is the appropriate treatment? Can Augmentin or Sulperazon be used?

Enterobacteriaceae

Susceptible strains of E. coli and Klebsiella are sensitive toAugmentin/UnasynCefuroxime (if resistant to above)Other anti gram-negative penicillins/cephs

also workFluoroquinolones (if allergic to beta-

lactams)

ESBL-producing Enterobacteriaceae

Extended-spectrum beta-lactamases Any bacterial enzymes that are capable of

inactivating third generation cephalosporins Generally regarded as resistant to penicillins and

cephalosporins Drug of choice

Urinary tract infection Cotrimoxazole, Augmentin, nitrofurantoin, levofloxacin /

ciprofloxain Other serious infections

Carbapenems: imipenem, meropenem, ertapenem (reliable activity vs. ESBL-producing Enterobacteriaceae)

Fluoroquinolone + aminoglycoside

Case 3

Augmentin and Sulperazon are not appropriate Patient is clinically septic (likely due to the ESBL-

producing strain of E. coli) The strain is only apparently susceptible to the

above agents

Appropriate agent Ertapenem (no activity vs. Pseudomonas) Imipenem (when activity vs. Pseudomonas

required)

Case 4

M/33 Victim of road traffic accident Experienced severe burns during accident Early excision and repair performed; silver

sulfadiazine cream topically High fever on day 5, blood culture grew

Pseudomonas aeruginosa on day 7

Question Appropriate known pathogen therapy?

Pseudomonas aeruginosa

Gram-negative bacilli Frequently present in small numbers in the

normal intestinal flora and on the skin of humans and is the major pathogen

Causes diseases in patients with abnormal host defenses, e.g. When mucous membranes and skin are disrupted When intravenous or urinary catheters are used When neutropenia is present (as in chemotherapy)

Intrinsically resistant to many antibiotics

Pseudomonas aeruginosa

Drug of choice Antipseudomonal penicillins/cephalosporins

Piperacillin, piperacillin/tazobactam (Tazocin), ticarcillin/clavulanate (Timentin)

Ceftazidime, cefoperazone, cefepime Carbapenems

Imipenem, meropenem (NOT ertapenem) Aminoglycosides

Gentamicin, tobramycin, amikacin Fluoroquinolones

Ciprofloxacin, levofloxacin (less activity than cipro)

Often a two-drug combination is employed except in uncomplicated UTI

Case 4

Tazocin (Piperacillin/tazobactam) plus gentamicin were prescribed

Microbiologist suggested using piperacillin plus gentamicin is sufficient for this patient

Question What is the difference in activities (and hence uses)

between Tazocin and piperacillin?

Piperacillin vs. Tazocin

Tazobactam in Tazocin®Tazobactam is a beta-lactamase inhibitorRenders the combination of Tazocin® more

active againstGram positive: MSSAGram negative: Haemophilus influenzae and

othersAnaerobe: Bacteroides fragilis

Piperacillin vs. Tazocin

Tazobactam in Tazocin®For Pseudomonas aeruginosa susceptible

to piperacillin, Tazocin 4.5g Q8H IV and Piperacillin 4g Q8H IV are equivalent

At common usual dose (HA Corp drug price as of May 2007)

Piperacillin 4g/vial: $56Tazocin® 4.5g/vial: $108

Multidrug resistantGram-negative organisms

Any treatment options forESBL-producing Enterobacteriaceae, orPseudomonas aeruginosa,

that are pan-resistant?

Colistin (Colomycin®)

Indeed an old, toxic drug! a.k.a. Polymyxin E, colistimethate sodium Now being used with increasing frequency due to necessity

(multidrug resistant Gram-negatives) Risk of neurotoxicity and nephrotoxicity

Spectrum of activity (check susceptibility!) Pseudomonas aeruginosa, Acinetobacter spp. E. coli and Klebsiella (incl. ESBL-producing strains),

Enterobacter spp. Citrobacter spp, Hemophilus spp.

Indications Disease due to Gram-negative bacteria, acute or chronic due

to sensitive strains of certain gram-negative bacilli

Case 5

F/67 Admitted due to subarachnoid hemorrhage Desaturated on day 21, given oxygen,

admitted to HDU Chest X-ray showed consolidation of right

middle and lower lobe Bronchoalveolar lavage grew heavy

Acinetobacter baumannii

Question Appropriate known pathogen therapy?


Common cause of nosocomial infection especially in ICU setting

Drug of choice Ampicillin/sulbactam or cefoperazone/sulbactam

(sulbactam highly active vs. Acinetobacter) or fluoroquinolone (ciprofloxacin, levofloxacin)

Gentamicin added to prevent resistance and for synergy

Imipenem, meropenem can be used

Case 5

Patient was given Unasyn + gentamicin for her hospital acquired pneumonia

QuestionAny treatment options for pan-resistant

strains?


Acinetobacter strains are often resistant to antimicrobial agents

Other agents with in vitro activity vs. Acinetobacter baumanniiMinocycline / doxycyclineTigecyclineColistin

Case 6

M/40 y/o, good past health Referred by GP Presented with fever, chills and night sweats; cough

initially nonproductive but became productive over past 2 months

Did not recognize weight loss A sputum smear revealed acid-fast bacilli, further

culture and sensitivity results pending Diagnosis: Pulmonary TB

Question What is the drug(s) of choice in tuberculosis?

Mycobacterium tuberculosis

Acid-fast bacilli, replicates very slowly (once every 24 hours vs. 20-40 mins in other organisms)

Contagious and spreads through the air Disease of poverty; affecting mostly young

adults in their most productive years Leading killer among HIV-infected people with

weakened immune systems 8.8 million new TB cases in 2005, and 1.6

million people died from TB worldwide A curable disease with appropriate treatment

Mycobacterium tuberculosis

Requires combination therapy The usual course of drug treatment for

pulmonary TB lasts 6 months: 4 drugs in the first 2 months: isoniazid, rifampin,

pyrazinamide, ethambutol/streptomycin 2 drugs in the subsequent 4 months: isoniazid,

rifampin Can be given daily or three times a week Given under DOT (directly observed treatment) by

healthcare staff

Case 6

Patient was started on isoniazid, rifampin, pyrazinamide and ethambutol

Culture of sputum grew Mycobacterium tuberculosis Resistant to isoniazid and rifampin

Question Is this a case of multidrug resistant TB? What agents are available?

Multidrug Resistant TB

MDR-TB (Multidrug Resistant TB ) Resistant to isoniazid and rifampin

Isoniazid and rifampin are “backbone” in first-line TB treatment Isoniazid exhibits very low MIC vs. the organism Rifampin allows short-course treatment (6-9

months) Treatment generally extends to at least 18 months without

rifampin Resistance to rifampin is frequently associated with

resistance to isoniazid



ManagementMicrobiologist consultation!Check susceptibility to other agents!


Tuberculosis

Modify treatment plan according to Weight Hepatic function

Hepatotoxic: isoniazid, rifampin Renal function

Nephrotoxic: aminoglycosides Dose adjustment: fluoroquinolones (except moxifloxacin) Pregnancy: Isoniazid, rifampin, ethambutol theoretically relatively

safe, insufficient safety data for pyrazinamide Penetration (e.g. in TB meningitis) Drug interactions (e.g. with anti-HIV drugs) Duration

May require longer treatment in specific drug combinations, extensive diseases / extrapulmonary diseases

Case 6

Patient was alarmed that the organism was resistant to isoniazid and rifampin (i.e. MDR-TB)

He heard of the term XDR-TB from newspaper some months ago and was very worried

Question Difference(s) between MDR-TB and XDR-TB?

Extensive Drug Resistant TB

MDR-TB (Multidrug Resistant TB) Resistant to isoniazid and rifampin

XDR-TB (Extensive Drug Resistant TB) In addition to resistance vs. isoniazid and rifampin, Resistant to any fluoroquinolones, and At least one of three injectable second-line drugs

(capreomycin, kanamycin and amikacin) Revised definition agreed by the WHO Global Task Force

on XDR-TB in October 2006


Situation worldwideXDR-TB found in

USA: 4% of MDR-TBLatvia: 19% of MDR-TBS. Korea: 15% of MDR-TB

May 2007: Italy reports first cases of TB resistant to all anti-TB drugs

2 cases R to all drugs and 11 XDR from 2888 culture-confirmed TB cases


The facts Grave public health threat especially in populations with high

HIV rates Occurs as a result of poorly-managed TB control programs If identified early, can be treated and cured in some cases

under proper TB control conditions, based on the experiences in a few successful programs where HIV prevalence was low

Underlines the need for investment in the development of new TB diagnostics, treatments and vaccines

XDR-TB strains have been found in all regions of the world, although still thought to be uncommon

Infection control measures must be strengthened everywhere, and especially where HIV prevalence is high, to protect the vulnerable and those at risk of XDR-TB



Reducing bacterial resistance

IMPACT (Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy) Available for download at:

HKU Centre of Infection

http://www.hku.hk/hkucoi/impact.pdf DH Centre for Health Protection

http://www.chp.gov.hk/files/pdf/reducing_bacterial_resistance_with_impact.pdf

HA intranet

http://ha.home/ho/ps/impact.pdf

Most updated: third version 2005 (version 3.0)

IMPACT guideline

Contents of IMPACT guidelineLocal antibiotic resistanceGuidelines for selected antimicrobial use,

e.g.VancomycinCeftazidime Imipenem/meropenem/ertapenemOnce daily aminoglycosidesSelected antifungal agents

IMPACT guideline

Contents of IMPACT guidelineRecommendations for empirical therapy of

common infectionsGuidelines for known pathogen therapyGuidelines for surgical prophylaxisCost and recommended dosage of

commonly used antimicrobial agents

Antibiotic Stewardship Program

Optimal selection, dosage, and duration of antimicrobial treatment that Results in the best clinical outcome for the

treatment or prevention of infection With minimal toxicity to the patient and With minimal impact on subsequent resistance


InvolvesPrescribing antimicrobial therapy only when

it is beneficial to the patientTargeting therapy to the desired pathogensUsing the appropriate drug, dose, and

duration


Should not be viewed simply as reduced use or a strategy for cost containment

A strategy to enhance patient safety byMinimizing exposure to drugsPerforming dose adjustmentsReducing redundant therapyTargeting therapy to the likely pathogens

ASP in Hospital Authority

Annual plan target of year 2005/06Objectives

Control the emergence and spread of antibiotic resistance

Optimize selection and use of antibioticsCost containment


Multidisciplinary, programmatic, prospective, interventional approach to optimizing the use of antimicrobial agents

The multidisciplinary team typically includes Clinical microbiologists Infectious diseases specialists Clinical pharmacists Infection control practitioners


Overall strategies Build an antibiotic usage database in terms of usage

density i.e. DDD/1000 patient-days (recommend consistent DDD definition throughout all HA units to maximize data utility)

Develop a HA-wide an antibiotic resistance database of selected organisms

Formation of multidisciplinary Antimicrobial Stewardship Teams (AST) in each hospital/cluster

Audit use of antimicrobials based on established guidelines, e.g. IMPACT guideline

Education and consensus-building Outcome measurement and user feedback


Procedures for Antibiotic Stewardship Program using the AOF + ICF model: Obtain consensus with targeted specialties

for the introduction of an Antibiotic Order Form (AOF) to monitor antibiotic usage

Targeted antibioticsBig guns antibiotics IV-PO switch


Logistics Daily review all AOFs and follow up targeted cases

by assigned personnel Provide immediate concurrent feedback on

prescribing to prescribers based on guidelines Monitor feedback acceptance Provide education and liaison based on guideline

(e.g. educational note or face-to-face intervention) Collate and analyze data, with user feedback of the

findings via educational activities


Big gun audit Tienam, Meropenem Ceftazidime, Cefepime Tazocin, Sulperazon Vancomycin and Teicoplanin

IV to oral switch Ciprofloxacin, levofloxacin, Clarithromycin, azithromycin Amoxicillin/clavulanate (Augmentin®) and

fluconazole

Big gun audit

Big gun auditTargets 2 types of antibiotics

Broad-spectrum antibiotics Tienam, Meropenem, Ceftazidime, Cefepime,

Tazocin, Sulperazon All these agents have good Gram-negative as well as

Pseudomonas coverage

Anti Gram-positive antibiotics Vancomycin and teicoplanin Active vs. methicillin-resistant Staphylococcus aureus To be used as second-line agents

Big gun audit

Big gun auditData collection form completed and faxed

with MAR on first order of big gunEncourage physicians to prescribe big guns

only when clinically indicated

Big gun audit

Big gun audit

IV-PO switch

IV-PO switch IV antimicrobials are always required in serious

infections or initial stages of infection to ensure tissue levels

PO antimicrobials are useful to complete a full course of antimicrobial therapy

Convenience in out-patient setting Cost effectiveness (cost of drugs + hospitalization) Decreased risk of IV-catheter related problems Except those infections of which PO antibiotics are

unreliable / inappropriate

IV-PO switch

IV-PO switchTargets IV antibiotics which

Have their oral counterparts (ease of switch)Exhibit good oral bioavailability

ExamplesPenicillinsCefuroximeMacrolidesQuinolonesFluconazole

IV-PO switch

IV-PO switch IV antimicrobials are indicated in

Meningitis Intracranial abscess Infective endocarditis Mediastinitis Severe infections during chemotherapy-related

neutropenia Inadequately drained abscess and empyema Severe soft tissue infections S. aureus or P. aeruginosa bacteremia

IV-PO switch

IV-PO switchCriteria (as per IMPACT)

1. No indication for IV therapy2. Patient is afebrile for ≥ 8 hours3. WBC count is normalizing

Falling towards or < 10 x 109/L

4. Signs and symptoms related to infection are improving

5. Patient is not neutropenic Neutrophil count > 2 x 109/L

IV-PO switch

IV-PO switchCriteria (as per IMPACT)

6. Able to take drugs by mouth (non-NPO)7. No continuous nasogastric suctioning8. No severe nausea or vomiting, diarrhea,

gastrointestinal obstruction, motility disorder9. No malabsorption syndrome

E.g. small bowel syndrome due to resection10. No pancreatitis or active gastrointestinal

bleeding or other conditions that contraindicated to the use of oral medications

IV-PO switch

IV-PO switchPoints to note

Prescribe dose based on creatinine clearance when antimicrobials require renal dosage adjustment

Augmentin®, Unasyn®, clarithromycin, ciprofloxacin, levofloxacin

Drug interactions Oral ciprofloxacin and levofloxacin with antacid,

sucralfate, didanosine, dairy products and enteral feeds

Useful guides to antimicrobial therapy

Sanford GuideCovers a broad range of infectious diseases

IMPACTWith commonly prescribed empirical

therapy and useful local resistance information

Local antibiogramBacterial resistance specific to an institution

or a cluster of institutions

Conclusion

New antibiotics intended to treat complicated diseases are under investigation

Need to protect our antibiotic arsenal Justified use of antimicrobials not only treats

infections, but also improves patient outcomes and reduces the risk of development of bacterial resistance

Adherence to clinical guidelines, antimicrobial stewardship program and education helps to promote appropriate antimicrobial use

Conclusion

Last but not least… Infection control is of utmost importance in

reducing risk of infection, use of antibiotics and hence emergence of bacterial resistance

Hand hygieneAppropriate isolation / contact restrictionPrompt reporting of certain infectious diseases

(e.g. MRSA infections)Many more!

End

Questions and Answers

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Antibiotic Update