Anti-infective Therapy

David Greenberg MD
Pediatric infectious Disease Unit
Soroka University Medical center

OBJECTIVES
Describe major classes of antimicrobials and their mechanisms of action Know the spectra of activity of commonly used antibiotics Understand the mechanisms of resistance to antibiotics

Anti-infective therapy
Empiric Specific

Principles of anti-infective therapy

Infective agent factors Host factors

Infective agent Identification

Identification of infecting organism:
Gram stain Immunologic methods (antigen detection) Polymerase chain reaction (PCR) Culture and biochemical identification Typing methods

Determination of antimicrobial susceptibility

Disc MIC

Host factors
Age ( immunologic status, dose, side effects) Immunologic status (AIDS, Malignancy) Genetic and metabolic abnormality (G6PD) Pregnancy Renal and hepatic function Site of infection Drug interactions

Antimicrobial combinations
Initial therapy Prevention of the emergence of resistant organisms Polymicrobial infections Synergism

Anti-infective agents
Antibiotics Antiviral Antifungal

Spectrum of Activity
Broad Spectrum Antibiotics:
Effective against many types
Example: Carbapenems

Narrow Spectrum Antibiotics:

Effective against very few types
Example: Penicillin

Bactericidal vs. Bacteriostatic

Bactericidal:
Kill bacteria Used when the host defense mechanisms are impaired Required in endocarditis, kidney infection

Bacteriostatic:
Inhibit bacteria Used when the host defense mechanisms are intact Used in many infectious diseases

Antibiotic groups
Penicillins Penicillins+lactamase inhibitors Cephalosporins Carbapenems Monobactams Aminoglycosides Tetracyclines Rifamicins

-lactams

Antibiotic groups-cont.
Glycopeptides (Vancomycin, Teicoplanin) Oxazolidinones (Linezolid, Eperezolid) Sulfonamides Quinolones Nitrofurantoin Macrolides Clindamycin MLS-Macrolides, Lincosamins, Streptogramin Chloramphenicol Metronidazole

MECHANISMS OF ACTION OF MAJOR GROUPS OF ANTIBIOTICS

STRUCTURE OF Beta-LACTAM ANTIBIOTICS

PENICILLIN HOME

Penicillin Home
Looks like a house with a new room added to the side Think of the R-group as of a funky antenna Changing antennae and or finishing the basement will create better homes (penicillin)

[Penicillin] Home Improvement Project

Adding a new antenna creates broad spectrum penicillins
Example: Ampicillin

Adding additional antennae and finishing the basement creates cephalosporins

Example: 1st, 2nd, 3rd, & 4th generation cephalosporins

MECHANISM OF ACTION OF Beta-LACTAM ANTIBIOTICS

Resistance of Microbial Populations

Resistance of Microbial Populations

Resistance of Microbial Populations

Resistance of Microbial Populations

Resistance of Microbial Populations

Bacterial resistance ( 3 mechanisms)

1. Destruction of antibiotic by -lactamase
2. Failure of antibiotic to penetrate to active site

3. Low affinity binding of antibiotic to PBPs

Antibiotic resistance
-lactam antibiotic:
Penicillin binding protein ( affinity) -lactamases (production, modify structure) antibiotic concentration inside cell (loss of porins, pump it out)

Aminoglycoside: enzymes inhibit transport across

the cytoplasmic membrane

Macrolides:
Alteration in the ribosomal target-site Esterase enzymatic inactivation

Quinolones: change of gyrA or B in DNA-gyrase

Penicillins
S CH-CO-NH-CH-CH CO benzylpenicillin C

N CH-COOH

-lactamase

Classification of penicillins
Natural penicillins: Penicillin G, Penicillin V Penicillinase-resistant: Methicillin, Nafcillin,
Cloxacillin, Oxacillin

Aminopenicillins: Ampicillin, Amoxicillin Carboxy-, indanyl penicillins: Carbenicillin,

Ticarcillin

Uridopenicillins: Azlocillin, Mezlocillin,

Piperacillin

Penicillins + -lactomase inhibitors

Augmentin (Amoxicillin+clavulinate) Timentin (Ticarcilin+clavulinate) Tazocin (Piperacilin+tazobactam) Unacin (Ampicillin+sulbactam)

Antimicrobial sensitivity
Pen Staph.aur Staph.coag.neg Strep.viridans PNC Strep A Listeria mon. E.Coli Klebsiella Enterobacter Proteus spp. Salmonella spp. Shigella Campilobacter spp. Heamohpilus I. B Pseudomonas Ampi/Amox Cloxa Mezlo Pipera

Antimicrobial sensitivity
Augmentin Tazocin Staph.aur Strep.viridans PNC Strep A Listeria mon. E.Coli Klebsiella Enterobacter Proteus Salmonella Shigella Campilobacter H.I.B. Pseudomonas Acinetobacter Bacteroides Timentin Unacin

Antibiotic resistance of 1,488 S. pneumoniae nasopharyngeal isolates from Bedouin children aged < 5 years in southern Israel, 1998-2005
90%

1998-2000 (N=67)
80%

2001 (N=51) 2002 (N=418)

70%

2003 (N=415)
60%

2004 (N=156) 2005 (N=376)

% Resistance

50%

40%

30%

P<0.001* P<0.001*

30%

P<0.001*

31%
P<0.001*

P<0.001*

30% 22% 16%

21%
13% 13%

20%

10%

8%

9%

0%
Pen-R (MIC1.0g/ml) Ery Chloram Tetracyclin TMP/SMX Clindamycin Non-susceptible Non susceptible 1 drug 3 drugs (MDR)

* Adjusted for age and antibiotic use during last month

Cephalosporins
Oral
First generation Cephalexin (Ceforal) Cefadroxil (Duracef) Second generation Cefaclor (Ceclor) Cefuroxime(Zinnat) Third generation Cefixime (Supran) Cefdinir

Parenteral
First generation
Cefazolin Cephalotin

Second generation
Cefotetan Cefuroxime (Zinacef)

Third generation
Ceftriaxone (Rocephin) Cefotaxime (Claforan) Ceftazidime (Fortum)

Fourth generation
Cefepime (Maxcef)

Cephalosporins
Mechanism of action like of other -lactam antibiotics Penetration into tissues is excellent Most of them are excreted through the kidney Half-life longer (ceftriaxone once daily)

cephalosporins

Antimicrobial activity
First generation against gram positive bacteria Second generation against gram positive and gram negative bacteria but not for meningitis Third generation against gram negative and less against gram positive, only few against pseudomonas Forth generation against gram positive consist Staph. aureus, gram negative consist pseudomonas

Cepalosporins are not effective against:

Listeria monocytogenes Enterococcus spp. Anaerobes

Adverse reactions to penicillins and cephalosporins

Allergic: anaphylaxis, urticaria, hemolitic anemia,
serum sickness, contact dermatitis

Idiopathic: skin rash, fever Gastrointestinal: diarrhea, enterocolitis, hepatic

dysfunction

Hematologic: neutropenia, platelets dysfunction Electrolyte disturbance:K, Na Neurologic: seizures, bizarre sensations Renal: interstitial nephritis, hemorrhagic cystitis

Carbapenems
Imipenem active against gram negative bacteria,
anaerobs, less against pseudomonas. Active against bacteria resistant to cephalosporins

Meropenem active against gram negative

bacteria, anaerobs, slightly less against gram positive. Active against bacteria resistant to cephalosporins. Approved by FDA in children

Carbapenems adverse reactions

Hypersensitivity Rapid infusionnausea and emesis AST, ALT Leukopenia Seizures

Monobactam
Astreonam
active against gram negative gram resistant to many others antibiotics, not active against gram positive bacteria Can be used safely in patient with allergic reaction to penicillins and cephalosporins

Aminoglycosides
Streptomycin Neomycin Gentamicin Amikacin Paromomycin Tobramycin Netilmicin Kanamycin

Aminoglycosides

Mechanism antimicrobial activity

Across the membrane and irreversibly trapped in the cytoplasm of bacteria (low pH, anaerobic environment this process)
Bind to ribosome, cause of miscoding of protein synthesis

Spectrum of activity
Effective against gram-negative bacteria, pseudomonas
brucella, listeria, streptococci Streptomycin used against Tuberculosis, Tularemia, Plague

Aminoglycosides

Usually not used as alone therapy in serious infections. Used as part of combination with lactams High activity in high concentration and postantibiotic effect rationale of once-daily regimen

Aminoglycosides

Toxicity
Nephrotoxicity injury of renal proximal tubules Ototoxicity damage of cochlea and vestibular apparatus (unilateral or bilateral) Neuromuscular blockade (weakness of
respiratory musculature, flaccid paralysis, dilated pupils) rare, but may be lethal

Aminoglycosides

Once-daily regimen
Decrease risk of nephro- and ototoxicity Peak serum level are obtained to ensure efficacy, trough serum level are obtained to reduce risk of toxicity In patients with normal renal functions trough level can be checked 18-24 hours after dosing once and after this only once-twice a week serum creatinine level monitoring

Tetracyclines
Short-acting: Oxytetracycline, Tetracycline
Intermidiate: Demeclocycline Long-acting: Doxycycline, Minocycline New cyclines- Tigecycline (TYGACIL)

Tetracyclines

Mechanism antimicrobial activity

Passive diffusion through porins into bacteria cell Bind to ribosome and prevents addition of new amino acids into the growing peptide chain (inhibit protein synthesis in host cells too)

Tetracyclines

Major indications
Borrelia infections Brucellosis Chlamydia infections (adult) Rickettsia infections Cholera PID syndrome (part of combinations)

Tetracyclines

Effective alternative therapy

Acne Anthrax Legionella Leptospira Mycoplasma Nocardia Rat-bite fever Syphillis Plague

Tetracyclin toxicity
Allergic reaction: rash, anaphylaxis, lupus-like
syndrome

Teeth and bones: gray-brown to yellow

discoloration of teeth in children under 8 years old, depression of skeletal growth in preterms GI: esophageal ulceration, vomiting, epigastric distress, hepatotoxicity in pregnant women and in patient with renal failure Vertigo, dizziness, tinnitus

Tigecyclin
Glycylcyclines are semisynthetic derivatives of tetracycline antibiotics This modification maintains the antibacterial effect but provides stability against mechanisms of tetracycline resistance. Tigecycline inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. In general, tigecycline is considered bacteriostatic

Tigecycline Is indicated for the treatment of adults with: Complicated skin caused

Complicated intra-abdominal infections

Macrolides
Erythromycin Clarithromycin Azithromycin

Macrolides

Mechanism of action
Inhibits RNA-dependent protein synthesis

Uses of Macrolides
Mycoplasma infections Diphtheria Pertussis Campylobacter jejuni gastroenteritis Chlamydia Alternative therapy in patients allergic to penicillin (Tonsillitis, RF, syphilis)

Clindamycin

Uses of clindamycin
Bacteroides fragilis and other anaerobic bacteria (abdominal and pelvic infections) Alternative therapy for Staph. aureus infections in patients allergic to penicillins Effective with penicillin in soft tissue Strep. A infections and toxin-mediated disease

Macrolides and clyndamycin

Adverse reactions
Allergic reactions Abdominal pain, diarrhea, pseudomemranous enterocolitis Hepatotoxicity Agranulocytosis, thrombocytopenia

Linezolid
Linezolid is the first of the oxazolidinone antibiotics to receive approval from the Food and Drug Administration (FDA). Oxazolidinones inhibit protein synthesis by binding at the P site at the ribosomal 50S subunit. Indications: for the treatment of infections caused by resistant pathogens such as: Vancomycin-resistant enterococcus (VRE) Methicillin-resistant Staphylococcus aureus (MRSA). Linezolid also has useful activity against some rapidly growing mycobacteria including: Mycobacterium fortuitum Mycobacterium chelonae Nocardia spp.

Linezolid - Safety
nausea diarrhea headache Reversible thrombocytopenia is the major hematologic consequence of linezolid use in adults, transient bone marrow suppression.

Sulfonamides
Sulfadiazine Sulfisoxazole Sulfamethoxazole
(+ trimethoprim = resprim)

Sulfadoxine

Sulfonamides

Clinical use
UTI (orally to non-complicated infection and as prophylactic therapy) Nocardia infections Toxoplasma infection (in pregnancy problematic, for congenital infection and to immuncompromised patients)

Sulfonamides

Adverse reactions
Nausea, vomiting, diarrhea Rash, fever Hepatic necrosis Drug-induced lupus and other hypersensitivity reactions Hemolysis In pregnancy increased fetal free bilirubin, increased risk to kernicterus

Vancomycin
Inhibits synthesis of cell wall Impair RNA synthesis Acts only on multiplying organisms Postantibiotic effect - 2 hours after its level fall below MIC

Vancomycin

Antimicrobial activity
Staphylococcus coagulase negative (Staph.
haemolyticus, epidermidis)

MRSA
Penicillin resistant Strep. pneumoniae (only for Meningitis) C. difficile PO therapy
Strep A, GBS, Listeria, Strep viridans, Enterococcus and others susceptible, but not direct indication

Vancomycin

Adverse reactions
Rapid administration is dangerous redman syndrome, anaphylactic reaction, hypotension, cardiac arrest Fever, chills, phlebitis, hypersensitivity Nephrotoxicity risk with high serum level and together with other nephrotoxic drugs Tinnitus and high-tone hearing loss depend on serum level

Quinolones
Nalidixic acid Ciprofloxacin Norfloxacin Oxloxacin Pefloxacin Levofloxacin and others

Quinolones

Mechanism of action
Rapidly inhibit bacterial DNA synthesis, followed by rapid bacterial cell death

Quinolones

Antimicrobial activity
Aerobic gram-negative bacilli (Enerobacteriaceae, Haemophilus spp.) Gram negative cocci (meningococci, gonococci, Moraxella spp.) Pseudomonas Mycobacterum New quinolones active against gram positive cocci

Quinolones

Clinical uses
UTI (orally very good absorption in GI) STD ( against gonococci) Dysentery (Shigella, E.coli, Salmonella) Nosocomial pneumonia or chronic lung infection Bone and joint infections (nail puncture wound osteochondritis)

Quinolones

Limitation
Limited to use in children under 18 years

Quinolones

Adverse effects
GI : anorexia, vomiting Allergic: drug-fever, vasculitis, angioedema, sickness-like Arthropathy Safety in pregnancy has not be established

Take Home Message

Major Groups of Drugs Antibiotic Targets Bactericidal v. Bacteriostatic Drugs Susceptibility Tests Mechanisms of Resistance Usage (Empiric vs. Specific) Spectrum of Activity and Indications