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ANTIMICROBIALS / ANTIBIOTICS
An antimicrobial is a substance that inhibits or kills microbes (viruses, , bacteria, fungi, parasites) antibiotic is a type of antimicrobial that is synthesized by a living microorganism, usually a fungus ex: penicillin G, is a natural product , synthesized by the mold Penicillium classification of antimicrobials : antibact, antiviral, anti fungal, antiparasitic bactericidal / bacteriostatic or bacteriostatic/fungistatic based on the amount of pathogens they kill in an inoculum. We think of “-cidal” agents as killing and “-static” agents as arresting growth
but a more accurate understanding is that cidal agents kill >99.9%, ,
while static agents only kill 90–99% So The in vitro microbiological determination of whether an antibacterial agent is bactericidal or bacteriostatic may be influenced by growth conditions, bacterial density (inoculum size) , test duration, and extent of reduction in
. bacterial numbers , as well as the concentration of the antimicrobial used The MIC is the lowest concentration of drug that still can inhibit microbial growth . Half- life : time taken by the body to metabolize half of a drug
concentration-dependent activity
. ex: aminoglycosides and fluoroquinolones these drugs, achieving a higher concentration in the blood over a short time with prolonged post antibiotic effect ; that is, they continue to suppress microbial growth long after drug concentration has declined. so . once-daily dosing is enough
time-dependent activity are best dosed with lower doses at an
. increased frequency over time ex: penicillin and vancomycin
Site of Mechanism of Action
Antimicrobial Cell wall
β-lactam (penicillin) Vancomycin Echinocandin
Cell membrane
Cyclic lipopeptide (daptomycin) Triazole (fluconazole)
Ribosome
Macrolide , Aminoglycoside , Linezolid , Tetracycline , clindamycin
Nucleic acid synthesis
Fluoroquinolones , Antiviral (acyclovir) 5-Flucytosine
Metabolic pathway
Trimethoprim-sulfamethoxazole , Ethambutol Explanation journey of peniciilin Naturally produced: penicillin G but no effect on gm –ve ;;;;;;;;so
. aminoacids added forming amoxicillin and ampicillin with gm –ve effect After that penicillinase producing bacteria appears, so will resist penicillin ,,,,,,,synthetise methicillin (pencillinase resistant), followed by nafcillin & oxacillin & dicloxacillin penicillins with antipseudomonal activity were developed, including . piperacillin Some bacteria produce b- lactamase so will distruct all b lactam ring containing antimicrobials(penicillin ,cephalosporen ,monobactam , carbapenem) So b lactamaze inhibitor is added so we had β-lactam/βlactamase inhibitor combinations include amoxicillin/clavulanate, . ampicillin/sulbactam, and piperacillin/tazobactam explanation Cephalosporins: 5 generations (. First (cefazolin and cephalexin) gm + and ecoli ,klesiella ,pseudomonas Second - include cephalosporins(possess increased activity against enteric Gram-negative bacilli and Neisseria spp) . with enhanced activity against H. influenzae (e.g, cefuroxime) cephalosporins with enhanced antianaerobic activity (e.g., . cefoxitin) Third- (e.g., cefotaxime and ceftriaxone) have enhanced activity against . Gram-negative bacilli Another point: it can cross the bbb so used in ttt of meningitis Forth - (cefipime), has broad-spectrum activity against Gram-negative bacteria, including Pseudomonas spp., and Gram-positive bacteria. It is recommended by the Infectious Diseases Society of America for use in . patients with neutropenia Ceftaroline , the fifth -generation( it is highly expensive) has activity against MRSA and penicillin-resistant S. pneumoniae, P. aeruginosa, and . enterococci. It is intended for use in community-acquired pneumonia
inhibiting the bacteria’s DNA gyrase enzyme responsible for unwinding the
. chromosome during replication and cell division DNA exists in the nucleus as a condensed, compact structure. To “ prepare DNA for replication, a series of proteins aid in the unwinding and separation of the double-stranded DNA molecule. These proteins are required because DNA must be single-stranded before replication can .“ proceed . Ciprofloxacin( gm –) brackets has limited activity against streptococci Levofloxacin ( pseudomonas ) and moxifloxacin ( anaerobe) against S. pneumoniae for their use in the treatment of community-acquired pneumonia Aminoglycosides such as gentamicin, tobramycin, and amikacin used in combination with other drugs against difficult-totreat, Gram- positive, and Gram-negative infections ex: used in conjunction with penicillins or vancomycin is needed to achieve cure in the treatment of endocarditis due to susceptible . Enterococcus spp Vancomycin is a glycopeptide that inhibits cell wall synthesis for MRSA infections The new MICs for vancomycin against S. aureus are sensitive ≤. , microgm/ml glycopeptide intermediate S. aureus (GISA) 4 to 8, and . vancomycin-resistant S. aureus (VRSA) ≥ There are three new lipoglycopeptides : telavancin, . dalbavancin, and oritavancin indicated for skin and soft tissue infections, whereas telavancin is also indicated for hospital-acquired pneumonia due to MSSA, MRSA, and GISA Oxazolidinediones Linezolid and tedizolid Action: inhibit protein synthesis and are considered bacteriostatic against Gram-positive organisms indicated principally in the treatment of infections caused by vancomycin- resistant enterococci and MRSA
s/e : thrombocytopenia with long treatment durations (>2 weeks), need f/up Trimethoprim/sulfamethoxazole is a synergistic combination of drugs that together exhibit a bactericidal effect by inhibiting bacterial folate synthesis treatment of Pneumocystis jirovecii pneumonia (PCP), infections due to
. Nocardia spp o treat the epidemic of unique strains of MRSA that cause community- acquired skin and soft tissue infections, but caution ( cause acute kidney . disease) Rifampin, a rifampicin inhibit bacterial DNA- dependent RNA polymerase used as prophylaxis in significant exposures to patients with meningitis . due to Neisseria meningitidis . Rifampin also has activity against most MRSA used in combination with other agents in the treatment of latent or active. . disease due to M. tuberculosis . Rifaximin is used in the treatment of C. difficile colitis Metronidazole requires conversion into its active form by an enzyme found only in anaerobic bacteria, metronidazole has no activity against aerobic bacteria unique indications for metronidazole include parasitic infections, such as vaginitis caused by Trichomonas vaginalis or intestinal infections due to . Entamoeba histolytica or Giardia lamblia Topical and orally nonabsorbable antimicrobials , for decolonization including bacitracin, neomycin, polymyxin B, mupirocin, and fusidic acid mupirocin is of special interest to IPs. This agent, when applied topically to the anterior nares, is part of a regimen for decolonization with MRSA ANTIVIRALS
Drugs such as chloroquine, primaquine, quinine, mefloquine, and doxycycline are used for the treatment or prophylaxis of malaria,
. protozoa . Schistosomiasis, caused by a platyhelminth, is treated with praziquantel The treatment of nematodes (roundworms) includes ivermectin and albendazole
Indications for Antimicrobial Use
PROPHYLAXIS
EMPIRICAL THERAPY
PATHOGEN-DIRECTED THERAPY
PROPHYLACTIC: Q
to prevent infection rather than treat known (THERAPEUTIC) or suspected (EMPIRIC) infection HOW? ( goal of administering preoperative systemic prophylactic antibiotics is to have the concentration in the tissues at its
. highest at the start and during surgery)
In general, any time the skin or mucosa is incised, prophylaxis should be considered
WHY PRESURGICAL PROPHYLAXIS SHOULD BE FOR SHORT
? DURATION
to minimize the emergence of resistant organisms, reduce the incidence of
. side effects, and reduce cost Q : THERE ARE Other unique medical conditions requiring antimicrobial : prophylaxis BECAUSE OF HIGH RISK OF INFECTION ) EXAMPLE ,prevention of endocarditis in patients with high-risk valvular lesions = spontaneous bacterial peritonitis in patients with ascites = malaria in patients traveling to endemic areas = ? Q : DIFFERENCE BETWEEN EMPIRIC AND THERAPEUTIC Empirical therapy, compared with pathogen-directed therapy, is broader in . spectrum due to uncertainty about the causative agent In pathogen-directed therapy, the use of the narrowest spectrum antimicrobial is believed to reduce the emergence of antimicrobial . resistance and superinfection. Minimizing the cost WHAT IS MENT BY SWITCH THERAPY? WHY: TO decrease hospital stay and cost ? Q : FACTORS AFFECTING SUCCESSFUL USE OF ANTIMICROBIALS prompt institution of antimicrobial use (formula) ( type , 1 spectrum , dose , route ) bug factors(virulence and suscptibility of the pathogen you deal 2 with) drug factor ( its effect on a particular site other than another) 3 Host factor( immunity , morbidities) 4
presence of renal failure requires a dose reduction of
antimicrobials excreted primarily by the kidney (e.g., aminoglycosides, fluoroquinolones, trimethoprim, tetracycline, vancomycin,) except cefatriaxone
hepatic insufficiency requires a dose reduction of antimicrobials
excreted primarily by the liver (e.g., chloramphenicol, clindamycin, doxycycline, macrolides, metronidazole, rifampin, sulfamethoxazole, ceftriaxone, nafcillin) site factor : ex in meningitis I can choose one and exclude another 5 according to bbb
. Antimicrobials interact in a variety of ways when coadministered
DISC DIFFUSION
E- TEST Clinical laboratories typically report results using the recommended qualitative result categories of susceptible, intermediate-
. susceptible, and resistant based on the breakpoints set by CLSI Major mechanisms of antimicrobial resistance include drug inactivation (produces an enzyme) EX: betalactamase alteration in target site (as observed in MRSA when the penicillin- binding protein (PBP) is altered to PBP2a, coded for by the better- , known mecA gene) decreased permeability or efflux (as in the case of P. aeruginosa , that has developed resistance to the carbapenems) bypass of a metabolic pathway (; resistance to . trimethoprim/sulfamethoxazole)
plasmids and transposons; together these mobile genetic elements
. or “jumping genes” are known as resistance factors (R factors) Plasmids consist of a circular segment of extrachromosomal DNA . that can replicate itself A transposon is a segment of DNA that can insert itself in the chromosome and be transmitted between cells via a plasmid . ( transformation or conjugation) or even a virus (transduction) Antimicrobial Stewardship Antimicrobial stewardship programs are important components of antimicrobial resistance management in healthcare institutions The Joint Commission’s Eight Elements of Performance for an Antimicrobial Management Team Element of Performance. Leaders establish antimicrobial stewardship 1 as a priority
Education of staff and independent 2 practitioners in processing/ordering antimicrobials Education of patients and their families 3 Include core group members (ID physician, 4 IP, pharmacist, and ( practitioner Include core elements in program: leadership 5 , commitment accountability, drug expertise, action, tracking, reporting, and education Use organization-approved multidisciplinary 6 protocols Collect, analyze and report data on 7 antimicrobial stewardship team Take action on improvement activities in 8 antimicrobial stewardship program
