Week 7 Basic Principles of Antimicrobial Therapy 2024 PDF

Week 7 2024-10-23 16:36 Basic principles of antimicrobial therapy - Antibiotic = chemical that is made by one microbe that has ability to harm other ○ Under this def only those compounds that are actually made by microorganisms qualify as abx ○ Lab made; not abx...

Week 7 2024-10-23 16:36 Basic principles of antimicrobial therapy - Antibiotic = chemical that is made by one microbe that has ability to harm other ○ Under this def only those compounds that are actually made by microorganisms qualify as abx ○ Lab made; not abx - Antimicrobial; any agent, natural or synthetic has ability to suppress or kill - But no benefit of using either of this terms diff so they can be used interchangeably - Selective toxicity ○ Ability of drug to target specific microbial target cell without injuring other cells ○ Make abx valuable - Achieving selective toxicity ○ There are microbial processes that happen in microbial cells that don’t happen in mammals; we can use this to target them ○ Disruption of bacterial cell wall § Bacteria have rigid cell wall; protoplasm has high [] of solutes so osmotic pressure is high; therefore the rigid cell wall keeps the cell intact , otherwise it would swell then burst/lyse □ Several abx weaken cell wall an promote bacterial lysis; penicillin, cephalosporin □ Mammalian don’t have cells walls; our cells are not affected - Inhibition of enzyme unique to bacteria ○ Sulfonamides ; selective toxicity bc they inhibit enzyme critical to bacterial survival § Inhibit enzyme needed to make folic acid (needed by all cells including mamamlians) but humans can get it from food; § Bacteria need folic acid from themselves bc they cant get it from environment § Bacteria take up para-mainobenzoic acid(PABA) -->convert to folic acid § Sulfonamides block conversion of PABA into folic acid - Disruption of bacterial protein synthesis ○ Same in both cells; protein synthesis is made by ribosomes but are not identical in bacterial and mammalian cells; ○ Abx can disrupt protein synthesis in bacterial - Classification of abx drugs ○ Broad spectrum vs narrow spectrum (preferred) ○ Antibacterial § Narrow: □ Gram + and narrow; penicillin G, vanco, erythromycin, clindamycin □ Gram -: aminoglycosides ; gentamicin, cephalosporins □ Tb drugs; isoniazid, rifampin, ethambutol, pyrazinamide § Broad spectrum □ Gram+ AND - ; ampicillin, cephalosporin (3rdgen), trimethoprim, carbapenems, sulfonamides, fluoroquinolones ○ Antiviral § Hiv; □ Reverse transcriptase inhibitors □ Protease inhibitors □ Fusion inhibitors □ Integrase inhibitors □ Ccr5 antagonist § Flu; adamantanes, neuaminidae inhibitors § Other; acyclovir, ribavirin, inteferon-alpha ○ Antiviral § Polyene abx, azoles, echinocandins; caspofungin - - Drugs that inhibit bacterial cell wall synthesis or activate enzymes that disrupt the cell wall. These drugs (e.g., penicillins and cephalosporins) weaken the cell wall and, hence, promote bacterial lysis and death. - Drugs that increase cell membrane permeability. Drugs in this group (e.g., amphotericin B) increase the permeability of cell membranes, causing leakage of intracellular material. - Drugs that cause lethal inhibition of bacterial protein synthesis. The aminoglycosides (e.g., gentamicin) are the only drugs in this group. We do not know why inhibition of protein synthesis by these agents results in cell death. - Drugs that cause nonlethal inhibition of protein synthesis. Like the aminoglycosides, these drugs (e.g., tetracyclines, clinda, eryhtromycin) inhibit bacterial protein synthesis. However, in contrast to the aminoglycosides, these agents only slow microbial growth; they do not kill bacteria at clinically achievable concentrations. - Drugs that inhibit bacterial synthesis of DNA and RNA or disrupt DNA function. These drugs inhibit synthesis of DNA or RNA by binding directly to nucleic acids or by interacting with enzymes required for nucleic acid synthesis. They may also bind with DNA and disrupt its function. Members of this group include rifampin, metronidazole, and the fluoroquinolones (e.g., ciprofloxacin). - Antimetabolites. These drugs disrupt specific biochemical reactions. The result is either a decrease in the synthesis of essential cell constituents or synthesis of nonfunctional analogs of normal metabolites. Examples of antimetabolites include trimethoprim and the sulfonamides. - Drugs that suppress viral replication. Most of these drugs inhibit specific enzymes—DNA polymerase, reverse transcriptase, protease, integrase, or neuraminidase—required for viral replication and infectivity. - Bactericidal = directly lethal - Bacteriostatic; slow bacterial growth; to get rid of pathogen, immune system must be working with phagocytic cells Acquired resistance to antimicrobial drugs - Acquired; over time drug sensitivity Is lost; resistant - Serious problem for enterococcus faeciu, staph aureus, enterbacter, lebsiella, cdiff ○ Methicillin resistant; staph.aureus, c diff - Microbial mechanisms of drug resistance - 4 basics mechanisms of resisting drugs 1) Reduction of drug [] at action site i. Most drugs; intracellular site of action; can either cease active uptake of certain drugs; tetracyclines, gentamicin or increase active export of tetracyclines, fluroquinolones, macrolides, etc 2) Alteration of drug target molecules - Most drug interact with target molecules/receptors to create effect but if receptor structure is changed; wont work - Eg. Streptomycin resistant d/t changes in bacterial ribosomes where streptomycin works 3) Antagonist production i. Microbe can make compound that antagonizes drug; ii. Eg. Increased PABA; resistance to sulfonamides 4) Drug inactivation i. Can make drug metabolizing enzymes; ii. Eg. Resistant to pencillin G bc of increased production of penicillinase; enzyme that inactivates it; iii. Other eg. Bacterial enzymes that inactive cephalosporin, carbapenems, fluoroquinolones - New delhi metallo-b-lactamase 1 (ndm-1 gene) ○ Extensive drug resistance is conferred by NDM-1 gene which codes for powerful form of β-lactamase. ; β-lactamases are enzymes that inactivate drug with β-lactamase ring § Form of β-lactamase that is coded by NDM-1 gene is resistant to all β- lactamase abx including pencillin, cephalosporins, carbapenems, § Dna segment that contains NMD-1 also contains genes that resistant drug efflux pumps, enzymes, etc § All of these genes are present on plasmid that can be easily transferred from one bacterium to another § Bacteria with NDM-1 gene are resistant to nearly all abx except for tigecycline, colistin - Mechanisms by which resistance is acquired ○ Spontaneous mutation § Random changes in microbe's dna § Low level resistance develops stronger § This type confers resistance to only one drug ○ Conjugation § Extrachromosomal DNA is transferred from one bacterium to another § To transfer resistance by conjugation, the transferring microbe must have 2 dna segments; one that codes for resistance and one for "sexual" apparatus for dna transfer □ Together the 2 constitute R factor (resistance) § Usually among gram - bacteria § Can be among same type or diff type of species; not species specific □ Therefore possible for pathogen bacteria to get r factor from normal flora in body; and this is more apparent and a concern § Multiple drug resistance bc dna can be transferred for several diff drug- metabolizing enzymes; highly resistant to diff drugs - Relationship bw abx use and emergence of drug resistant microbes ○ Abx promote drug resistance but do not directly cause genetic changes ○ Spontaneous mutation and conjugation are random events whose incidence depends on drug use ○ Abx promote resistance by promoting environment for them to flourish § Microbes secrete compounds toxic to other microbes and microbes compete with each for available nutrients in an ecological location (gut, gu tract, skin) § If no drug resistant microbe is present; all bacteria will be affected with drug § If drug resistant microbe is present; abx will kill healthy bacteria and promote growth of the drug resistant one § Drug may eliminate toxins from healthy bacteria and letting pathogen flourish - Abx that promote resistance ○ All promote but some are more likely to promote ○ Broad spectrum abx kill more competing organisms than narrow; can cause more resistance - Affect of increased abx use on emergence of resistance ○ Not only do increased abx promote resistance of pathogens but can also promote overgrowth of flora that possess mechanisms for resistance ○ Drug use can increase resistance of normal flora which may further transfer resistance to pathogens by conjugation; § Therefore avoid if not needed; ○ Hai ; most difficult to treat - Superinfection ○ NEW infection that appears during course of tx of primary infection ○ Can be d/t abx inhibit influence of normal flora; letting second infection to flourish ○ Eg. Vaginal candida tx with broadspectrum abx § Broadspectrum kill more abx; - Selection of abx ○ Produce maximal abx effect while causing minimal harm to host ○ 3 factors when choosing 1) Identity of infecting organism 2) Drug sensitivity to organism 3) Host factors; site of infection, status of host defenses - Empiric therapy before completion of lab tests - Drug selection must be based on clinical evaluation and knowledge of microbes that most likely cause infection at that site - Broad spectrum can be used; swithc to selective once determined - Get samples/cultures before abx - Identifying infecting organism ○ Match drug with bug 1) Microscopic exam of gram stained preparation § From sputum, blood, urine, etc ○ If only small # of organisms; might need culture to grow out; ○ Sample should not be exposed to oxygen, low temp, antiseptic 2) Polymerase chain rxn; PCR or nucleic acid amplification; - Can detect low liters of bacteria and viruses - Done by using enzyme either dna polymerase or rna polymerase to generate thousands of copies of dna/rna - C. diff, s.aureus, Tb, neisseria gonnorrhea, chlamydia, h.pylori, hiv, flu - Determining drug susceptibility - Not always necessary; only if pathogen is usually resistance - Eg. S. aureus or gram - bacilli; drug test should be done - Need to identify microbe first - Host factors that modify drug choice, route of administration, dosage - Host defense; primarily immune cells and phagocytic cells (macrophages, neutrophils) § Need this for successful abx tx § Goal is to suppress microbial growth so balance is tipped in favor of host § If immunocompromised; then we can use bactericidal - Site of infection § Abx must be present at site of infection in a [] > minimal - inhibitory concentration (MIC) § Some sites might be hard to penetrate like meningitis bc of bbb, endocarditis bc of bacterial vegetations in heart, and infected abcess bc lack of blood flow § 2 choices for meningitis □ Choose one that crosses BBB or inject into subarachnoid space □ If exudate present; drainage § Foreign materials (cardiac pacemakers, prosthetic joints, valves, shunts) ;phagocytes can react and attempt to destroy them; and less able to attack bacteria; removal is necesarry - Other host factors - Previous allergic rxns; especially common in penicillins § Also sulfonamides, trimethoprim, erythromycin, - Genetic factors § Some abx can cause hemolysis in some pts like sulfonamides; bc they lack Glucose-6-phosphate dehydrogenase (g6pd) causes cell lysis § Metabolism rate; eg. Metabolism of isoniazid can be slow or fast; - Antimicrobial pt centred care § Infants; toxicity ; sulfonamides in newborn cause kernicterus d/t displacement of bilirubin from plasma proteins § Children; tetracycline; discoloured teeth § Pregnancy; gentamicin can cause hearing loss § Older; toxicity - Dosage and duration of tx - Abx needs to present in MIC [] at site of infection; - Dosage should be adjusted to produce drug [] that are equal or > in MIC; often 4-8 times MIC desirable - Therapy with abx combinations - Routine use is not recommended unless needed; if single agent use one abx - Antimicrobial effects of antibiotic combinations § 2 abx together can cause additive, potentiative or antagonistic § Additive; antimicrobial effect of combination = sum of effects of 2 drugs alone § Potentiative interaction = synergistic □ Effect of combination > sum of effects of individual agents □ Eg. Trimethoprim and sulfa § Antagonism; if abx togther is less effective than one of the agents by itself d/t bacteriostatic agent (tetracycline) combined with bactericidal drug (penicillin0 □ Bacteriostatic suppress bacterial growth but bactericidal cant kill organisms unless theyre active □ If host defenses are intact; little difference but if not in tact - Indications for abx combination - Initial tx for severe infection § Unknown etiology; especially in neuropenic host § Wide antimicrobial coverage is appropriate until organism identified § Get culture samples - Mixed infections § Brain abcesses, pelvic infection, infections from resulting from § When infectious microbes differ from one another in drug susceptibility, tx is needed - Preventing resistance § Usually multiple abx use can promote drug resistance; § But needed in TB tx; drug comination is needed for suppressing emergence of resistant bacteria - Decreased toxicity § Abx combo can reduce toxicity to host □ Eg. combining flucytosine with amphotericin B in the treatment of fungal meningitis, the dosage of amphotericin B can be reduced, thereby decreasing the risk for amphotericin-induced damage to the kidneys. - Enhanced Antibacterial Action - Combo of abx can have greater antibacterial action than on e single - Eg. Pencillin and aminoglycoside in tx of enterococcal endocarditis § Pencillin; weaken bacterial cell wall; § Aminglycoside suppress protein synthesis - Disadvantages of abx combinations 1) Increased risk for toxic, allergic rxns 2) Possible antagonism of antimicrobial effects 3) Risk of super infections 4) Drug resistance 5) Increased cost - Prophylactic use of antimicrobial drugs ○ Uncalled for ○ Sx § Can decrease incidence of infection in certain types of surgery § Cardiac , peripheral vascular, orthopedic, gi, csection, § And for contaminated surgery; on perforated abd organs, compound #, animal bites; risk is 100% □ In this case its tx ; and it is needed § Post op abx is unnecessary; first gen should be good; cefazoline ○ Bacterial endocarditis § Congenital or vulvar heart diseases, prosthetic valves susceptible to bacterial endocarditis □ Need prophylaxtic abx before these procedures ○ Neutropenia § High risk of infection; may also induce fungi infection bc of killing of flora which normally suppress fungal growth ○ Antimicrobial prophylaxis § Reccurent uti; prophylaxis with trimethoprim/sulfa § Oseltamivir; anriviral for flu ○ Misuses of antimicrobial drugs § 1 in 3 outpt abx is inappropriate or unecessary § Viral infection; mumps, chicken pox, cold; don’t response □ Instead harm of drugs □ Acute upper resp tract infection;cold; § Tx of fever unknown; not recommended □ Hepaitits, arhritis, cancer; unless proven, abx not recommended □ Exception: ® Because fever may indicate infection and because infection can be lethal to the immunocompromised patient, these patients should be given antibiotics when fever occurs—even if fever is the only indication that an infection may be present. ○ Improper dosage § If too low; risk of adverse effects without beenefit § If too high; super inection ○ Omission of surgical drainage § Limited efficiacy; surgical drainage, cleansing to promote antimicrobial effects; in presence of tissue, exudate ○ Monitoring antimicrobial therapy § Resolution of signs; fever, improvent of breath sounds, etc § Lab results § Serum drug levels to watch for toxicity and if in suffiecient dosage for effect § No more growth; sterile □ May take time to become sterile for weeks; in tb - Drugs that weaken the bacterial cell wall l - Penicillins ○ Belong to beta-lactam family; contain beta lactam ring int heir structure ○ Abx weaken cell wall; cell swells; lysis ○ Known as beta-lactam abx ○ Principle adverse effects; allergic rxns ○ Beta lactams § Cephalosporin, carbapenem, azetronam § All do the same thing; destroy cell wall ○ Mechanism of action § Bacterial cell wall; rigid mesh like structure outside of cytoplasmic membrane § Inside of cell; osmotic pressure is high; if broken, cell will lyse § Penicillin weaken cell wall; take in lots of water; rupture § Penicillin are bactericidal --> only work against bacteria undergoing growth and division § Weaken cell wall by 2 actions 1) Inhibition of transpeptidases a) Enzymes needed for cell wall synthesis that catalyze peptidoglycan polymer strands that form cell wall by creating cross bridges 2) Activation of autolysins; a) Cleave bonds in cell wall § Molecular targets of penicillin; transpeptidase, autolysins, bacterial enzymes = penicillin-binding proteins; PBPs □ Penicillin bind to them on cytoplasmic membrane; □ Bacteria only express PBP during growth/division § Safe for humans bc we don’t have cell wall - Mechanisms of bacterial resistance - 3 mechanisms; inability of penicillin to reach cell wall/pbp, inactivation of penicillin by bacterial enzymes, production of pbps that have low affinity for pencillin ○ Gram - cell envelope § All bacteria have cell envelope but the envelope of gram - is diff from gram + § Some penicillins are ineffective against gram - § Gram + only have 2 layers; cytoplasmic membrane, and cell wall which penicillin can penetrate; § Gram- has THREE LAYERS; cytoplasmic membrane, thin cell wall, additional outer membrane □ The cell wall can be penetrated by pencillins but the outer layer is difficult to pass □ Only certain pencillins can; ampicillin ○ Penicillinases ; b-lactamases § Enzymes that cleave beta-lactam ring; § Some are specific for penicillin (penicillinases) □ and others for other beta lactams like cephalosporin § Penicillinases are made by both types of gram -/+ bacteria □ Gram + make more and export it out □ Gram -; make less and secrete in periplasmic space § Genes that code for b-lactamases are on chromosomes and plasmids (extrachromosomal dna) and can be transferred (conjugation) to other bacteria; causing resistance § Eg. Staph aureus used to be tx with penicillin but now as many as 80% are resistant □ Methicillin (penicillin resistant) still works for staph. Aureus bc it is not inactivated by b-lactamases but may be inactivated for other reasons ○ Altered penicillin-binding proteins § Certain bacterial strains; methicillin resistant s. aureus ; MRSA is resistant bc it the PBP have low affinity for pencillins and b-lactam abx § It has genes that code for low affinity ○ MRSA - Staphylococcus aureus = gram + that often colonizes skin, nostrils fo healthy ppl - Infection usually involves skin, soft tissues causing boils, abcess, cellulitis, impetigo into sepsis - Mrsa are bacteria resistant to methicillins, pencillins, cephasloporins, d/t low affinity for the abx - 2 types; HCA- MRSA (health care) and CA-MRSA - HCA-MRSA; contact, more serious usually □ Tx; for skin/soft tissues is iv vanco, linezolid, cindamycin, - CA-MRSA □ Mild infections of skin/soft tissue; but can lead to necrotizing penumonia, sepsis □ Sports, razors, etc, atheletes, □ Tx; trimeth/sulfa; doxycycline, clindamycin, - Chemistry ○ All penicillin are derived from common nucleus; 6- aminopenicillanic acid; contains b-lactam ring to 2nd ring ○ B-lactam ring is essential for antibacterial actions ○ Properties of individual pencillins are made by additions to nucleus and determine - Affinity for pbp, resistance to penicillinases, ability to penetrate gram - cell envelope, resistance to stomach acid, pharmacokinetic properties - Classification of pencillins 1) Narrow spectrum penicillin - penicillinase sensitive - Penicillin g, v ; streptococcus spp, neisseria, anaraeobes, 2) Narrow spectrum penicillin - penicillinase resistant - Dicloxacillin, nafcillin - Good against staph. aureus 3) Broad spectrum penicillin - Ampicillins, amox - Good against; ecoli, hflu, neisseria gonorrhoea 4) Extended spectrum penicillin - Piperacillin; - Penicillin G - First penicillin available; and often referred to as pencillin by itself - Bactericidal to gram + and some gram - bacteria - Antimicrobial spectrum - Active against most gram + bacteria; except pencillnase producing staph., gram - cocci (neisseria meningitidis), anareobic bacteria, spirochetes - Considered narrow spectrum - Pharmacokinetics - Absorption □ Available as 4 salts that dissoaciate to release pen.g ® Potassium penicillin g ® Procaine penicillin g ® Benzathine penicillin g ® Sodium penicillin g □ Intramuscular; ® Potassium and sodium penicillin g is rapid but procaine and benzathine salts is slow but can remain for weeks; benzathine is good for syphilis causing bacteria - Distribution □ Well to most tissues/fluids □ Entry into csf, joints, eye is only good with inflammation - Metabolism and excretion □ Minimal metabolism and is eliminated by kidney □ Half life is short - Side effects/ toxicities - Least toxic, safest - Allergic rxns main consdern - Certain effects may be d/t salts; eg. Hyperkalema, electrolyte imbalances; should be on low sodium diet if on sodium penicillin g - Penicillin allergy - Penicllins = most common cause of drug allaergy; minor to anaphylaxis - No direct relationship with bw size of dose or intesnity of response; - Prior exposure to penicllin but could also be bc of exposure to penicillins made by fungi, or those in foods of animal origin - Bc of cross sensitivity; if allergic to one; should be considered allergic to others - If mild; can use cephalosporins - Types of allergic rxns □ Immediate, accelerated, delayed □ Immediate 2-30 min; accelerated 1-72 hrs; delayed days/weeks □ Immediate/accelerated by igE - Development of penicillin allergy □ Small molecules like penicillin and most drugs are unable to induce antibody formation directly; but need to bind to larger molecule like protein ; small molecule is hapten □ Hapten-protein = antigen □ Hapten that stimulates production of penicillin antibodies is rarely penicillin itself but the degradation of penicillin - Skin test for penicillin allergy □ Allergy to penicllin can decrease over time □ Skin test can be used to assess sensitivity □ Allergen is injected intradermally; positive test = presence of IgE antibodies; - Management of pts with hx of penicillin allergy □ Ask if they have allergy, what rxn is □ Mild = cephalosporin; and oral is preffered □ Vanco, eryhtromycin, clindamycin are effective □ For pt with hx of anaphyaxis but has life threatning infection like nterococcal endocarditis needing pencillin; try desensitization therapy; small dose followed by bigger doses - Penicillin V/ vk - Diff from penicillin G. Bc of acid stability; it is stable in stomach acid; - Therefore better for oral therapy; can be taken with meals - Penicillinase resistant penicillin (antistaphylococcal penicillins) - Pencillins that resistant to inactivation by beta-lactamases - Nafcillin, oxacillin, dicloxacillin - Narrow antimicrobial spectrum; only used against staphylococci strains that produce penicillinase; which is most of staphyloccal infections - Do not use against non-penicillinase producing staphylocci bc less active than pencillin g - Mrsa; use vanco - Broad spectrum penicillins/ aminopenicillins - Ampicillin and amoxicillin - Same antimicrobials pectrum as pencillin G plus increased activity against gram - bacilli includig hflu, eclo, salmonella,shigella - Bc they have ability to penetrate gram - cell envelope; - Both drugs are inactivated by b-lactamases; and ineffective against most infections caused by s.aureus - Ampicillin □ First broad spectrum penicillin □ Useful against enteroccus fecali, salmonella, h.flu, e coli □ Side effects; rash, diarrhea □ Rash can begin 3-10 days after therapy □ Oral or iv □ Available with sulbactam (b-lactamase inhibitor) - Amoxicllin □ Similar to ampicillin; but amoxillin is more acid stable □ Preferred oral □ Milder diarrhea bc less amoxicillin remains unabsorbed in intestine □ Combo with clavulanic acid ; inhibitor of beta- lactamase - Extended spectrum penicillin (antipseudomonal pencillins) - Piperacillin is the only one - Susceptible to aminopenicllins ; pseumonas areuginosa, enterobacter specifis, klebseilla - Susceptible to b-lactamase; not effective for staph a. - Primarily for infection with p. aeruginosa □ Often in immunocompromised and hard to get rid of □ Aminoglycoside (gentamycin, tobramycin,) may be added to help kill pseudomonas ® DO NOT MIX TOGETHER; penicllin may inactive aminoglycoside - Piperacillin □ Broad antimicrobial spectrum but is pencillinase sensitive; □ Good against p. areuginosa; □ Can cause bleeding secondary to platelet disfunction; □ Needs to be iv bc acid instability □ Can be be in fixed dose with tazobactam; b lactamase inhibitor ; zosyn - Penicillin combined with beta lactamase inhibitors □ Drugs that inhibit b-lactamases can be combined with penicillinase sensitive penicillin to extend spectrum □ Sulbactam, tazobactam, clavulanic acid - Summary of pencillins Therapeutic Goal: Treatment of infections caused by sensitive bacteria Baseline Data: Samples for microbiologic culture to identify the infecting organism Monitoring: Renal impairment can cause penicillins to accumulate to toxic levels. Monitor function in patients with renal disease. Identifying High-Risk Patients: Penicillins should be used with extreme caution in patients with a history of severe allergic reactions to penicillins, cephalosporins, or carbapenems. Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects—reduction in fever, edema, pain, and inflammation. Minimizing Adverse Effects: For patients with prior allergic responses, a skin test may be ordered to assess current allergy status. Drugs that weaken the bacterial cell wall part 2; - By inhibiting cell wall synthesis; cause bacterial lysis and death - Cephalosporins - Beta lactam abx similar in structure/actions to pencillins - Bactericidal, and often resistant to b-lactamases, and active against broad spectrum of pathogens - Low toxicity ; popular; most used abx - Chemistry - All are derived from same nucleus containing b-lactam ring which is needed for antibacterial activity - Mechanism of action - Bind to penicillin-binding proteins (PBP) to 1) disrupt cell synthesis and 2) activate autolysins (enzymes that cleave bonds in cell well) - Most effective against cells undergoing active growth cells - Resistance - Can be d/t beta-lactamases that inactive b-lactam ring ; enzymes that do this called = cephalosporinases - Some b-lactamases that act on cephalosporins can also cleave b-lactam ring on penicillin - It depends on what generation of cephalosporin is sensitive to beta-lactamases; □ First gen; destroyed by it □ 2nd gen; less sensitive □ 3rd, 4th, 5th = resistant to beta lactamase - Can also be d/t change in pbp that have low affinity for cephalosporins □ MRSA; □ 5th gen cephalosporin (ceftaroline); has activity against MRSA - Classification and antimicrobial spectra - Progressing from 1st gen to 5th gen; □ Increased activity against gram - bacteria/anaerobes □ Increasing resistance to beta-lactamases □ Increasing ability to reach csf - Pharmacokinetics - Absorption □ Poor gi tract absorption; given IM/IV (parenterally) - Distribution □ Well to most of body fluids/tissues □ Therapeutic [] in pleural, pericardial, peritonieal fluids □ Ocular fluids = low [] □ Bc of poor distribution to csf in first and 2nd; don’t use for meningitis - Elimination □ All by kidneys; by glomerulr filtration and active tubular secrection □ Impaired kidney secrection; lower dose to prevent toxicity □ Ceftriaxone is eliminated largely by liver; - Adverse effects - Well tolerated; safest - Allergic rxns; □ Maculopapular rash several days after onset of tx □ Severe immediate rare □ Bc of similarity wth pencillin and cephalosporin, few pts allergic to one drug type experience cross sensitivity - Drug interactions - Alcohol □ 2 cephalosporins; cefazolin, cefoetan can induce state of alcohol intolerance ® If take alcohol; disulfiram rxn can occur (disulfiram effect can be d/t accumulatoin of acetaldehyde) - Drugs that promote bleeding - Cefoetatan, cefazoline, ceftraixone ; promote bleeding bc they contain side chain that interfers with vitamin k metabolism; inhibiting formation of clotting factors - Caution if giving with other drugs; anticoagulnts, thrombolytics, nsaids, antiplatelets - Therapeutic uses - Broad spectrum bactericidal drugs with high therapeutic index - First and second gen are rarely used - First gen; gram +; surgical prophylaxis; cefazolin, cephalexin - Second gen; gram + an d-; it is, sinusitis, resp tract infections; cefuroxime, - Third Is preferred and fourth and fifth are used against resistant organism - Third; gram -; gonorrhea, meningitis, p.aureginosa; ceftriaxone - Fourth; gram -; pseudomonas ; hap, abd and gi tract infections - Fifth; skin, MRSA ; ceftaroline - Drugs that inhibit cell wall synthesis - Cephalosporin; cephalexin - Carbapenem; imipenem - Other; vanco - Drug selection - 19 cephalosporins; - Can be grouped into 3 categories - Antimicrobial spectrum - Adverse effects - Pharmacokinetics; (route of admin, penetration to csf, time course, mode of elimination) - Summary of cephalosporins - Baseline; take culture sample - Monitoring; no routine lab work needed - Identifying high risk pts; allergic rxn to penicillins, or cephalosporins - Evaluating therapeutic effects; antimicrobial effects like reduction in fever, pain, edema, etc - Minimize adverse effect; promote cdiff. ; ask pt to report increase in stool - Carbapenems - B-lactam abx with broad spectrum coverage except no MRSA - 4 available; all are parenteral; impinem, meropnem, ertapenem, doripenem - To prevent emergence of resistance; should be only for those that cant be treated with narrow spectrum agents - Imipenem - B-lactam abx; extremely broad; one of the most broadest coverage - Useful for mixed infections in which anaerobes; s.aureus and gram - bacilli involved - Supplied in combination with cilastin = compound that inhibits destruction of imipenem by renal enzymes - Mechanism of action - Binds to 2 PBP; (PB1, PB2) --> weakens cell wall --> cell lysis - Drug is resistant to b-lactamases and abilite to penetrate gram - cell envelope - Antimicrobial spectrum - Active against most bacterial pathogens; - Highly active against gram + cocci, gram - cocci, bacilli, - Most effective b-lactam abx for anaerobic bacteria - Pharmacokinetics - Imipenem is not absorbed from gi tract; needs to be ic - Well distributed in body including csf - Renal elimination; - When given alone it is inactivated by dipeptidase; enzyme in kidneys; should be given with cilastin (dipeptidase inhibitor) - Adverse effects; - Gi effects; nause,a vomiting, diarrhea; common - Superinfections ; uncommon - Seizures; rare - Cross sensitivity with other b-lactam abx; - Interaction with valproate - Imipenem can reduce blood levels of valproate; used for siezures --> can cause siezure activity - Therapeutic use - Used widely; serious infections by gram + cocci, negative cocci, negative bacilli, anaerobic bacteria - Good for mixed infections - Don’t give alone for pseudomonas aeruginosa; can cause resistance; give with another antipseudomonal drug Summary of carbapenems; - Therapeutic Goal: Treatment of infections caused by susceptible organisms. - Baseline Data: Take samples for culture to determine the identity and sensitivity of the infecting organism. - Monitoring: No routine laboratory monitoring is suggested. Identifying High-Risk Patients: Patients using valproate to control - seizures should not be placed on imipenem. - Evaluating Therapeutic Effects: Monitor for indications of - antimicrobial effects, including reduction in fever, pain, edema, and inflammation. - Minimizing Adverse Effects: Dosage should be reduced in patients with renal impairment. - Pt care across life span; cephalosporin, carbapenems, others - Infants; 3rd gen used for bacterial infections - Children; bacterial infections; otitis media, penumococcol - Pregnant; televancin has black box warning; but cephalosporin safe - Elderly; impaired renal functoin; watch - Other inhibitors of cell wall synthesis - Vancomycin - Most widely used in hospitals - Indication; c diff, mrsa, those allergic to pencillins - Toxicity; renal failure - Vanco does not contain b-lactam ring - Mechanism of action - Vanco inhibits cell wall synthesis and promotes cell lysis but does not contain beta lactam ring so does not interact with PBPs - Works instead by disrupting cell wall by binding to molecules that serve as precursors for cell wall biosynthesis - Antimicrobial spectrum - Only active against gram + ; especially staph. Aureus, and staphylococcus epidermis; event those that are MRSA - Good against streptococci, penicillin-resistant pneumococci, c.diff - Pharmacokinetics - Absorption from gi is poor; given parenterally - Oral is only for intestine; cdi - Well distributed to most tissues; mild to csf so might not be sufficient enough for meningitis - Eliminated unchanged by kidneys; reduce dosage in renal impairment - Therapeutic use - Should be reserved for serious infections; - Agent of choice for MRSA, s. epidermis, and SEVERE CDI (not mild) - Alternative to pencillins/cephalosporing for severe infections; staphylococcal streptococcal endocarditis to those allergic - Adverse effects - Renal toxicity; dose related, and with increased concurrent use of other nephrotoxic drugs; (amingolycosides, cyclosorine, nsaids) - Tough serum levels ® Increase in serum creatinine level; reduce - Clostriodies Difficile infection - Gram + , spore forming, anareobic bacilli that infects bowel - Injury results form relase of toxin A and B - Symp mild; mild abd discomfort, diarrhea, fever, nausea to severe (toxic megacolon, pseudomembranous colitis, colon perforation, sepsis) - More common d/t a more virulent strain - NAP1/B1027; releases more toxins - In hospitals rate of cdiff exceeds those caused by MRSA - Can be managed using vanco or metronidazole (flagyl) - Almost alwaus preceded by use of abx which kill normal gut flora; - Abc that are most likely to promote cdi; clindamycin, 2nd/3rd gen cephalosporins, fluoroquinolones (ciproflaxin, levoflaxin especially can cause more toxic strain) - Acquired by ingesting c.diff spores; shed In feces; ® Resistant to drying, temp changes, alcohol, viable spores can remain in environment for weeks - Defined by: ® Passage of 3-4 unformed stols in 24 hrs AND positive stool test for c.diff or its toxins ® Intestinal damage is caused by toxins a and b that attack lining of colon ® Symptoms range from watery diarrhe to life threatening to life threatening pseudomembranous colitis; characterized by pus, inflammation - Complications include; ® Dehydration, electrolyte disturbances, toxic megacolon, bowel perforation, renail failure, sepsis, ® Recurrence rate is 15-30% - Tx; ® Abx; higher amongst older ppl ◊ Risk factors; gi sx, immunosuppression, ◊ Stopping oen abx and starting another; } Stop the one the pt was on – Bc it will reduce risk of reinfection after CDI cleared; and in 1/4 of pts it will help infection resolve } Start abx to eradicate cdiff; – Choose based on wbc count and creatinine level – Oral vanco or fidaxomicin (narrow macrolide) – Tapering vanco is recommended - Alternatives and supplements to vancomycin and fidaxomicin are as follows: Rifaximin, approved for diarrhea caused by Escherichia coli, can reduce CDI recurrence following treatment with vancomycin. Monoclonal antibodies directed against C. diff. toxins A and B can reduce CDI recurrence when given concurrently with metronidazole or vancomycin. Bezlotoxumab (Zinplava) was the first monoclonal antibody approved for this indication. Inoculating the bowel with a benign strain of C. diff. can protect against developing CDI. Presumably, when the benign strain colonizes the bowel, it occupies the same niche that a virulent strain would occupy and, hence, prevents the virulent strain from becoming established. Vancomycin Therapeutic Goal: Treatment of serious infections, including C. diff. infection, infection with methicillin-resistant S. aureus, and serious infections caused by susceptible organisms in patients allergic to penicillin. Baseline Data: Take samples for culture to determine the identity and sensitivity of the infecting organism. Monitoring: Vancomycin drug levels should be monitored during IV administration. Identifying High-Risk Patients: Use with caution in patients with renal impairment. Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects, including reduction in fever, pain, edema, and inflammation. - Telavancin - Part of new class of agents; lipoglycoproteins; synthetic derivative of vanco - Like vanco; only works against gram + bacteria - Kills with 2 mechanisms 1) Inhibits cell wall synthesis 2) Binds to bacterial cell membrane and disrupts membrane function - Iv therapy for complicated skin infections by s.aureus (incluindg mrsa strains); streptoccus pyogens, streptococcus agalactiae, streptococcus anginosus, enteroccus fecalis (vanco sensitive) - To delay development of resistance, telavancin should be reserved for treating vancomycin- resistant infections or for use as an alternative to linezolid (Zyvox), daptomycin (Cubicin), or tigecycline (Tygacil) in patients who cannot take these drugs. - Adverse effects § Taste, nausea, vomiting, foamy urine § As with vanco; red man syndrome; flushing, rash, pruritus, urticaria, tachycardia, hypotension § Telavancin can prolong the QT interval. However, serious dysrhythmias have not been reported. Nonetheless, telavancin should not be given to patients at high risk, including those with congenital long-QT syndrome, uncompensated heart failure, or severe left ventricular hypertrophy and those using other QT drugs. - Drug interactions icaution in patients taking other drugs that § can damage the kidneys (e.g., NSAIDs, angiotensin-converting enzyme inhibitors, and aminoglycosides) and in patients taking drugs that prolong the QT interval (e.g., clarithromycin and ketoconazole). - Aztreonam - Belongs to b-lactam abx known as monobactams; contain b-lactam ring but it is not fused with 2nd ring - Mechanism of action § Binds to PBP3; inhibits cell wall synthesis; § Does not bind to PBPs made by anaerobes or gram + bacteria - Antimicrobial spectrum/therapeutic use § Narrow; only against gram -; § Neisseria species, hflu, p.areuginosa, enterobacteriae (ecoli, klebsiella, salmonella, shinges, proteus) § Highly resistant to b-lactamases; active against gram - aerobes § Not active against gram + or anaerobes - Adverse effects § Well tolerat similar to other b-lactams § Common; pain and thrombophlebitis at site of injection § Little cross sensitivity; good for allergies - Fosfomycin § Abx - single dose for women with uncomplicated uti; acute cysitis caused by ecoli or e. faecalis § Kills bacteria by disrupting synthesis of peptidoglycan polymer that make up the cell wall § The most common adverse effects; diarrhea, vaginitis, nausea, headache, abd pain, rhinitis, dizziness, rash § Can be with or without food § Should improve 2-3 days - Bacteriostatic inhibitors of protein Synthesis Protein synthesis results in bacteriostatic properities; - except for aminoglycoside which is a bactericidal - Inhibition of protein synthesis; suppress growth; don’t kill outright - 2nd line agents; used for infections resistant to first line - Tetracyclines - Broad spectrum - Seven; tetracycline, demeclocycline, doxycycline, eravycline, omadcyline, sarecyline, minocycline - Similarites are more than differences so discussed as a group under tetracycline - Mechanism of action § Suppress bacterial growth by inhibiting protein synthesis § Bind to 30s ribosomal subunit; inhibit binding of transfer RNA to mrna-ribosome complex § Bacteriostatic; prevent growing peptide § Selective toxicity d/t por ability to cross mammalian cell membranes § They must first enter cell membrane via energy dependent transport system; - Mammalian cells lack this transport system so don’t accumulate the drug - Antimicrobial spectrum § active against a wide variety of gram-positive and gram-negative bacteria. Sensitive organisms include Rickettsia, spirochetes, Brucella, Chlamydia, Mycoplasma, Helicobacter pylori, Borrelia burgdorferi, Bacillus anthracis, and Vibrio cholerae - Therapeutic uses § Infectious diseases - Extensive use of tetracycline has caused bacterial resistance; use of this has declined - Only first line of drug for the following: rickettsial diseases (rocky mountin, typhus, q fever), infections by chlamydia, bucellosis, chlorea, pneumonia by mycoplasma pneumoniae, lyme disease, anthrax, gastric infection with h.pylori § Acne tx - Topically and oral for severe acne vulgaris - Suppress growth/metabolic activity of propionibacterium acne; secrete inflammatory chemicals - Oral doses low § Peptic ulcer disease - H.pylori = bacterium that lives in stomach contributes to peptic ulcer disease - Tetracyclines +metronidazole+bismuth subsalicyate tx h.pylori § Periodontal disease - Doxycycline and minocycline are used for periodontal disease - Doxycycline is used orally and topically - Minocycline is used topically - Oral therapy - Used to inhibit collagenase ; enzyme that breaks down collagen in gums; small doses 20 mg; too low to harm bacteria - Topical therapy - Topical doxycycline and minocycline are used for scaling, root planing - Suppress bacterial growth § Pharmacokinetics - Individual diff bw tetracyclines is in half life, route of elimination, and degree to which food alters absorption - Tetracycline; po; short acting - Intermediate acting; declocycline; po - Long acting; doxycycline, etc - Also increase digoxin levels by increased absorption in gut; - and increase INR by changing vitamin k producing flora in gut - Pts on digoxin/warfarin need drug level monitoring § Pt centered care across lifespam - Children/; do not use; can discolor teeth permanently - Pregnancy; unsafe - Breastfeeding; during teeth development can cause perm. Staining; avoid - Older; interact with digoxin, warfarin, etc. § Major precautions - Tetracycline and demeclocycline are eliminated in urine and will accumulate to toxic levels in pts with kidney disease - Do not use in kidney disease - Cause discolouration of diciuous perm teeth; don’t use in pregnant or children - Diarrhea indicates light threatning superinfection of bowel; - Avoid high dose iv therapy; can affect liver Tetracyclines - Therapeutic Goal: Treatment of tetracycline-sensitive infections, acne, and periodontal disease. - Baseline Data: None required. - Monitoring: None recommended. - Identifying High-Risk Patients: Contraindicated in pregnant women - and in children younger than 8 years. - Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects—reduction in fever, pain, or inflammation. Minimizing Adverse Effects: GI distress can be reduced by taking tetracyclines with meals. Advise patients to avoid prolonged exposure - - Macrolides - Broad spectrum abx that inhibit bacterial protein synthesis - Called macrolides bc theyre big - Erythromycin; older - Azithromycic, clarithromycin ; newer derivatives of erythromycin - Azithromycin; po. Iv - Clarithromycin; po - Erythromycin; po/iv - Erythromycin §Broad antimicrobial spectrum; preferred or alternative tx for 3 of infections; safer and protype for macrolides - Mechanism of actions § Inhibition of protein synthesis by binding to 50s ribosomal subunit; blocking amino acids to growing peptide chain § Usually bacteriostatic but in large [] can be bactericidal § Selectively toxic to bacteria bc ribosomes In cytoplasm of mammalian cells don’t bind to drug; - erythromycin cannot cross the mitochondrial membrane and therefore does not inhibit protein synthesis in host mitochondria - Antimicrobial spectrum § Erythromycin has abx spectrum similar to penicillin; active against gram + as well as some gram - § Sensitivty depends on if it can gain access to inside of cell - Therapeutic uses § Commonly used § First choice for crynebacterium diphtheriae § Can be used as alternative to pencillin g in pencillin allergy § Treatment of choice for acute dipheteria ; diarrhea § Both macrolides and tetracyclines are drugs of first choice for chlamydial infections (urethritis, cervisitis) and pneumoniae; mycobacterium pneumoniae - Pharmackokinetics § Absorption - Oral ; 3 forms ; erythromycin base and 2 derivatives of base - Base is unstable in stomach acid so absorption is varable; bioavability has been improved by newer derivatives and acid resistant coating; - Food decreases absorption of erythromycin base and stearate; but absorption of ethyl succinate is not affected - Only erythromycin base is biologically active; the derivatives must be converted to the base (either in the intestine or after absorption) in order to work. When used properly (i.e., when dosage is correct and the effects of food are accounted for), all of the oral erythromycins produce equivalent responses - Also availble for iv use; § Distribution; readily to most tissues except csf - Crosses placenta; effects unknown § Elimination; mainly by hepatic mechanisms; CYP3A4; isoenzyme of cytochrome p450; concentrated in liver, then bile § Adverse effects; safest; small risk of prolong QT - Gi effects; common; epigastric pain, nausea, vomiting, diarrhea - Can be reduced by giving with meals but should only be done with erythromycin ethyl succinate or enteric coated formulations - Prolonged qt; in high []; risk for torsades de pointes; ventricular dysrhythmias; - When given with cyp3a4 inhibitor; bigger risk for sudden cardiac death ◊ Including calcium channel blockers, azole antifungal, hiv protease, nefazadone - Drug interactions - Increases plasma levels and half life of other drugs by inhibiting heptic cytochrome p450 drug metabolizing enzyme - Elvated levels are concern with theophylline (asthma med), warfarin (anticoagulant), carbamazipine (seizure and antipyschotic) - Erythromycin prevents binding of chloramphenicol and clindamycin to bacterial ribsomes; antagonizing antibacterial effects - Also should not be used with drugs that can inhibit erythromycin metabolism; diltiazem, hiv protease inhibitors, azole antifungal Macrolides summary - Therapeutic Goal: Treatment of respiratory infections, infections caused by H. pylori, disseminated Mycobacterium, and as alternatives to penicillin in patients with penicillin allergy. - Baseline Data: None indicated. - Monitoring: None recommended. - Identifying High-Risk Patients: Use with caution in patients with QT prolongation. - Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects—reduction in fever, pain, or inflammation. - Minimizing Adverse Effects: Avoid use in patients with QT prolongation. GI disturbances can be reduced by administering with meals. - Other bacteriostatic inhibitors of protein synthesis - Clindamycin § Can promote severe CDAD; can be fatal § Clindamycin use is limited; only for certin anerobic infections outside of cns § Mechanism of action - Binds to 50s subunit of bacterial ribosomes; inhibiting protein synthesis - Site it binds at overlaps same site for erythromycin and chloramphenicol; together they might antagonize each other; § Antimicrobrial spectrum - Active against most anreobic bacteria; gram+ and - - Anaerobes; Bacteroides fragilis, Fusobacterium species, Clostridium perfringens, and anaerobic streptococci. Clindamycin is usually bacteriostatic. However, it can be bactericidal if the target organism is especially sensitive. Resistance can be a significant problem with B. fragilis. § Therapeutic use - Bc of effiacy against gram + cocci; been used as alternative to pencillin - Used for anareobic infections outside of cns; doesn’t cross bbb - Choice of drug for severe group A streptococcal infection and gas gangrene as it can suppress synthesis of bacterial toxins § Adverse effects - CDAD - Most severe toxicity of clindamycin - Cause is usperinfection of bowel with c.difficile = anoerobic gram + bacillus - 10-20 loose watery stools; abd pain, fever, leukocytosis, - Stools have mucus;blood - Symptoms first week or 4-6 weeks after - Report diarrhea; stop and given vanco or flagyl; do not use bowel motility like anticholinergics and opioids - Linezolid § First in class oxazolidinone abx; - Activity against multi drug resistant gram + pathogens including VRE, MRSA § Mechanism, resistance, antimicrobial spectrum - Bacteriostatic inhibitor of protein synthesis; binds to 23s portion of 50s ribosome subunit; blocks formation of initation complex - Linezolid is active primarily against aerobic and facultative gram-positive bacteria. Susceptible pathogens include Enterococcus faecium (vancomycin- sensitive and vancomycin-resistant strains), Enterococcus faecalis (vancomycin- resistant strains), S. aureus (methicillin-sensitive and methicillin-resistant strains), Staphylococcus epidermidis (including methicillin-resistant strains), and Streptococcus pneumoniae (penicillin-sensitive and penicillin-resistant strains). Linezolid is not active against gram-negative bacteria, which readily export the drug. - Therapeutic uses linezolid has five approved indications: Infections caused by VRE Hospital-acquired pneumonia caused by S. aureus (methicillin- susceptible and methicillin-resistant strains) or S. pneumoniae (penicillin-susceptible strains only) Community-associated pneumonia (CAP) caused by S. pneumoniae (penicillin-susceptible strains only) Complicated skin and skin structure infections caused by S. aureus (methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae Uncomplicated skin and skin structure infections caused by S. aureus (methicillin-susceptible strains only) or S. pyogenes - Adverse effects - Diarrhea, nausea, headache; common - Oral suspension contains; phenylalanine so avoid in those with phenylketonuria - Reversible myelosuppression; anemia, leukopenia, thrombocytopenia; § Do cbc weekly - Neuropathy; in prolonged use - Drug interactions - Moa inhibitor; can cause hypertension with indirect sympathomimetic action (cocaine, ephedrine, pseudoephedrine) etc. - With ssri; risk fo serotonin syndrome; bc inhibition of moa increases serotonin content; § Avoid paroxetine, duloxetine - Tedizolid - Second oxazolidinone - Effective in MRSA and other bacterial, skin soft tissues caused by sensitive staphyloccocus and streptococcus species - Adverse; diarrhea, nausea, headache, § Serious; neuropathy, myelosuppression - Drug interactions; inhibitor of moa; htn criss risk; avoid sssris - -