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Antibiotic Therapy

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

The Bacteria









Non Spore





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 .


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

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

Appropriate use of

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

Toxicity & Adverse


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 .