Ceutics - Penicillin (NN) PDF

PRINCIPLES OF ANTIMICROBIAL THERAPY · dig  PHARMACEUTICAL CONSIDERATIONS OF ANTIMICROBIALS (AM) Physicochemical properties (solubility, lipophilicity, charge, …) I Stability (stability in solution, acid-stability, storage stability, interactions)...

PRINCIPLES OF ANTIMICROBIAL THERAPY · dig  PHARMACEUTICAL CONSIDERATIONS OF ANTIMICROBIALS (AM) Physicochemical properties (solubility, lipophilicity, charge, …) I Stability (stability in solution, acid-stability, storage stability, interactions) Administration: suitable route of administration and drug delivery systems (oral, IV, IM, …) ADME: absorption, distribution, metabolism, excretion, protein binding PKs & pharmacodynamics of AM & relation to MIC  PHYSICOCHEMICAL PROPERTIES OF ANTIMICROBIALS have to be nonpolar- > to be absorped to the circulation. Solubility: 4 polar bioavalibility positively charged. Highly ionizable AMs (e.g., aminoglycoside polycations) are freely soluble in water, therefore not absorbed orally. - directly to the circulation. Some AMs (e.g., penicillin G) are insoluble in water, they can be administered in their soluble Na or K salts. IV IM- procain benzythine , Reducing the solubility of AMs can be intentionally done to mask their bitter taste (e.g., chloramphenicol palmitate) or to prolong their action (e.g., benzathine penicillin). Flame 117 in can'tgive infregently absorption Lipophilicity (Log P) reduce solubility to get actioneffect The development of more lipophilic AM derivatives improve their oral bioavailability (e.g., contain ( cloxacillin, dicloxacillin 2Ch and flucloxacillin are more bioavailable than oxacillin). C F - Clindamycin (7-chlorolincomycin) has higher log P value and better oral bioavailability than lincomycin  bioavalibility S.gg fynI solubility Ly logP lipo solidify perentrally ionized logP hydro bioavalibility Isle soluble soluble 1 taste 2 action  shelf o STABILITY CONSIDERATIONS OF ANTIMICROBIALS Some AM are acid stable and have high oral bioavailability (e.g., oral cephalosporins cefaclor, cefadroxil, cefprozil, cephalexin, ceftibuten) Some AMs are liable to degradation by the acidic pH in stomach. This can be overcome by: Developing acid-stable derivatives (e.g., penicillin V & ampicillin instead of Of penicillin G) can be administered orally. drivatives esters FAs Formulating enteric coated products (e.g., erythromycin) co - = alkalinizer Fosfomycin tromethamine: tromethamine (pH elevating agent) slows down the acid-catalyzed hydrolysis of fosfomycin better oral bioavailability. drevatives PerG Peanut perentrally enteric erythromycin agents int it pHelevating Fosfomycin tromethamine fosfygm.me one  Solution stability susp powder most antibiotics STABILITY CONSIDERATIONS OF ANTIMICROBIALS Not stable in solutions. AMs are mostly prepared as powders for reconstitution as they have stability oo problems in solution (e.g., oral penicillins). Procaine penicillin is formulated as stable aqueous suspension ready for use, while benzathine penicillin is marketed as dry powder for reconstitution with in G sterile water immediately before use. vial solution Not water additives adjusted PH - , many , A ready injection that is not a powder for reconstitution will be most stable at the pH at which it has been formulated (e.g., sulfamethoxazole/trimethoprim Infusion & m III IV infusion, pH 9-11). with sulfonamides diluted with talkaline not directly to the circulation => , 1153511. diluted Admixture of antibiotics with other drugs can accelerate their degradation. B e.g., acid-catalyzed hydrolysis penicillins is accelerated by the addition of acidic drugs. diluted Nacl does'd 8 1 s's É S Canula 1 JI.ws p g ty i 91 8551951 D sled J 6 Stability J 82 Stable diluted with Nacl directly in canula Stable for short period Should not mixed with anything find another vein  someimesI (blood ( ROUTES OF ADMINISTRATION 100 bioavalibility % > - drug reach the circulation. ORAL ANTIMICROBIALS (PO) OO Formulation of oral AM is a function of their solubility, acid stability and lipophilicity. Lipid-soluble drugs, such as metronidazole and rifampin, penetrate capillaries better than one water soluble drugs, such as beta-lactams, aminoglycosides, and glycopeptides. Oral AM formulations differ substantially in their bioavailability. Some antibiotics have 100% bioavailability asO IV level (e.g., fluoroquinolones, tetracycline, minocycline, doxycycline, DO 15 metronidazole, linezolid, isoniazid, rimethoprim-sulfamethoxazole, dapsone). 1 to O O Several AMs have very good oral bioavailability, but their oral doses are lower than the IV O doses as high oral doses can lead to excessive GI tract toxicity. oral- > ↓ close - side effects/toxicity tl Some AMs are not suitable for oral administration due to extensive gastric degradation (e.g., É penicillin G), first pass metabolism, poor bioavailability (aminoglycosides) perermi E > will - stay in stomach (time Some AMs have almost zero bioavailability when administered orally but take advantage of dependent this clinically to eradicate pathogens in the GI tract (e.g., vancomycin -locally and aminoglycosides).. distribution - > in the stomach - * zerobicavalibity- orally &BLC-stay > ulcers (side effects) orally 51g or_ gentamicin butstill can be used orally stay  ROUTES OF ADMINISTRATION PARENTERAL ANTIMICROBIALS The acid-unstable penicillin G is administered IV in the form of Na/K salt or IM as Susp procaine/benzathine penicillin. Some cephalosporins are only administered parenterally (e.g., cefotaxime, ceftazidime and ceftriaxone). some Itv2 orally mperetally cann't Some AMs with short half-life can be administered by IV infusion every 6-8h (e.g., egiven penicillins, carbapenems). However, frequent injection cause& phlebitis (inflammation _o e of veins). one shot frequently_ t.FI ↑ Estey While some AM are recommended to be injected as IV bolus, others are - inflammation recommended as slow infusion over several hours. -- Vancomycin is given as short-term intermittent infusion (1-2h) as rapid infusion can cause red neck syndrome. IV X - Vancomycin - > incusion.  UPO hpo Bacampicillin - ampicillin prodrug inactive active Bacampicillin is an ester prodrug for ampicillin. It is ANTIMICROBIAL - - more lipophilic better oral absorption. - - PRODRUGS - Tedizolid is a prodrug for linezolid allows& - - oral - administration. oral bioavalibility Tedizolid-linezolid prodrug i e msn.si PK rally IV - Max Conc at time zero.. Cmax tmax-twero Ouboly O PHARMACOKINETICS bioavalibility = 700 % OF AM - IV The pharmacokinetics of AMs are key to the effectiveness of the drugs in clinical practice. = Pk describes the time course of drug levels in body fluids as a - result of absorption, distribution, and elimination of a drug after - administration. - - O When the entire dose is administered by the IV route, G 100% of that dose is bioavailable. Cmax determined when Rates of IV administration can vary from a bolus infusion (in which the incusion is the total IV dose is given over a very short interval of time, eg, a minute or less) to a very slow infusion over many hours. completed Delivery of drugs by the IV route is complete by the end of the infusion, when a peak plasma level is achieved. - The height of the peak plasma drug level is determined by the rate - - of IV infusion, the size of the dose, the size of the drug's volume of - - - distribution, and its rate of elimination. - -.rate 1 of infusion 3. volume of distribution infusion - No absorption Cmax 2 size of the dose & Not same rate as IV. 4. rate of elimination 811m infusion Bidseverinfection bolus - severe cases ,rate , I conc in shorter duration , bolus or infusion. highest peak. PHARMACOKINETICS OF AM - IV ↓ conc. ↑ elimination bolus a Peak plasma drug levels will be the highest after bolus administration - - because the duration of infusion is too short for significant distribution or - m u ↑ elimination of the drug to occur. For these reasons, relatively rapid IV - administration is most often chosen for antimicrobial therapy of a patient who has severe infection. infusions - Slowing the rate of IV infusion allows distribution of the drug in the body - and drug elimination to take place, and consequently, lower peak plasma - drug levels occur. bolus - concentration dependent drug toxicities. Use of bolus administration, however, may be limited by concentration- - - peak dependent drug )( - toxicities (eg, red-person's syndrome, which is related to g rapid infusion of vancomycin). Also, bolus infusion will expose the vein through which the drug is infused to high drug concentrations that induce venous irritation and pain. For - > - distribution example, to avoid phlebitis when infused by peripheral vein, quinupristin/ blood- > tissue. dalfopristin must be infused using a [central venous catheter,] in which greater dilution of the drug will occur. - IV drug w/t conc - > central venous catheter.  same drug given orally IV willhavediff profiles diff bloodlevels bioavalibility - > ratio of systemic exposure of oral- IV PK OF ORAL ANTIMICROBIALS iVbolu not be complete. Because & - eleminate The extent of absorption of an orally administered AM may - absorption and distribution is taking place while a drug is being absorbed after oral = administration, peak plasma levels can be delayed and usually are not as high as those achieved by IV infusion. The ratio of the systemic exposure profile by oral absorption - to that of IV administration defines the1bioavailability.1 - - - Cma oae.ie.ie - Administration of a 500-mg AM by0 oral andOIV routes can lead to distinctively different blood levels. - - Because for some AMs, the response is linked to the peak concentration (Cmax) [I or the total exposure (area under - - the concentration-time curve [AUC]), factors that affect - absorption can affect AM response. response-Cmax Cactors affect absorption will affect response FACTORS AFFECTING PK OF AM 1 Factors affecting the oral absorption of ABs include:. 2 3 solubility, degradation by acid or proteolysis gut. - metabolism- - and first-pass liver metabolism,5influx and - - 6 efflux transporters as well as interaction with other. - - compounds or food. msn.nl i > in degradation. - - stability Some ABs are highly dependent on gastric acidity for - better adequate absorption (e.g., Itraconazole, Posaconazole suspension, Atazanavir, Rilpivirine). It is thus important to avoid concomitant use of drugs that raise gastric pH - (antacids, proton pump inhibitors, histamine-2 receptor - - - Pt with ulcer takingprotonpump inhibitor - antagonists) when patients are started on these drugs. - - stops acid secreations bioavalibility of the gastric acid dependentantibiotic. antacids 1 2. proton pump inhibitors 3. histamine C - FACTORS AFFECTING PK OF AM A. Food has no effect on the bioavailability of the fluoroquinolones, - metronidazole, minocycline, doxycycline, linezolid, and trimethoprim-sulfamethoxazole. B Food can improve the absorption of some AM (e.g., Posaconazole - suspension, Atazanavir, Darunavir, Rilpivirine). Bioavailability of clofazimine is increased 2-fold by& - high-fat meals. C. soooo AM absorption can be also impaired by food (e.g., rifampin, - - in isoniazid, pyrazinamide, erythromycin and azithromycin). Food - decreases - the Cmax of rifampin, therefore it is recommended to be administered 1-2 h before/after meals. However, the - administration of rifapentine tablets with fatty meal increases the AUC. chelation 2] Tetracyclines and fluoroquinolones can bind to coadministered minerals such asCo- - calcium, iron, aluminum, and zinc reduced absorption. - Care fett A 3 2n 2  PK & TROUGH CONCENTRATION Idlijdrugsi Imm Trough concentration of some AMs should be - monitored. => 5 ⑨ Eige stability /I oemmsensiikriicoEmsaoemesna.ee Steady-state vancomycin trough levels O O 15 O µg/mL increased incidence of nephrotoxicity. - 10 15mcglm vancomycin  ATimedependent PHARMACOKINETIC/PHARMACODYNAMIC RELATIONSHIPS conc dependent TIME- VS CONCENTRATION-DEPENDENT ACTIVITY - = - To help define the response to AM treatment, a Cmacc combination of PK parameters and bacterial sensitivity minimum inhibitory (MIC) were recognized : infusion > - distribution concentration 9gy.EE For certain AMs, activity against microorganisms correlates with the duration of time that the concentration of the drug 1111 - time conc remains above the MIC (time-dependent - 1= activity, T > MIC ). metabolism For other AMs, antibacterial activity correlates with the ratio of the peak concentration of the drug to the MIC Tax -bolus (concentration-dependent activity, Cmax/MIC ). , immediate For some AMs, the best predictor of activity is the ratio of - MIC (Minimum Inhibitory the area under the concentration–time curve (AUC) to the concentration) is a measure of the MIC te (AUC/MIC). e - potency of an antimicrobial drug. =>  No rule for it , dependent on the AMitself. B-lactam-time dependent. TIME- VS CONCENTRATION- DEPENDENT ACTIVITY The practical implications of Both these findings are in the design of antibiotic dosing schedules: Aminoglycosides are now penicillin short t fregentadministration frequently given as a single __ bolus large dose daily to leverage the Timedependent concentration-dependent activity. Some clinicians are administering beta-lactam drugs such as ceftazidime as immediate controled continuous or prolonged infusion infusions because of their time- dependent activity.  effecting :8 & concentration below M1 · & gloding POST ANTIBIOTIC. EFFECT (PAE) > - below MI , butthere is effect. PAE refers to the persisting 5 1 suppression of bacterial growth (a delay before microorganisms recover and reenter a log-growth period) after a limited exposure to an antimicrobial agent. or The period of time after which the stillaffectbacteria antimicrobial concentration has Wt fallen below the MIC, during which cy evenbelow MIC c meat growth of the target bacteria is suppressed. affect frequency of the doses. nodrug conc 1 39 butthere's effect way Tsigis dosing schedule  species dependent drug dependent - (bacterial) POST ANTIBIOTIC EFFECT (PAE) PAE is species and drug dependent: Aminoglycosides, metronidazole & fluroquinolones exhibit the most toxicity sideeffects spoof pronounced PAEs (2 to 6 h against gram-negative bacilli). 1-1 (+ ) - > - X PAEIhr -Lactam antibiotics (except for imipenem) produce little or no PAE against These gram-negative organisms but induce 2-h PAE against gram-positive organisms. PAE should be considered for antimicrobial dosing schedules. AMs with long PAE can be dosed less frequently than an antimicrobial agent lacking a PAE. Alternatively, AMs with little or no PAE may be most effective if it is given as a continuous infusion so that the serum concentration always exceeds the MIC. DISTRIBUTION OF ANTIMICROBIALS c Most sites of infection are extravascular, and treatment of infections in these sites depends on movement of the antimicrobial agent out of the bloodstream and into interstitial and sometimes intracellular fluid. The ability of a drug to do so depends on tissue-related factors (such as perfusion to the tissues, the surface area of the tissue's vasculature, tight junctions or capillary pores) and drug-related factors (such as lipid solubility, molecular size, the drug's pKa, and plasma protein binding). The AM concentration in tissues can be similar to, lower than, or greater than that in the blood. Thus, AM may be more or less effective in a particular tissue than would be expected based on its concentrations in the blood. Microbiological susceptibility testing does not account for distribution and is based on achievable bloodstream concentrations. For example, the AM concentrations in the cerebrospinal fluid (CSF) are typically much lower than their bloodstream concentrations, limiting their effectiveness in the treatment of meningitis. On the other hand, the macrolide antibiotics are more effective in lung infections based on their blood levels, because they concentrate in pulmonary macrophages. PATIENT CHARACTERISTICS AFFECTING DISTRIBUTION OF AM Conditions that reduce blood flow to tissues can reduce antibiotic concentrations at the site of infection. Patients with severe infections can develop abscesses or areas of dead and devitalized tissue; distribution of antibiotics into these “protected” sites of infection can be significantly impaired. These patients are perfect setups for treatment failure and development of resistance. > - locally. The extent of systemic absorption of oral vancomycin is unpredictable and usually minimal, and according to current guidelines absorption does not occur. However, in presence of bowel inflammation, or if high doses are used for prolonged periods, systemic absorption may occur, resulting in therapeutic levels of vancomycin. Obesity: another important consideration is the extent to which AMs distribute into adipose tissue. Depending on the characteristics of the AM, it is possible to underdose patients or overdose them. Thus, you may see = - recommendations for AM dosing based on body weight. depending on the - site it works in ANTIMICROBIALS & PROTEIN BINDING AMs bound to proteins are not able to diffuse across membranes into different tissues; thus, antibiotics that are highly protein bound are less likely to reach effective concentrations in certain tissues (such as the CNS). Daptomycin high protein binding, prolonged t ½ , low distribution. can be used to manage time dependent drugs. The antimicrobial activity & elimination are limited to the unbound fraction of the drug. The free/unbound drug concentration should exceed the minimal inhibitory concentration (MIC) at steady state. In certain cases, despite apparently adequate total plasma levels of highly protein-bound drugs, the concentration of free (ie, active) drug might be less than the MIC of the pathogen, which will necessitate the use of higher doses. ↑ binding Iti & distribution. ANTIMICROBIALS & PROTEIN BINDING Ceftriaxone undergoes extensive binding to plasma proteins (albumin) longer half-life (i.e. the drug circulates for longer duration with the blood). Ceftrioxone concentration < 5% enters the CNS in patients with meningitis. However, large doses (2 g twice daily in adults) of ceftriaxone can be given safely to adults, resulting in high serum levels (peak levels of around 200 mg/L). In addition, the MIC is very low (1 mg/L or less); thus, a concentration far in excess of the organism’s MIC can be obtained (200 mg/L × 5% = 10 mg/L). METABOLISM & EXCRETION OF AM Renal excretion of drugs and their metabolites is determined by three processes: glomerular filtration, tubular secretion, and passive tubular reabsorption. > - renal. Most beta-lactams, aminoglycosides, tetracycline, vancomycin, - daptomycin, and sulfonamides are renally excreted either by glomerular filtration, tubular secretion, or both. The aminoglycosides, tetracycline, and vancomycin are excreted primarily by glomerular filtration. Tubular secretion occurs by way of two active transport mechanisms: one for anions (weak organic acids) and one for cations (weak organic bases). METABOLISM & EXCRETION OF AM PROBENECID BLOCKS OAT Competition between drugs for the carriers can occur within each transport system. The organic acid transport mechanism contributes to the elimination of many beta-lactam antibiotics, fluoroquinolones, and some sulfonamides. Competition between probenecid and these beta- lactams, fluoroquinolones, acyclovir, and sulfonamides = for the organic acid transport carriers can prolong the blocks one of the ways of duration that these antimicrobial drugs are in the body. the renal excretion In other words, Probenecid decreases the tubular secretion of these AM by blocking the organic acid transpoter (OAT) pathway higher plasma level, longer t ½ of the AM. - > accumulatio- > toxicity.  active metabolites - i Excreted unchanged > - Excreted metabolized - - inactive metabolites METABOLISM & EXCRETION OF AM - DYSFUNCTION & Many antimicrobials are excreted from the body, either in the urine or feces, unchanged (i.e. in the same form as they were administered). When an AM is excreted unchanged, it can reach very high concentrations in the area in which it is eliminated, making it potentially more effective for infections in those systems than would be anticipated based on blood concentrations. For example, the concentrations of nitrofurantoin achieved in the blood and tissues are generally inadequate to inhibit bacterial growth. However, it is removed from the bloodstream by the kidneys and accumulates in the bladder until its final clearance. The concentrations achieved in the bladder are manyfold higher than those in the bloodstream, making nitrofurantoin an effective drug for treatment of bladder infections. ↑ conc in the Kidney can treat UTI. > ->. In people whose kidney or liver function has declined, the "normal" dosage of a drug may result in accumulation of the drug if the dosage or the dosing interval is not altered. When the body does not inactivate the AM, an important consideration is to appropriately reduce the administered dose if there is damage to the organ responsible for excreting the drug. For example, the doses of most beta-lactams should be reduced for patients with kidney dysfunction to avoid accumulation of toxic levels of the drug. METABOLISM & EXCRETION OF AM - DYSFUNCTION Other AM may be extensively transformed by the body prior to their excretion. In certain cases, active metabolites can be obtained (e.g., hepatic metabolism of the antiprotozoal drugs quinine, chloroquine by CYP3A4). Dose has to be adjusted with hepatic impairment. Sometimes, the metabolites are more active than the original compound. In other cases, inactive metabolites are formed no dose adjustment is necessary if there is dysfunction in the excretion site. Some drugs or their metabolites that are excreted in bile may be the drug goes from 61-liver reabsorbed into the bloodstream to the GIT and recycled by a process called enterohepatic circulation. then returns back to the 61 ↑ exposure ↑ absorption.  Sooooo PENICILLINS PHARMACEUTICAL CONSIDERATIONS OF PENICILLINS Solubility Stability Route of administration ADME  Penicillin G Water insoluble Acid labile Cannot be absorbed orally Penicillinase sensitive Pen G Na/K salts Water-soluble acid instable IV very hydrophilic - > X absorption. Benzathine Pen G dry powder = Month long C. Depot formulation prolonged antimicrobial activity for 26 days release The formulation is a dry powder for reconstitution with sterile water immediately before use. To be administered IM & should NOT be given IV due to serious toxicity Procaine Pen G suspension. > contain - additives Viscous opaque suspension ready for immediate use without reconstitution or dilution to be injected intramuscularly. Prolonged release of Pen G over 1 week. Shorter t ½ than Benzathine Pen G Penicillin V orally Used as water soluble K salt Acid stable Administered orally Rapidly absorbed (Cmax 30-60 min) Short t ½ frequent administration ↓ bioavalibility Food interferes with Pen V absorption administered 0.5 h before / 2 h after meals Penicillinase sensitive To Ampicillin Aminopenicillins Amino Pen G changed at pH 7 = Acid stable Highly polar, zwitter ion at neutral pH - Orally administered Acid stable Administered orally or IM Hydrolyzed by eta-lactamases Low bioavailability due to polarity Can be combined with eta-lactamase Penicillinase sensitive inhibitors (e.g., amoxicillin clavulanate, ampicillin sulbactam). 2 Amoxicillin More stable in acid than ampicillin Administered orally better oral absorption than ampicillin (2-2.5 time higher) but also has to be taken frequently. 3. Bacampicillin add ester. ↑absorption ↑ logp value O Ester prodrug of ampicillin. = More lipophilic complete oral absorption PENICILLIN/BETA-LACTAMASE INHIBITOR COMBINATIONS AGENTS: AMPICILLIN/SULBACTAM, AMOXICILLIN/CLAVULANATE, PIPERACILLIN/TAZOBACTAM Beta-lactamase inhibitors counter beta-lactamases; these drugs mimic the structure of beta-lactams but have little antimicrobial Ampicillin sulbactam activity on their own. they bind to the so -B-lactamst inhibitors/ 13 structure /I enzyme & inhibit its work. They bind to beta-lactamases irreversibly, preventing the beta- Unasyn lactamase from destroying any beta-lactams that are Administered IV / IM coadministered and enabling the therapeutic beta-lactam to be effective. Amoxicillin clavulanate Unlike the other members of this class, amoxicillin/clavulanate is available orally. The dose of clavulanate is fixed in all oral dosage Augmentin forms (125 mg). the dose is constant even if I changed the amoxacillin dose > - & the dose , required to block the enzyme. & Oral / IM Various doses are available, but higher doses are associated with more diarrhea. PENICILLINASE RESISTANT PENICILLINS Acid unstable Methicillin Not administered orally Higher acid stability relative to methicillin Nafcillin Oral, IM, IV Acid stable Oxacillin Oral More lipophilic (Cl) better oral absorption Cloxacillin Lower dose 2Cl higher lipophilicity higher Dicloxacillin bioavailability lower dose ↓ side effects. - Flucloxacillin 1 Cl + 1 F, similar properties like dicloxacillin ADME Penicillin Oral bioavailability Pen G = < 30 % - > lowest. Pen V 60-70 % Absorption Ampicillin 30-55 % Amoxicillin 74-92 % - > highest - Effect of food: Penicillin V is better absorbed in the fasting state. Amoxicillin is equally well absorbed with food or in the fasting Metabolism state. However, when amoxicillin is combined with clavulanate, absorption of clavulanate potassium is enhanced when it is administered at the start of a meal. Short le t ½ = 30 - 90 min Excretion Frequent administration Frequent injection phlebitis - inflammation of veins. solved by benzatinean ADME Absorption Renal: Glomerular filtration If excreted unchanged/as active metabolite dose adjustment in renal dysfunction Metabolism > blocks the transporter -. used to & treat gout Probenecid decreases the tubular Excretion secretion of penicillins by blocking OAT -sk (turic acid pathway higher plasma level, longer t1/2 penicillin will accumulate dose ha to be > - adjusted. THANK YOU