1 / 139

Definitions

Definitions. Bacteremia: Presence of bacteria in the blood Under normal circumstances, the blood is a sterile environment. Systemic Inflammatory Response Syndrome (SIRS). An inflammatory response, to a wide variety of clinical insults, characterized by two or more of the following:

sharne
Download Presentation

Definitions

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Definitions • Bacteremia: Presence of bacteria in the blood • Under normal circumstances, the blood is a sterile environment

  2. Systemic Inflammatory Response Syndrome (SIRS) • An inflammatory response, to a wide variety of clinical insults, characterized by two or more of the following: • Temperature greater than 38 oC (100.4 oF) • Heart rate greater than 90 beats per min • Respiratory rate greater than 20 breaths per min • White blood cell count greater than 12,000/mL

  3. Sepsis Sepsis is a systemic inflammatory response to a documented infection In addition to preceding criteria, at least one of the following must be present: Alteration in mental state Hypoxemia (lower pressure of oxygen in blood) Elevated plasma lactate

  4. Lipopolysaccharide is Part of the Outer Membrane of Gram Negative Bacteria

  5. Bacterial lipopolysaccharides are toxic to animals. When injected in small amounts LPS or endotoxin activates several host responses that lead to fever, inflammation and shock.

  6. Endotoxins may play a role in infection by any Gram-negative bacterium. The toxic component of endotoxin (LPS) is Lipid A. The O-specific polysaccharide may provide for adherence or resistance to phagocytosis, in the same manner as fimbriae and capsules.

  7. The O polysaccharide (also referred to as the O antigen) also accounts for multiple antigenic types (serotypes) among Gram-negative bacterial pathogens. • Thus, E. coli O157 (the Jack-in-the-Box and Stock Pavillion E. coli) is #157 of the different antigenic types of E. coli and may be identified on this basis.

  8. Allergic Responses to Antibiotics • Uticaria: A skin rash involving dark red itchy bumps.

  9. Allergic Responses • Anaphylaxis: A severe, life-threatening allergic response, having many potential manifestations, including loss of consciousness, labored breathing, swelling of the tongue, low blood pressure, etc.

  10. Shock • Shock is characterized by low blood pressure (hypotension) and tachycardia • Septic shock is a result of the infection itself (bacteremia, sepsis). • Anaphylactic shock is an allergic response to a foreign agent (antibiotic, bee sting, etc.)

  11. Vancomycin Carbohydrate Peptide Linkages Vancomycin is called a ‘glycopeptide’, meaning that it is a cyclic peptide, with sugar residues attached to it.

  12. Discovery Vancomycin was discovered in a soil sample sent to the pharmaceutical company Eli Lilly by a missionary in Borneo in the 1950’s.

  13. Vancomycin Mechanism of Action • Bacterial Cell Wall Synthesis (review) • http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/ppgsynanim.html • http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/vanres.html • Link Penicillin Mechanism of Action (review) http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/penres.html

  14. Mechanism of Action of Vancomycin Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits, preventing them from being incorporated into the cell wall by penicillin-binding proteins (PBPs). In many vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is replaced with D-alanyl-D-lactate, which is not recognized by vancomycin. Thus, the peptidoglycan subunit is appropriately incorporated into the cell wall.

  15. Vancomycin Uses • Vancomycin is used to treat aerobic Gram + bacteria, including MRSA and strains of penicillin-resistant Streptococcus pneumoniae • Vancomycin is most often administered intravenously • Vancomycin can also be used to treat anearobic Gram + bacteria, including Clostridium difficile (in the case of a GI infection, Vancomycin can be administered orally). • Vancomycin cannot be used to treat Gram – bacteria, since the large size of the vancomycin molecule prohibits its passing of the outer membrane.

  16. Vancomycin Resistance • Some Enterococci have developed resistance to vancomycin (Enterococcus faecium and Enterococcus faecalis). • These bacteria are called Vancomycin Resistant Enterococci (VRE)

  17. The mechanism of resistance involves the transformation of the D-Ala-D-Ala linkage in the peptide side chain into D-Ala-D-Lac (i.e. replacement of the amide NH by an O) • This terminal linkage is still recognized by the essential PBP’s (so the cell wall can still be constructed), but is not recognized by vancomycin (thus resulting in resistance).

  18. Antimicrobial Activity of Vancomycin

  19. Daptomycin • Daptomycin is called a lipopeptide antibiotic • Approved for use in 2003 • Lipid portion inserts into the bacterial cytoplasmic membrane where it forms an ion-conducting channel. • Marketed under the trade name Cubicin Lipophilic Tail

  20. Step 1: Daptomycin binds to the cytoplasmic membrane in a calcium-dependent manner Step 2: Daptomycin oligomerizes, disrupting the membrane Step 3: The release of intracellular ions and rapid death Link

  21. Uses of Daptomycin (Cubicin) • Daptomycin is active against many aerobic Gram-positive bacteria • Includes activity against MRSA, penicillin-resistant Streptococcus pneumoniae, and some vancomycin-resistant Enterococci (VRE) • Daptomycin is not active against Gram negative strains, since it cannot penetrate the outer membrane.

  22. Primarily been used to treat skin and soft tissue infections (complicated skin and skin structure infections, including MRSA). • Also approved for S. aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis • Poor activity in the lung, thus not used for pneumonia

  23. Cubicin (Daptomycin) is administered intravenously. • It is not orally bioavailable.

  24. Antimicrobial Activity of Daptomycin

  25. Rifamycins • Rifampin is the oldest and most widely used of the rifamycins • Rifampin is also the most potent inducer of the cytochrome P450 system

  26. The Rifamycins Rifampicin (Rifampin) Rifabutin (Mycobutin) Rifaximin (Xifaxan (US), Spiraxin (EU)) Rifapentine (Priftin)

  27. Therefore, Rifabutin (brand name Mycobutin) is favored over rifampin in individuals who are simultaneously being treated for tuberculosis and HIV infection, since it will not result in oxidation of the antiviral drugs the patient is taking.

  28. Rifaximin is a poorly absorbed rifamycin that is used for treatment of travelers’ diarrhea.

  29. Mechanism of Action of Rifampin • Rifampin inhibits transcription by inactivating bacterial RNA polymerase

  30. Resistance develops relatively easily, and can result from one of a number of single mutations in the baqcterial gene that encodes RNA polymerase. • Therefore, Rifampin is rarely used as monotherapy (i.e. not used as a single agent) but usually combined with other antibiotics

  31. Uses of Rifampin • Used, in combination with other drugs, to treat Mycobacterium tuberculosis • Used to treat some Staphylococcal infections. • Rifampin and the other rifamycins are orally bioavailable.

  32. The Rifamycins include Rifampin, Rifabutin, Rifapentine, and Rifaximin, all of which can be administered orally. Rifampin can also be administered parenterally.

  33. Aminoglycosides The structure of the aminoglycoside amikacin. Features of aminoglycosides include amino sugars bound by glycosidic linkages to a relatively conserved six-membered ring that itself contains amino group substituents.

  34. Aminoglycoside Mechanism of Action • Aminoglycosides bind to the 30S subunit of the bacterial ribosome, thereby inhibiting bacterial protein synthesis (translation) • Link • LINK • Link

  35. The ribosome target of aminoglycosides is a combination of RNA (below) and proteins

  36. Uses of Aminoglycoside Antibiotics • Unlike vancomycin, the aminoglycosides have excellent activity against Gram – aerobic bacteria • Their extensive positive charge enables them to bind to and penetrate the negatively charged outer membrane and get into the periplasm • They are further transported into the cytoplasm by a bacterial transport system.

  37. Bacterial resistance to aminoglycosides occurs via one of three mechanisms that prevent the normal binding of the antibiotic to its ribosomal target: • Efflux pumps prevent accumulation of the aminoglycoside in the cytosol of the bacterium. • Modification of the aminoglycoside prevents binding to the ribosome. • Mutations within the ribosome prevent aminoglycoside binding.

  38. The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (topical, oral).

  39. Aminoglycosides Streptomycin Streptomycin was the first aminoglycoside to be discovered (1944) and it still valuable (in combination with other antibacterial agents) in the treatment of multidrug resistant tuberculosis (although not a first line drug for tuberculosis)

  40. Aminoglycosides Gentamicin • Gentamicin is most commonly used of the aminoglycosides • Active against aerobic Gram-negative infections (and sometimes Gram positive) • Can be used synergistically, together with a cell wall targeting agent (e.g. a penicillin) • Available in parenteral, opthalmic, and topical formulations

  41. Aminoglycosides Tobramycin • Tobramycin has better activity against Pseudomonas aeruginosa than does gentamicin • Tobramycin may be given either intramuscularly or intravenously • It is also administered by inhaler, particularly useful for individuals with cystic fibrosis (frequently contract P. aeruginosa infections)

  42. Amikacin • Amikacin has the broadest antimicrobial spectrum of the aminoglycosides • It is more resistant to aminoglycoside-inactivating enzymes than the other aminoglycosides • It is often used in hospitals where gentamicin- and tobramycin-resistant microorganisms are prevalent

  43. Neomycin • Neomycin is widely used for topical administration • Like other aminoglycosides, it is not absorbed well orally, and is used to prepare the bowel for surgery.

  44. The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral).

  45. Macrolides and Ketolides The structures of erythromycin and telithromycin Circled substituents and distinguish telithromycin from the macrolides.

  46. Chemical Definitions • Macrolide = macrocyclic lactone (cyclic ester) • Macrolide antibiotics usually have ring sizes of 14, 15, or 16 atoms Ester Linkage Cladinose Sugar

  47. Substituent allows telithromycin to bind to a second site on the bacterial ribosome.

More Related