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Antibiotic Therapy

Sasinuch Rutjanawech, MD
Division of Infectious Diseases
Faculty of Medicine
Thammasat University

The Bacteria

Bacteria
Gram
negative

Gram
positive
cocci
In
cluster

Staphylococcus
Micrococcus

cocci

bacilli
In
chain

Streptococcus
Enterococcus

Spore
forming

Bacillus
Clostridium

Non Spore
forming

Lactobacillus
Listeria
Erysipelothrix
Corynebacterium
Propionebacterium
Mycobacteria
Actinomyces
Nocardia

Neisseria
Moraxella

bacilli

Enteobactericeae
Pseudomonas
Burkholderia
Stenotrophomonas
Vibrio
Aeromonas
Hemophilus
ACEK
Acinetobacter

carbapenem Beta lactam/ Beta lactamase inhibitor Aminoglycoside Quinolone Colistin Vancomycin . cephalosporin.Overview of Antibiotics       Beta lactam: penicillin.

Sites of Action of Antimicrobial Agents in Clinical Use .

penicillin-resistant S.pneumoniae (PRSP) Gram-positive rods – most Spirochetes .Penicillin Penicillin G (IV) Penicillin V (PO) Gram-positive cocci-most except staphylococci.

Not active against MRSA Dicloxacillin (PO) .Drug of Choice for MSSA .Antistaphylococcal Penicillins Cloxacillin (IV/PO) .

Salmonella spp. .Shigella spp.Escherichia coli . ..Haemophilus influenzae .Broad Spectrum (Amino) Penicillins Ampicillin (IV.Proteus mirabilis . PO) Amoxicillin (PO) • Amino side chains enhances diffusion through porin channels of gram-negative bacilli • Added activity against : .

enterococci.Broad Spectrum (Ureido) Penicillins Piperacillin (IV) • More active against Klebsiella. and Bacteroides • Active against P. aeruginosa .

Risk Factors For Pseudomonas aeruginosa Infection        Hospital-acquired infection Neutropenic patients Structural lung abnormality Previous broad spectrum antibiotic within one month Steroid use (> 10 mg/day of prednisolone) Hemodialysis Nursing home reidency .

MRSA.most except Bacteroides . Klebsiella . Proteus mirabilis.E.First Generation Cefazolin (IV) • Gram-positive cocci .except enterococci.except Listeria • Gram-negative cocci .coli.Cephalosporins .poor against Haemophilus influenza • Anaerobes . PRSP • Gram-positive bacilli .except Neisseria Cephalexin (PO) • Gram-negative bacilli .

Second Generation Cefuroxime Cefamandole (IV.Cephalosporins .PO) (IV) Cefaclor (PO) Cefprozil (PO) Loracarbef (PO) • Increased activity against Haemophilus influenzae and Moraxella catarrhalis .

and Neisseria gonorrhea .Cephalosporins .Second Generation (Cephamycin) Cefoxitin (IV) • Increased activity against Bacteroides spp.

aeruginosa .Cephalosporins . aureus (MSSA) • Not active against enterococci. Listeria. Neisseria. P.influenzae.Third Generation Cefotaxime Ceftriaxone (IV) (IV) Cefixime (PO) • Highly active against Enterobacteriaceae. MRSA. H. streptococci • Decreased activity against S.

influenza • Most active against P.Cephalosporins – Third Generation (Anti-Pseudomonal) Ceftazidime (IV) Cefoperazone (IV) • Highly active against Enterobacteriaceae.. and H. aeruginosa • Decreased activity against Gram-positive bacteria . Neisseria spp.

gramnegative include Pseudomonas • No activity against anaerobes .Cephalosporins – Fourth Generation Cefepime (IV) Cefpirome (IV) • Gram positive.

3a Ceph.Anti-Bacterial Spectrum of Cephalosporins Bacteria Ceph. 0 0 0 0 0 2+/4+ 3+/4+ 4+ 4+ 4+ 0 /1+ 1+/2+ 3+/4+ 2+/3+ 4+ 3+/4+ 3+/4+ Enterobacteriaceae Community-Acquired Hospital-Acquired P.4 Streptococci. Staphylococci 4+ 2+/3+ 3+ 0 /1+ 3+ Pen. S.3a = Cefotaxime. Aeruginos 0 0 0 4+ B.3b Ceph. fragilis 0 0* 0 0 Ceph. Ceftriaxone * Cefoxitin 0 Ceph.3b = Ceftazidime .1 Ceph.pneumoniae 0 0 3+ 0 MRSA 0 0 0 0 0 Enterococcus spp.2 Ceph.–Resist.

Stenotrophomonas .Carbapenems Imipenem(+cilastatin) (IV) Meropenem(IV) Doripenem (IV) Ertapenem (IV) • Broadest spectrum – Gram-positives. Gram-negatives. Nocardia • Stable to all -lactamases except carbapenemases • No activity to MRSA. anaerobes. Enterococcus faecium • Drug of choice for ESBL-producing strain .

ESBL  One class of beta lactamase  Report only in E.mirabilis  Risk factors: hospital-acquired infection.oxytoca. K. P. 3rd gen cephalosporin. quinolones .pneumoniae. K.coli.

data in prolonged infusion • Imipenem: has activity to Enterococcus faecalis. not active against Pseudomonas . less neurotoxicity.Carbapenems • Meropenem: approved for treatment of meningitis. nephrotoxicity from cilastatin • Ertapenem: narrowest spectrum. more active against gram negative bacilli • Doripenem: has lower MIC for Pseudomonas.

Organisms Resistant to Imipenem and Meropenem • Stenotrophomonas maltophilia • Burkholderia cepacia • Enterococcus faecium • MRSA • Diphtheroids .

Beta Lactam/ Beta Lactamase Inhibitor  Amoxicillin/Clavulanic acid (Augmentin)  Ampicillin/ Sulbactam (Unasyn)  Piperacillin/ Tazobactam (Tazocin)  Cefoperazone/ Sulbactam (Sulperazon. Sulcef) .

.Neisseria gonorrhoeae .Bacteroides spp.-Lactamase Inhibitors Clavulanate Sulbactam Tazobactam • Little intrinsic antibacterial activity • Irreversible binding to -lactamases of : .Staphylococcus aureus .Some Enterobacteriaceae .Haemophilus influenzae .

Rational for Beta-Lactam / BetaLactamase Inhibitor Combination Beta-Lactamase Enzyme Bacteria Beta-Lactam .

Rational for Beta-Lactam / BetaLactamase Inhibitor Combination Beta-Lactamase Enzyme Beta-Lactamase Inhibitor Bacteria Beta-Lactam .

Aminoglycoside .

Antibacterial activity  rapidly bactericidal against a broad range of aerobic gram-negative bacilli including P. aeruginosa   used for combination therapy such as enterococci and staphylococci with betalactam antibiotics and vancomycin to achieve synergistic bactericidal activity Lack activity against anaerobes .

   Nephrotoxicity Toxicity Oto-vestibular toxicity .cochlear and vestibular bodies of the inner ear Neuromuscular blockade .interference of neurotransmission at neuromuscular junctions .

Clinical implication    Combination therapy with other antimicrobial agents for serious gram-negative bacillary infections Mycobacterial infections Less common pathogens -Yersinia pestis. Brucella spp. and Francisella tularensis .

staphylococcal. streptococcal endocarditis . enterococcal.Clinical implication  Combination with cell-wall–active antibiotics synergistic bactericidal activity for serious gram-positive coccal infections .

Quinolones .

some Gram+ (S.Generation 1st 2nd 3rd Drug Names Spectrum nalidixic acid Gram. aureus) and some atypicals levofloxacin moxifloxacin Same as 2nd generation with extended Gram+ and atypical coverage *withdrawn from the market in 1999 .(including Pseudomonas species).but not Pseudomonas species norfloxacin ciprofloxacin ofloxacin Gram.

Quinolones Antibacterial activities   Aerobic gram-negative bacilli: **Enterobacteriaceae and Haemophilus spp. and Moraxella (Branhamella) catarrhalis. Gram-negative cocci such as Neisseria spp. .

and some strains of Mycobacterium chelonae but fair or poor activity against Mycobacterium aviumintracellulare . and moxifloxacin: active against M. ciprofloxacin. Mycobacterium fortuitum. tuberculosis. and ofloxacin: limited activity against streptococci and many anaerobes Ciprofloxacin. ofloxacin. Mycobacterium kansasii.Quinolones Antibacterial activities   Norfloxacin. levofloxacin.

and Chlamydophila pneumoniae . ofloxacin.genital pathogens such as Chlamydia trachomatis. moxifloxacin: active against . levofloxacin. Mycoplasma pneumoniae.Atypical pneumonias.  Moxifloxacin: increased potency against anaerobes .Quinolones Antibacterial activities  Ciprofloxacin. including Legionella pneumophila. Ureaplasma urealyticum. and Mycoplasma hominis.

Colistin .

Polymyxins Colistin: Polymyxin E Spectrum of Activity • Narrow spectrum • Most aerobic gram-negative bacilli including P. . aeruginosa & Acinetobacter spp.

Parenteral colistin dosing  CCr > 40 150 mg iv q 12 h  CCr 31-40 100 mg iv q 12 h  CCr 21-30 75 mg iv q 12 h  Ccr 11-20 100 mg iv OD  Ccr < 10 75 mg iv OD *** loading 300 mg not related to Cr Cl .

Aerosolized polymyxins  To improve concentrations of polymyxins in the distal airway and reduce the systemic toxicity  Dosing 75-300 mg/day of colistin base. q 4-12 h for inhalation  Aerosolized therapy as an adjunct to systemic treatment appears promising  Current published data. too limited to allow determination .

and viable treatment option for MDR GNB infection. intravenous treatment with polymyxins alone is not recommended. . effective.Intrathecal colistin administration   Central nervous system infection Generally. since they are considered to penetrate poorly in CSF. Intrathecal use of colistin is a potentially safe.

54:290-2 Clin Infect Dis. 2000. 2005.38:3523 J Infect.28:916-7 J Clin Microbiol.50: 348-52 . 2004.6 to 20 mg/day (q12-48h) J Clin Microbiol. 2005. 1999. ranging from 1.Intrathecal colistin administration   Case report Dosing Variable doses of intrathecal colistin.43:4916-7 J Antimicrob Chemother.

weakness. vertigo. neuromuscular blockade which can lead to respiratory failure or apnea Dose dependent & reversible . ataxia.Adverse Effects    Nephrotoxicity (10% .20%) : ATN Neurotoxicity (7%) : Dizziness. visual disturbances. confusion. facial paresthesia.

sore throat.Adverse Effects Polymyxins in nebulization   Induce bronchospasm Other minor symptoms .reported cough. chest tightness .

Glycopeptides  Mechanism of Action   Inhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through binding tightly to D-alanyl-D-alanine precursor of the cell wall Bactericidal .

Glycopeptides  Agents   Vancomycin Teicoplanin  Spectrum of Activity  Gram Positive         Staphylococcus MRSA Streptococcus Enterococcus Coagulase negative staphylococcus No coverage of VRE Clostridium difficile Gram Negative  No coverage .

VANCOMYCIN .

Streptococci. Bacillus spp. anaerobic cocci. aureus and Enterococci.Staphylococci. Actinomyces.Corynebacteria. and Clostridia First line treatment for MRSA infection combination of vancomycin and gentamicin is synergistic against S. Enterococci. Streptococci . Listeria monocytogenes.VANCOMYCIN    Constant activity against all common gram-positive bacteria .

Pharmacodynamic  Total trough serum vancomycin concentrations of 15–20 mg/L are recommended in S. aureus infection of bacteremia endocarditis osteomyelitis meningitis hospital acquired pneumonia .

Pharmacodynamic In order to achieve rapid attainment of this target concentration for seriously ill patients -> loading dose of 25–30 mg/kg (based on ABW)  .

Therapeutic monitoring of
vancomycin

Monitoring of trough serum vancomycin
concentrations to reduce nephrotoxicity is
best suited to patients receiving aggressive
dosing
targeted to produce sustained trough drug
concentrations of 15–20 mg/L or who
are at high risk of toxicity

Appropriate use of
Vancomycin

Serious infections due to beta-lactam-resistant GP
pathogens
GP infections in patients with serious beta-lactam
allergies
Antibiotic-associated colitis

Toxicity & Adverse
Reaction
-

-

Fever
Rash
Phlebitis
Neutropenia
Nephrotoxicity
Auditory toxicity
Interstitial nephritis
Infusion-related reactions

Linezolid      Bind to 50S rRNA. inhibiting protein synthesis Bacteriostatic Used for MRSA and VRE infections IV and PO bioavailabilities are similar May cause dose dependent. reversible thrombocytopenia and anemia .

injecting site irritation . including VRE (not E. fecalis). hepatitis. MRSA May cause thrombocytopenia.Quinupristin/Dalfopristin     Inhibits protein synthesis at 50S rRNA May be bacteriostatic and cidal Active against grm +.

cyanosis. shock due to neonates inability to conjugate drug Achieves high CSF levels Low cost and good availability .000 patients) Grey baby syndrome: Abdominal distension. flaccidity. may be weeks to months following treatment (1:30.Chloramphenicol      Exhibits dose-related bone marrow suppression Idiosyncratic aplastic anemia.

mycoplasmas. some anaerobes. spirochetes. and rickettsiae May cause depression of skeletal growth and tooth enamel hypoplasia in children.Tetracyclines     Inhibit protein synthesis at 30S rRNA sub-unit Bacteriostatic Have broad spectrum of activity against gram +. chlamydiae. in addition to brown/grey discoloration and should not be used in children under 8 . gram -.

azithromycin. May decrease metabolism of drugs metabolized by CYP3A subclass of P-450 system. rickettsia. some mycobacteria and actinomycetes New macrolides are longer lasting.Macrolides     Erythromycin. legionella. including activity against chlamydia. less GI side effects. Has led to ventricular arrhythmias with terfenadine and astemizole . mycoplasma. clarithromycin Broad spectrum.

intraabdominal infections Adverse reaction include rash/hypersensitivity.Clindamycin     Good gram positive and anaerobic coverage Good for aspiration pneumonia.1 to 10% of patients treated with Clindamycin . diarrhea C. difficile colitis in 0.

Tigecycline  Mechanism of Action   Inhibits bacterial protein synthesis by binding the 30S and possibly the 50S ribosomal subunits Bacteriostatic .

Tigecycline  Spectrum of Activity  Gram Positive  Streptococcus  Staphylococcus including MRSA  Enterococcus including VRE  Covers listeria  Gram Negative  Broad gram negative activity except  Pseudomonas  Providencia  Proteus  ESBL  Atypicals  Legionella  Mycoplasma  Chlamydia  Rickettsia .

Trimethoprim-Sulfamethoxazole  Act synergistically to inhibit bacterial folic acid synthesis resulting in decreased nucleotide synthesis .

PCP.TMP-SMX cont. bronchitis. toxoplasmosis Resistance may be occur via export of drug. S. over-production of PABA or decreased binding of drug . nocardia. maltophilia.     Bacteriostatic Similar PO/IV bioavailability Used often for UTI’s.

may have metallic taste .Metronidazole     Potent bactericidal agent that lead to generation of toxic mediates Used chiefly for anaerobic and protozoan infections Well absorbed orally Rare reversible neutropenia. peripheral neuropathy.

Daptomycin  Mechanism of Action   Potassium efflux causing loss of membrane potential Bactericidal .

Daptomycin  Spectrum of Activity  Gram Positive Staphylococcus  MRSA  Coagulase negative staphylococcus  Streptococcus  Enterococcus  VRE   Gram Negative  No gram negative coverage .