ANTIMICROBIAL THERAPY V. Geršl According to:

ANTIMICROBIAL THERAPY V. Geršl According to: - H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore: Pharmacology, 5th ed. - R.A.Howland, M.J.Mycek: Lippincott’s Illustrated Reviews: Pharmacology, 3rd ed. Antimicrobial drugs (ATBs) - effective in the treatment of infections because of their selective toxicity-the ability to kill an invading microorganismwithout harming the cells of the host. The selective toxicity is relative – it is necessary to control the concentration of ATB - to attack the microorganism while still being tolerated by the host. Selective antimicrobial therapy – advantage of the biochemical differences that exist between microorganisms and human beings. SELECTION OF ANTIMICROBIAL AGENTS depends on: 1) the organism´s identity, 2) its susceptibility to an agent, 3) site of the infection, 4) patient factors, 5) safety of the agent, 6) cost of therapy.

A.Identification and sensitivity of the organism is central to the selection of the proper drug. It is essential to obtain a sample culture of the organism prior to initiating treatment if possible. Empiric therapy prior to organism identification: Ideally - to treat when the organism was identified and its susceptibility established. However, acutely ill patients usually require immediate treatment (after specimens for laboratory analyses are obtained but before the results of the culture are available). The choice of drugin the absence of sensitivity data - influenced by patient (e.g., age), site of the infection, and results of the Gram stain. Possible - initiate empiric therapy with ATB or a combination of ATB covering infections by both G+ and G- microorganisms.

B. Selecting a drug:In the absence of susceptibility- influenced by the site of infection, and the patient's history (hospital x community-acquired, patient's travel record and age). Broad-spectrum - when the identity of the organism is unknown or the site makes a polymicrobial infection likely. Also guided by known association of particular organisms with infection (e.g., a G+ coccus in the spinal fluid of a newborn infant - most likely Streptococcus agalactiae; G+ coccus in older (cca 40 years) patient - probablyS. pneumoniae). C. Determination of antimicrobial susceptibility of infective organismsThe susceptibility of bacteria to specific ATB - guide in choosing therapy. Some pathogens (streptococcus pyogenes, Neisseria meningitidis) - usually have predictable susceptibility to certain ATB. Most G- bacilli, enterococci, and staphylococcal species - often unpredictable susceptibility.

1. Bacteriostatic vs. bactericidal drugs: Bacteriostatic - arrest the growth and replication of bacteria at serum levels achievable in the patient -they limit the spread of infection while the body's immune system attacks, immobilizes, and eliminates the pathogens. If the drug is removed before the immune system has scavenged the organisms, enough viable organisms may remain to begin a second cycle of infection. Bactericidal -kill bacteria at drug serum levels achievable in the patient. - often drugs of choice in seriously ill patients. It is possible for ATB to be bacteriostatic for one organism and bactericidal for another. 2. Minimum inhibitory concentration (MIC): the lowest concentration of ATB that inhibits bacterial growth. Effective antimicrobial therapy - ATB concentration in body fluids should be greater than the MIC. 3. Minimum bactericidal concentration (MBC): the lowest concentration of antimicrobial agent that results in a 99.9 % decline in colony count after overnight broth dilution incubations.

D. Effect of the site of infection on therapy: The blood-brain barrier- the single layer of tile-like endothelial cells fused by tight junctions that impede entry from the blood to the brain of molecules, except those that are small and lipophilic. 1. Lipid solubility of the drug: Compounds without a specific transporter must pass from the blood to the CSF. The lipid solubility is very important. E.g., lipid-soluble quinolones - penetration to the CNS. Ionizedb-lactam antibiotics (PNC) have limited penetration through the intact BBB. In infections (meningitis) - local permeability is increased. Some b-lactam ATBs can then significantly enter the CSF. 2. Molecular weight: Low M.w. - enhanced ability to cross the BBB; high M.w. (vancomycin) penetrate poorly. 3. Protein binding of the drug: A high degree of protein binding in the serum - limited entry into the CSF. The amount of free (unbound) drug in serum, rather than the total amount is important for CSF penetration.

E. Patient factors 1. Immune system: Elimination of infecting organisms from the body depends on an intact immune system. Decreased e.g. in: alcoholism, diabetes, immunosuppresion, malnutrition, advanced age.Higher-than-usual doses of bactericidal agents or longer courses of treatment are required. 2. Renal dysfunction: Poor kidney function (10 % or less of normal) - accumulation in the body of ATB eliminated by this route - serious adverse effects – it is necessary to adjust the dose or the dosage schedule of ATB. Direct monitoring of serum levels of some ATB (e.g., aminoglycosides) is preferred to identify maximum and minimum values. The renal function decreases with age. ATB that undergo extensive metabolism or are excreted via the biliary route may be favored. 3. Hepatic dysfunction: ATB that are concentrated or eliminated by the liver (e.g., erythromycin and tetracycline) - contraindicated patients with liver disease.

4. Poor perfusion: Decreased circulation (e.g., in the lower limbs of a diabetic) - reduced amount of ATB - difficult to treat. 5. Age:Renal or hepatic elimination processes are often poorly developed in newborns - neonates particularly vulnerable to the toxic effects of chloramphenicol and sulfonamides. Young children – do not use TTC. 6. Pregnancy:All ATB cross the placenta. Adverse effects to the fetus are rare, except for tooth dysplasia and inhibition of bone growth encountered with the tetracyclines. But - some anthelmintics are embryotoxic and teratogenic. Aminoglycosides- ototoxic effect on the fetus. 7. Lactation:Drugs may enter the nursing infant via the breast milk.The total dose to the infant may be enough to cause problems.

F. Safety of the agent • Toxicity of the drug: • Many ATB (e.g. penicillins), are among to least toxic of all drugs because they interfere with a site unique to the growth of microorganisms. • Other ATB (e.g. chloramphenicol) - less specific; potential for serious toxicity. • - Patient factors. • G. Cost of therapy

ROUTE OF ADMINISTRATION Oral route– mild infections, outpatient basis. If i.v. therapy initially - the switch to oral agents occursas soon as possible. Some ATB (e.g., vancomycin, the aminoglycosides, amphotericin) - poorly absorbed from GIT -adequate serum levels cannot be obtained by oral administration. Parenteral administration- drugs that are poorly absorbed from GIT, treatment of serious infections.

RATIONAL DOSING • Rational dosing of ATB - based on their pharmacodynamics (relationship of drug concentrations to antimicrobial effects) and their pharmacokinetics • Important pharmacodynamic properties with significant influence on the frequency of dosing: • concentration-dependent killing • post-antibiotic effect.

Concentration-dependent killing SomeATB (aminoglycosides, fiuoroquinolones)- significant increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64-fold the MIC of the drug for the infecting organism. Giving such drugs by a once-a-day bolus infusion achieves high peak levels, favoring rapid killing of the infecting pathogen. Other ATB (b-Iactams, glycopeptides, macrolides, clindamycin)do not exhibit this property; i.e., increasing the concentration of ATB to higher multiples of the MIC does not significantly increase the rate of kill. The clinical efficacy of ATB that have a nonsignificant, dose-dependent killing effect is best predicted by the percentage of time that blood concentrations of a drug remain above the MIC. Called -concentration-independent or time-dependent killing.E.g., for PNC and cephalosporins, dosing schedules that ensure blood levels greater than MIC for 60 – 70 % of the time was showed to be clinically effective. Thus, severe infections are best treated by continuous infusion of these agents rather than by intermittent dosing.

Post-antibiotic effect(PAE) A persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC. Antimicrobial drugs with a long PAE (several hours) often require only one dose per day.E.g., aminoglycosides and fluoroquinolones, particularly against gram-negative bacteria.

CHEMOTHERAPEUTIC SPECTRA - Narrow spectrum (act only on a singleor a limited group of microorganisms, e.g. INH is active only against mycobacteria). - Extended spectrum (effective against G+ organisms and also against a significant number of G- bacteria - e.g., ampicillin has extended spectrum because it acts against G+ and G- bacteria). - Broad spectrum (e.g. tetracycline and chloramphenicol affect a wide variety of microbial species). Their administration can drastically alter the normal bacterial flora and precipitate a superinfection of an organism, e.g., candida. COMBINATIONS OF ANTIMICROBIAL DRUGS It is better to treat patients with the single agent that is most specific for the infecting organism. It- reduces the possibility of superinfection, - decreases the emergence of resistant organisms, - minimizes toxicity. However, situations in which combinations of drugs are employed do exist (e.g., the treatment of tuberculosis).

DRUG RESISTANCE Bacteria are said to be resistant to an antibiotic if their growth is not halted by the maximal level of that antibiotic that can be tolerated by the host. Some organisms are inherently resistant to an antibiotic (e.g., gram-negative organisms are inherently resistant to vancomycin). However, microbial species that are normally responsive to a particular drug may develop more virulent, resistant strains through spontaneous mutation or acquired resistance and selection. Some of these strains may even become resistant to more than one antibiotic. A. Genetic alterations leading to drug resistance Resistance develops due to the ability of DNA to undergo spontaneous mutation or to move from one organism to another. - Spontaneous mutations of DNA: Chromosomal alteration by insertion, deletion, or substitution of one or more nucleotides within the genome. - DNA transfer of drug resistance:- of particular concern is resistance acquired due to DNA transfer from one bacterium to another.

B. Altered expression of proteins in drug-resistant organisms • Modification of target sites:E.g., S. Pneumoniae resistance to b-lactam ATB involves alterations in one or more of the major bacterial penicillin-binding proteins - decreased binding of ATB. • - Decreased accumulation:Decreased uptake or increased efflux of an antibiotic- drug is unable to access to the site of its action in sufficient concentrations to injure or kill the organism. • - Enzymic inactivation: The ability to destroy or inactivate ATB. • Examples of ATB-inactivating enzymes: 1) beta-lactamases ("penicillinases") hydrolytically inactivate the b-Iactam ring of penicillins, cephalosporins, and related drugs; 2) acetyltransferases- transfer an acetyl group to ATB (inactivation of chloramphenicol, aminoglycosides; and 3) esterases that hydrolyze the lactone ring of macrolides. • Multiple drug resistance - significant problem (e.g., methicillin-resistant Staphylococcus aureus is also resistant to all ATBs except vancomycin and possibly ciprofloxacin, rifampin and imipenem/cilastatin).

PROPHYLACTIC ANTIBIOTICS The use of ATB for the prevention rather than the treatment of infections. But, the indiscriminate use of ATBs can result in bacterial resistance and superinfection, »»»prophylactic use is restricted to clinical situations where benefits outweigh the potential risks. Examples. - Prevention of streptoccocal infections in patients with history of rheumatic heart disease. Patients may require years of treatment. - Pretreatment of patients undergoing dental extractions who have implated prosthetic devices (e.g., artificial heart valves) to prevent seeding of the prosthesis. - Prevention of tuberculosis or meningitis in those who are in close contact with infected patients. COMPLICATIONS OF ANTIBIOTIC THERAPY - Hypersensitivity - Direct toxicity - Superinfections

Classification of some antibacterial agents by their sites of action. THFA = tetrahydrofolic acid; PABA = p-aminobenzoic acid CELL WALL CELL MEMBRANE DNA Inhibitors of cell membrane function THFA Ribosomes Isoniazid Amphotericin B mRNA PABA Inhibitors of nucleic acid function or synthesis Inhibitors of protein synthesis Inhibitors of cell wall synthesis Inhibitors of metabolism Tetracyclines Aminoglycosides Macrolides Clindamycin Chloramphenicol Fluoroquinolones Rifampin b-Lactams Vancomycin Sulfonamides Trimethoprim (according to Lippincott´s Pharmacology, 2006)

Summary of antimicrobial agents affecting cell wall synthesis INHIBITORS OF CELL WALL SYNTHESIS b-LASTAMASE INHIBITORS Clavulanic acid Sulbactam Tazobactam OTHER ANTIBIOTIC b-LASTAMASE ANTIBIOTIC Bacitracin Vancomycin CARBAPENEMS MONOBACTAMS PENICILLINS CEPHALOSPORINS Imipenem/cilastatin Meropenem* Ertapenem Amoxicillin Ampicillin Cloxacillin Dicloxacillin Indanyl carbenicillin Methicillin Nafcillin Oxacillin Penicillin G Penicillin V Piperacillin Ticarcillin Aztreonam 3rd GENERATION 4th GENERATION 1st GENERATION 2nd GENERATION Cefadroxil Cefazolin Cephalexin Cephalothin Cefaclor Cefamandole Cefprozil Cefuroxime Cefotetan Cefoxitin Cefdinir Cefixime Cefoperazone Cefotaxime Ceftazidime Ceftibuten Ceftizoxime Ceftriaxone Cefepime (according to Lippincott´s Pharmacology, 2006)

INHIBITORS OF CELL WALL SYNTHESIS Selectively interfere with synthesis of the bacterial cell wall-a structure that mammalian cells do not possess. The cell wall is a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. To be maximally effective, these agents require actively proliferating microorganisms. Little or no effect on bacteria that are not growing !! The most important:beta-lactam antibiotics (named after the beta-Iactam ring that is essential to their activity) and vancomycin

PENICILLINS 1928, A. Fleming Belong among the most widely effective ATBs and also the least toxic drugs known - increased resistance limited their use. The nature of their side chain affects the spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes (b-Iactamases). A. Mechanism of action Bactericidal - they interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage) - osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. Effective only against rapidly growing organisms that synthesize a peptidoglycan cell wall. Inactive against organisms devoid of this structure(e.g., mycobacteria).

1. Penicillin-binding proteins: PNCs inactivate proteins on the bacterial cell membrane. These penicillin-binding proteins (PBPs) are enzymes involved in the synthesis of the cell wall. Exposure to PNC - not only prevent cell wall synthesis, but also lead to morphologic changes or lysis of susceptible bacteria.Alterations in some of these target molecules - resistance to PNCs.[Methicillin-resistant Staphylococcus aureus (MRSA) apparently arose because of such an alteration.] 2. Inhibition of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains. PNCs inhibit this transpeptidase-catalyzed reaction. 3. Production of autolysins: G+ cocci produce degradative enzymes (autolysins - that participate in the remodeling of the bacterial cell wall). In the presence of PNC -the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Antibacterial effect of a PNC - the result of both inhibition of cell wall synthesis and destruction of cell wall by autolysins.

Antibacterial spectrum The antibacterial spectrum is determined, in part, by their ability to cross the bacterial peptidoglycan cell wall and to reach the penicillin-binding proteins. In general, gram-positive microorganisms have cell wall that are easily traversed by PNC and therefore (in the absence of resistance) are susceptible to these drugs. Gram-negative microorganisms have an outer lipid membrane surrounding the cell wall - a barrier to the water-soluble PNCs. This presents a barrier to the water-soluble PNCs that cannot reach the site of action. However, gram-negative bacteria have proteinsinserted in the lipopolysaccharide layer that act as water-filled channels(porins) that permit transmembrane entry. [Pseudomonas aeruginosa lacks porins, making these organisms intrinsically resistant to many antimicrobial agents.] Note: For this reason, PNCs have little use in the treatment of intracellular pathogens.

1. NATURAL PENICILLINS a. PENICILLIN G (benzylpenicillin) - infections caused by a number of gram-positive and gram-negative cocci,gram-positive bacilli, and spirochetes. Susceptible to inactivation by beta-lactamases. b. PENICILLIN V - a spectrum similar to penicillin G, but it is not used for treatment of septicemia because of its higher minimum bactericidal concentration (MLC). Penicillin V is more acid-stable than penicillin G.

2. ANTISTAPHYLOCOCCAL PENICILLINS: METHICILLIN NAFCILLIN OXACILLIN CLOXACILLIN DICLOXACILLIN penicillinase-resistant PNCs Use: treatment of infections caused by penicillinase-producing staphylococci. Methicillin-resistant strains are usually susceptible to vancomycin, and possibly to ciprofloxacin, rifampin.

3. EXTENDED SPECTRUM PENICILLINS: AMPICILLIN and AMOXICILLIN: Destroyed by -lactamases !!! Antibacterial spectrum similar to penicillin G, but are more effective against gram-negative bacilli - extended-spectrum PNCs. Ampicillin - drug of choice for the gram-positive bacillus Listeria monocytogenes. Widely used in the treatment of respiratory infections; amoxicillin is employed prophylactically by dentists for patients with abnormal heart valves who are to undergo extensive oral surgery. Resistance - a problem because of their inactivation by plasmid-mediated penicillinase (E. coli and H. influenzae - frequently resistant). Formulation with a beta-lactamase inhibitor (e.g. clavulanic acid, sulbactam) can protect the PNC from enzymatic action.

4.ANTIPSEUDOMONALPENICILLINS: • CARBENICILLIN • TICARCILLIN • PIPERACILLIN • S. aureus are resistant. • Piperacillin is the most potent. • Effective against many G- bacilli, ineffective against Klebsiella (it constitutes penicillinase). • Formulation of ticarcillin or piperacillin with clavulanic acid or tazobactam extends the antimicrobial spectrum (i.e. it includes penicillinase-producing organism).

5. ACYLUREIDO PENICILLINS: • MEZLOCILLIN • also effective against E. aeruginosa as well as a large number of gram-negative organisms. It is susceptible to breakdown by beta-lactamase. • AZLOCILLIN • 6. REVERSED SPECTRUM PNCs:MECILLINAM • More potent against Gram-negative enteric bacteria, hydrolyzed by • beta-lactamases. Pivmecillinam is a pro-drug, hydrolyzed to mecillinam.

Penicillins and aminoglycosides: The antibacterial effects of all the b-Iactam antibiotics are synergistic with the aminoglycosides. Because cell wall synthesis inhibitors alter the permeability of bacterial cells, these drugs can facilitate the entry of other ATBs (aminoglycosides). This can result in enhanced antimicrobial activity. These drug types should never be placed in the same infusion fluid, because on prolonged contact, the positively charged aminoglycosides form an inactive complex with the negatively charged PNCs.

C. Resistance • Natural resistance - organisms that lack the peptidoglycan cell wall • (e.g. mycoplasma) or have cell wall that is impermeable to the drug. • Acquired resistance to PNCs by plasmid transfer - clinical problem. • Beta-lactamase activity: Enzymes hydrolyze the cyclic amide bond • of the beta-lactam ring - loss of bactericidal activity. Enzymes are • constitutive or (more commonly) acquired by the transfer of plasmids. • Some of the beta-lactam ATBs are poor substrates for beta-lactamases • and resist cleavage - they have activity against beta-lactamase • producing organisms. • - Decreased permeability of PNCs through the outer cell membrane • prevents reaching the target penicillin-binding protein.The presence of an efflux pump can also reduce the amount of intracellular drug. • - Altered penicillin binding proteins: Modified PBPs show a lower • affinity for beta-lactam antibiotics, requiring greater concentrations • of the drug to effect binding and inhibition of bacterial growth.

Pharmacokinetics • Administration: The route of administration of a b-Iactam antibiotic is determined by the stability of the drug to gastric acid and by the severity of the infection. • E.g.: Penicillin V, amoxicillin, amoxicillin+clavulanic acid are only available as oral preparations. • Others are effective by the oral, IV, or IM routes. Some PNCs only IV or IM. • b. Depot forms:Procaine penicillin G and benzathine penicillin G- administered IM; serve as depot forms. Slowly absorbed into the circulation and persist at low levels over a long time period.

2. Absorption: Most of PNCs incompletely absorbed after oral administration and reach the intestine in sufficient amounts to affect the composition of the intestinal flora. However, amoxicillin is almost completely absorbed »»» it is not appropriate therapy for the treatment of salmonella-derived enteritis (therapeutically effective levels do not reach the organisms in the intestinal crypts). Absorption of PNC G and all the penicillinase-resistant PNCs is impeded by food in the stomach »»» they must be administered 30-60 minutesbefore meals or 2-3 hours postprandially. Other PNCs are less affected by food.

3. Distribution: Distribution of the free drug is good. All PNCs cross the placental barrier but none have been shown to be teratogenic. Penetration into certain sites (e.g. bone or cerebrospinalfluid) is insufficient for therapy, unless these sites areinflamed. During the acute phase (first day), the inflamed meninges are more permeable to PNC »»» increased ratio in the amount of drug in CNS compared to the amount in the serum. As the inflammation subsides, permeability barriers are reestablished.Levels in the prostate are insufficient to be effective against infections. 4. Metabolism:Host metabolism of the beta-Iactam antibiotics is usually insignificant.

5. Excretion: The primary route - tubular secretion and glomerular filtrationof the kidney. Patients with impaired renal function - adjust dosageregimens ! T1/2 of penicillin G can increase from a normal of 0.5-1.0 hour to 10 hours in renal failure. Probenecid inhibits the secretion of penicillins !! Nafcillin- eliminated primarily through the biliary route. [Note: This is also the preferential route for the acylureido penicillins in cases of renal failure.] PNCs are also excreted into breast milk and into saliva.

E. Adverse reactions: PNCs are among the safest drug, although adverse reactions do occur. - Hypersensitivity:The most important. The major cause is metabolite, penicilloic acid, which reacts with proteins and serves as a hapten to cause an immune reaction. Cca5% of patients have some kind of reaction(from urticaria to angioedema and anaphylaxis). Cross-allergic reactions can occur among the beta-lactam antibiotics ! - Diarrhea: Caused by a disruption of the normal balance of intestinal microorganism, a common problem. Especially in agents that are incompletely absorbed or with extended spectrum.Also pseudomembranous colitis may occur.

- Nephritis: Acute interstitial nephritis in high doses of methicillin. • Neurotoxicity:PNCs are irritating to neuronal tissue and can provoke • seizures if injected intrathecally or if very high blood levels • are reached: Epileptic patients are especially at risk. • - Platelet dysfunction:»»» decreased agglutination (observed with • the antipseudomonal PNCs and, to some extent wit penicillin G). • Concern when treating patient predisposed to hemorrhage or • receiving anticoagulants. • Cation toxicity: PNCs generally administered as the Na or K salt. • Toxicity may be caused by the large quantities of Na or K. • - Hoigné syndrom (if the suspension of PNC is by mistake injected • i.v. »»» embolisation of pulmonary veins »»» tachypnea, anxiety, dyspnea) • - Nikolau’s syndrom (suspension of PNC by mistake i.a. »»» • embolisation in arteries »»» even amputation necessary)

CEPHALOSPORINS b-Iactam antibiotics that are closely related both structurally and functionally to the penicillins. Mostly produced semisynthetically. They have the same mode of action as penicillins, and they are affected by the same resistance mechanisms. However, they tend to be more resistant than the PNCs to b-Iactamases. A. Antibacterial spectrum Classified as first, second, third, or fourth generation, based largely on their bacterial susceptibility patterns and resistance to b-Iactamases. They are ineffective against MRSA, L. monocytogenes, Clostridium difficile, and the enterococci.

First generation: They act as penicillin G substitutes; they are resistant to the staphylococcal penicillinase; also have activity against Proteus mirabilis, E. coli, and Klebsiella Pneumoniae (the acronym PEcK) . Second generation: Greater activity against three additional G- organisms: H. influenzae, Enterobacter aerogenes, and some Neisseria species(HENPEcK); Activity against gram-positive organisms is weaker. They are, however, effective against Bacteroides fragilis; cefoxitin is the most potent.]

Third generation: Inferior to first-generation in activity against G+ cocci, but they haveenhanced activity against gram-negative bacilli, as well as most other enteric organisms plus Serratia marcescens. Ceftriaxone or cefotaxime- agents of choice in the treatment of meningitis. Ceftazidime- against Pseudomonas aeruginosa. Fourth generation: Cefepime- must be administered parenterally. Wide spectrum, active against streptococci and staphylococci (but only those that are methicillin-susceptible). Also effective against aerobic G- organisms (e.g., enterobacter, E. coli, K. pneumoniae, p. mirabilis, and p. aeruginosa).

B. Resistance The same as those described for the penicillins. [Note: Although they are not susceptible to hydrolysis by the staphylococcal penicillinase, cephalosporins may be susceptible to extended spectrum b-Iactamases.] C. Pharmacokinetics - Administration:Some orally, most of cephalosporins must be administered IV or IM because of their poor oral absorption.

- Distribution:All distribute very well into body fluids. However, adequate therapeutic levels in the CSF, regardless of inflammation, are achieved only with the third-generation cephalosporins(ceftriaxone or cefotaxime - effective in the treatment of neonatal and childhood meningitis caused by H. influenzae). Cefazolin - prophylaxis prior to surgery because of its half-life and activity against penicillinase-producing S. aureus. Its ability to penetrate bone is especially useful in orthopedic surgery. All cephalosporins cross the placenta. - Fate: Biotransformation is not clinically important. Elimination through tubular secretion and/or glomerular filtration. Doses must be adjusted in severe renal failure !!! Cefoperazone [sef oh PER a zone] and ceftriaxone - excreted in bile into the feces - frequently employed in patients with renal insufficiency.

D. Adverse effects The cephalosporins produce a number of adverse affects. - Allergy:Patients who have had an anaphylactic response to PNCs should not receive cephalosporins. The cephalosporins should be avoided or used with caution in individuals who are allergic to PNCs (cca 15 % show cross-sensitivity). In contrast, the incidence of allergic reactions to cephalosporins is 1-2 % in patients without a history of allergy to PNCs. - Disulfiram-like effect: When cefamandole, cefotetan, or cefoperazone if ingested with alcohol or alcohol-containing medications. They block the second step in alcohol oxidation -accumulation of acetaldehyde. - Bleeding:Associated with agents that contain the MTT group - because of anti-vitamin K effects. Administration of the vitamin corrects the problem. -Nephrotoxicity, diarrhea.

OTHER BETA-LACTAM ANTIBIOTICS A. CARBAPENEMS - IMIPENEM,MEROPENEM Synthetic beta-lactam ATB. Imipenem is compounded with cilastatin to protect it from metabolism by renal dehydropeptidase. 1. Spectrum: Imipenem/cilastatin is the broadest spectrum beta-lactam antibiotic currentlyavailable. It is active against pencillinase-producing gram-positive and gram-negative organisms, anaerobes, and pseudomonas aeruginosa, although other pseudomonas strains are resistant. However, resistant strains of P. aeruginosa have been reported. Imipenem resists hydrolysis by most beta-lactamases, but not the metallo-beta-lactamases. The drug plays a role in empiric therapy. Meropenem has antibacterial activity similar to that of imipenem.

2. Pharmacology: Administered i.v., penetrates well into CNS. Excreted by glomerular filtration and undergoes cleavage by a dehydropeptidase found in the brush border of the proximal renal tubule to form an inactive metabolite that is potentially nephrotoxic. Compounding the imipenem with cilastatin, (dehydropeptidase inhibitor) protects the parent drug from cleavage and thus prevents the formation of a toxic metabolite. This allows the drug to be active in the treatment of urinary tract infections. Note: The dose must me adjusted in patients with renal insufficiency. MEROPENEM – it is not cleaved in the kidney !! 3. Adverse effects: nausea, vomiting, and diarrhea. Eosinophilia and neutropenia are less common. High levels of these agents may provoke seizures.

MONOBACTAMS - AZTREONAM Aztreonam is unique because the beta-lactam rings is not fused to another ring. Monobactams also disrupt cell wall synthesis. The drug's narrow antimicrobial spectrum precludes its use alone in empiric therapy. Aztreonam is resistant to the action of beta-lactamases. Spectrum: primarily directed against the enterobactericeae. Aztreonam is unique among the beta-lactam group because of its effectiveness against Pseudomonas aeruginosa and other aerobicgram-negative bacteria, and because of its lack of activity against gram-positive organisms or anaerobes. Pharmacology: IV or IM, excreted in theurine »»» can accumulate in patients with renal failure. Adverse effects:relatively nontoxic, but it may cause phlebitis, skin rash, and occasionally, abnormal liver function tests. Low immunogenic potential, little cross-reactivity with antibodiesinduced by other beta-lactam »»» an alternative for patients allergic to penicillin.

BETA-LACTAMASE INHIBITORS Hydrolysis of the beta-lactam ring (either by enzymatic cleavage a beta-lactamase or by acid) destroys antimicrobial activity. Beta-lactamase inhibitors, e.g. CLAVULANIC ACID and SULBACTAM, TAZOBACTAM contain a beta lactam ring, but they do not have significant antibacterial activity. They bind to and inactive beta-lactamases »»» protection of the antibioticsthat are normally substrates for these enzymes. The beta-lactamase inhibitors are formulated with the penicillin derivatives to protect the latter from enzymatic inactivation AUGMENTIN (amoxycillin and clavulanic acid) TIMENTIN (ticarcillin and clavulanic acid) Piperacillin + tazobactam Ampicillin + sulbactam Not all beta-Iactamases are inhibited. E.g., tazobactam (compounded with piperacillin) does not affect p. aeruginosa beta-Iactamase. Therefore, this organism remains refractory to piperacillin.

OTHER AGENTS AFFECTING THE CELL WALL VANCOMYCIN TEICOPLANIN (similar, longer acting) The emergence of staphylococci resistant to most antibiotics except vancomycin led to the reintroduction of this agent. 1. Action: Inhibition of the synthesis of the cell wall phospholipids as well as peptidoglycan polymers. This preventsthe transglycosylation step in peptidoglycan polymerization andweakening the cell wall and damaging the underlying cell membrane. 2. Antibacterial spectrum:Bactericidal. Present use - infections caused by methicillin-resistantstaphylococci, and pseudomembranous colitis caused by Clostridiumdifficile or staphylococci.

Effective primarily against gram-positive organisms . It may be lifesaving in the treatment of MRSA, methicillin-resistant Staphylococcus epidermidis infections and enterococcal infections. Increase in resistant strains - the increase in vancomycin-resistant bacteria (e.g., Enterococcus faecium, Enterococcus faecalis) – it is necessary to restric the use of vancomycin to the treatment of serious infections caused by b-Iactam-resistant, gram-positive microorganisms, or for patients with gram-positive infections who have a serious allergy to the b-Iactams. Oral vancomycin - limited to treatment for potentially life-threateningantibiotic-associated colitis due to C. difficile or staphylococci. Used in individuals with prosthetic heart valves and in patients undergoing implantation with prosthetic devices. Vancomycin acts synergistically with the aminoglycosides - can be used in the treatment of enterococcal endocarditis.

3. Resistance: due to plasmid-mediated changes. 4. Pharmacology: Slow i.v. infusion - treatment of systemic infections or for prophylaxis. Vancomycin is not absorbed after oraladministration - treatment of antibiotic-induced colitis due toC. difficile. Inflammation allows penetration into the meninges - often necessary to combine withother ATB – e.g., ceftriaxone. Metabolism – minimal (90 - 100 % excreted by glomerular filtration) – adjust dosage in renal failure – accumulation of the drug. The normal half-life: 6-10 hours; over 200 hours in end- stage renal disease. 5. Adverse effects:Serious problem (fever, chills, and/or phlebitis at the infusion site). Flushing ("red man syndrome").Shock as a result of rapid administration. Rashes. Ototoxicity and nephrotoxicity - more common when administered with other drug (e.g., an aminoglycoside) that can also produce these effects.

B. BACITRACIN • - a mixture of polypeptides that inhibits bacterial cell wall synthesis. • Active against a wide variety of gram-positive organisms. • Use is restricted to topical application because of its • nephrotoxicity. • C. POMYMYXIN B and COLISTIN • Cationic detergent properties, bactericidal on G – (pseudomonas, coliform); not absorbed from GIT • Adverse effect: neuro- and nephrotoxicity • Use: gut sterilisation, topical treatment (eye, ear, skin)

Protein Synthesis lnhibitors A number of ATBs exert their antimicrobial effects by targeting the bacterial ribosome, which has components that differ structurally from those of the mammalian cytoplasmic ribosome. The mammalian mitochondrial ribosome, however, more closelyresembles the bacterial ribosome. Thus, although drugs that interact with the bacterial target usually spare the host cells, high levels of drugs such as chloramphenicol or the tetracyclines may cause toxic effects as a result of interaction with the mitochondrial ribosomes.

ANTIMICROBIAL THERAPY V. Geršl According to: