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. - H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower: Pharmacology, 6th ed. - R.A.Howland, M.J.Mycek: Lippincott’s Illustrated Reviews: Pharmacology,3rd ed. - B.G.Katzung: Basic and clinical pharmacology, 10th ed.

PRINCIPLES OF ANTIMICROBIAL THERAPY ATB are effective in the treatment of infections because of their selective toxicity-the ability to kill an invading microorganism without harming the cells of the host. However, the selective toxicity is relative (not absolute)  concentration of the drug must be controlled (to attack the microorganism while being tolerated by the host). Selective antimicrobial therapy – advantage of the biochemical differences between microorganisms and human beings. SELECTION OF ANTIMICROBIAL AGENTS depends on: 1) the organism´s identity, 2) its susceptibility to an agent, 3) the site of the infection, 4) patient factors, 5) the safety of the agent, 6) the cost of therapy.

A)Identification and sensitivity of the organism = main for the • selection of the proper drug. • Essential is to obtain a sample culture prior the treatment (if possible). • Empiric therapy prior to organism identification: • Ideally - to treat when the organism was identified and itsdrug • susceptibility established. • However, acutely ill patients usually require immediate treatment • (initiated before results of the culture are available). • The choice of drugin the absence of sensitivity data is influenced by: • patient (e.g., age), • location of the infection, • - 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, patient's history (hospital- or community-acquired, immunocompromised patient, patient's travel record and age). Broad-spectrum - initially for serious infections(identity of the organism is unknown or the site makes a polymicrobial infection likely. Also by known association of particular organisms with infection in a given clinical setting (G+ coccus in the spinal fluid of a newborn infant - unlikely to be S.pneumoniae - most likely Streptococcus agalactiae -sensitive to PNC G). But, G+ coccus in older (cca 40 years)– v.s.S. pneumoniae (frequently resistant to PNC G3rd-generation cephalosporin (cefotaxime or ceftriaxone) or vancomycin.

C. Determination of antimicrobial susceptibility of infective organisms Susceptibility to ATB - a guide in choosing antimicrobial therapy. Some pathogens (S. pyogenes, N. meningitidis) - usually predictable susceptibility to certain ATBs. In contrast, most G- bacilli, enterococci, and staphylococcal species - often unpredictable susceptibility to various ATB (i.e., require susceptibility testing). The minimum inhibitory and bactericidal concentrations of a drug can be experimentally determined.

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 2nd cycle of infection. Bactericidal-kill bacteria at drug serum levels achievable in the patient.- often drugs of choice in seriously ill patients. However, it is possible for ATB to be bacteriostatic for one organism and bactericidal for another. E.g.: chloramphenicol (static against G- rods and is -cidal against other organisms, e.g.S. pneumoniae).

2. Minimum inhibitory concentration (MIC): the lowest concentration of ATB that inhibits bacterial growth. For effective therapy, ATB concentration in body fluids should be greater than the MIC. 3. Minimum bactericidal concentration (MBC): the lowest concentration of ATB that results in a 99.9 percent decline in colony count after overnight broth dilution incubations.

D. Effect of the site of infection on therapy: The blood-brain barrier Capillaries with varying degrees of permeability carry drugs to the body tissues. The endothelial cells of the walls of capillaries of many tissues– they have fenestrations that allow most drugs not bound by plasma proteins to penetrate. However, natural barriers to drug delivery are created by structures of the capillaries in the prostate, the vitreous body of the eye, and the CNS. HEB- single layer of tile-like endothelial cells fused by tight junctions impede entry from the blood to the brain of molecules (except those that are small and lipophilic).

1. Lipid solubility: Agents without a specific transporter  pass from the blood to the CSF. Lipid solubility = major determinant of ability to penetrate into CNS. Lipid-soluble(quinolones, metronidazole) - penetration to the CNS. Xb-lactam ATB (PNC)- ionized  low solubility in lipids limited penetration through the intact BBB. Infections (meningitis) - BBB does not function effectively  local permeability . Some b-lactam ATB can enter CSF in therapeutic amounts. 2. M.w.:Low M.w. -  ability to cross BBB; High M.w. (vancomycin) - penetrate poorly, even in the presence of meningeal inflammation. 3. Protein binding: High degree of protein binding in the serum limited entry into CSF the amount of free (unbound) drug in serum, rather than the total amount of drug, is important for CSF penetration.

E. Patient factors Important in selecting an ATB. 1. Immune system: Elimination of infecting organisms from the body depends on an intact immune system. The host defense system must eliminate invading organisms. Alcoholism, diabetes, immunodeficiency virus, malnutrition, advanced age affect a patient's immunocompetency. Higher-than-usual doses of bactericidal ATB or longer courses of treatment - required to eliminate infective organisms in these individuals.

2. Renal dysfunction: Poor kidney function (10 % or less of normal)- accumulation of ATB(eliminated by kidney) - serious adverse effectsadjust the doseof ATB. Monitoring of serum levels of some ATB (e.g., aminoglycosides). Note: The number of functioning nephrons decreases with age. Elderly patients - particularly vulnerable to accumulation of drugs eliminated by the kidneys. ATB that undergo extensive metabolism or are excreted via the bile may be favored. 3. Hepatic dysfunction: ATB concentrated or eliminated by the liver (e.g., erythromycin and tetracycline) are contraindicated in liver disease.

4. Poor perfusion:circulation to an area (e.g., lower limbs of a diabetic)  amount of ATB that reaches that area infections difficult to treat. 5. Age:Renal or hepatic elimination - often poorly developed in newborns – neonates - particularly vulnerable to chloramphenicol and sulfonamides. Young children - not to be treated withtetracyclines(bone growth). 6. Pregnancy:All ATB cross the placenta. Adverse effects to the fetus are rare (exceptingtooth dysplasia and inhibition of bone growth by TTC). Some anthelmintics are embryotoxic and teratogenic. Aminoglycosides- avoid in pregnancy - ototoxic effect on the fetus. 7. Lactation:Drugs may enter the nursing infant via the breast milk.Though the concentration of ATB is usually low, the total dose to the infant may be enough to cause problems.

F. Safety of the agent • Inherent toxicity of the drug: • Many ATB (e.g. PNCs) - among to least toxic of all drugs (they interfere with a site unique to the growth of microorganisms). • Other ATBs (e.g. chloramphenicol) - less specific reserved for life - threatening infections because of their serious toxicity. • Patient factors • G. Cost of therapy

ROUTE OF ADMINISTRATION Oral route– mild infections, outpatient basis, economic pressures. If i.v. therapy initially - the switch to oral agents as soon as possible. Some ATB (e.g., vancomycin, aminoglycosides, amphotericin) - poorly absorbed from GIT -adequate serum levels cannot be obtained by oral administration. Parenteral administration- drugs 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 pharmacokinetic. • 2 important pharmacodynamic properties with a 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 ATB increases from 4- to 64-fold the MIC of the drug administration by a once-a-day bolus infusion achieves high peak levels rapid killing of the infecting pathogen. Concentration-independent or time-dependent killing 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efficacy of ATBwithout dose-dependent killing effect is best predicted by the percentage of time that blood concentrations of drug remain above the MIC. E.g., PNC and cephalosporins, dosing schedules that ensure blood levelsgreater than MIC for 60 – 70 % of the time was showed to be clinically effectivesevere infections - better treatment by infusion 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 • It refers the species of microorganisms affected by that drug. • - Narrow spectrum (ATB acting only on a single or a limited group of microorganisms- e.g. isoniazid is active only against mycobacteria). • - Extended spectrum (ATB that are effective against G+ and also against a significant number of G- bacteria - e.g., ampicillin is considered to have an extended spectrum because it acts against G+ and G- bacteria). • Broad spectrum (e.g. TTC and chloramphenicol) - affect a wide variety of microbial species. • Their administration can drastically alter the nature of the normal bacterial flora and precipitate a superinfection of an organism, e.g., candida.

COMBINATIONS OF ATB • Treatment with the single agent that is most specific for the organism it: • reduces the possibility of superinfection, • decreases the emergence of resistant organisms, • minimizes toxicity. • (e.g., the treatment of tuberculosis). • However, situations where combination of ATB is necessary. (TBC…).

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)

INHIBITORS OF CELL WALL SYNTHESIS Interfere with synthesis of the bacterial cell wall-a structure that mammalian cells do not possess. The cell wall = polymer called peptidoglycan (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 ATB (containbeta-Iactam ring that is essential to their activity) and vancomycin

Summary of antimicrobial agents affecting cell wall synthesis INHIBITORS OF CELL WALL SYNTHESIS b-LACTAMASE INHIBITORS Clavulanic acid Sulbactam Tazobactam OTHER ANTIBIOTIC b-LACTAM 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)

PENICILLINS 1928, A. Fleming The most widely effective ATBs and also the least toxic drugs known - increased resistance limited their use. They differ in the substituent attached to the 6-aminopenicillanic acid residue. The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes (b-Iactamases). A. Mechanism of action Bactericidal - interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage)osmotically less stable membrane cell lysis can occur (through osmotic pressure or through the activation of autolysins). PNCsare only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall i.e.,inactive against organisms devoid of this structure(e.g., mycobacteria, protozoa, fungi, and viruses).

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.]Inhibition of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains. PNCs inhibit this transpeptidase-catalyzed reaction. 2. 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 Determined, in part, by the ability of PNC to cross the bacterial peptidoglycan cell wall and to reach PNC-binding proteins. G+ microorganisms have cell wall that are easily traversed by PNC  susceptible to these drugs. G- microorganisms have an outer lipid membrane surrounding the cell wall =a barrier to the water-soluble PNCs (they cannot reach the site of action). However, G- bacteria have proteinsinserted in thelipopolysaccharide layer that act as water-filled channels(porins) that permit transmembrane entry. [P. aeruginosa lacks porins these organisms are resistant to many antimicrobial agents.] PNCs have little use in the treatment of intracellular pathogens.

1. (NATURAL) PENICILLINS a. PENICILLIN G (benzylpenicillin) - therapy for infections caused by a number of G+ and G- cocci, G+ bacilli, and spirochetes. Susceptible to inactivation by beta-lactamases. b. PENICILLIN V(phenoxymethylPNC)- a spectrum similar to PNC G, but it is not used for treatment of septicemia (because of its higher minimum bactericidal concentration - MLC). Treatment of oral infections, where it is effective against some anaerobic organisms. Penicillin V is more acid-stable than penicillin G. c.PROCAINE PENICILLIN G prolonged action, i.m. d. BENZATHINE PENICILLIN Very long action; depo form, i.m.

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

3. EXTENDED SPECTRUM PNC: AMPICILLIN and AMOXICILLIN: Destroyed by -lactamases !!! Spectrum similar to PNC G, but moreeffective against G- bacilli - extended-spectrum PNCs. Ampicillin - drug of choice for the G+ bacillusListeria monocytogenes. Also widely used in the treatment of respiratoryinfections, and amoxicillin is employed prophylactically by dentistsfor patients with abnormal heart valves who are to undergoextensive oral surgery. Resistance is now a problem (inactivation byplasmid-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 • the antipseudomonal penicillins. S. aureus is resistant. • Broad spectrum; susceptible to breakdown by beta-lactamase. • Effective against many G- bacilli, ineffective against Klebsiella (it constitutes penicillinase). • Formulation of ticarcillinwith clavulanic acid or sulbactamextension of antimicrobial spectrum (i.e. it includes penicillinase-producing organism).

5. ACYLUREIDO PENICILLINS: • PIPERACILLIN - the most potent. • Broad spectrum; susceptible to breakdown by beta-lactamase • also effective against P. aeruginosa and large number of G- organisms. • Formulation with tazobactamextension of antimicrobial spectrum (i.e. it includes penicillinase-producing organism). • MEZLOCILLIN • also effective against P. aeruginosa and large number of G- organisms. It is susceptible to breakdown by beta-lactamase. • AZLOCILLIN

Penicillins and aminoglycosides: Antibacterial effects of all b-Iactam ATB synergistic with aminoglycosides. Cell wall synthesis inhibitors alter the permeability of bacterial cells they can facilitate the entry of other ATBs (e.g., aminoglycosides). This can result in enhanced antimicrobial activity. These drug types should never be placed in the same infusion fluid(on prolonged contact, the positively charged aminoglycosides form an inactive complex with the negatively charged PNCs).

C. Resistance • Natural resistance - organisms: • - lack the peptidoglycan cell wall(e.g. mycoplasma) • - cell wall impermeable to the drug • Acquired resistance to PNCs: • by plasmid transfer= clinical problem (multiplication of these organisms •   dissemination ofresistance genes). • -lactamase activity: hydrolysis the cyclicamide bondof the beta-lactam • ring -loss of bactericidal activity.Enzymes are constitutive or • (more commonly) acquiredby the transfer of plasmids. • Some -lactam ATBs are poorsubstrates for -lactamases • resist cleavage activity against -lactamaseproducing organisms.

- Decreased permeability of PNCs through the outer cell membrane - • prevents reaching the penicillin-binding protein. • - Efflux pump  amount of intracellular drug. • Altered PNC binding proteins:Modified PBPs - lower affinity for -lactam ATB  greater concentrations of ATBnecessary. • This may explain methicillin-resistant staphylococci.

Pharmacokinetics • Administration: determined by the stability of ATB to gastric acid and by the severity of the infection. • Routes of administration: • Ticarcillin, carbenicillin, piperacillin, combinations of ampicillin with sulbactam, ticarcillin with clavulanic acid, and piperacillin with tazobactam must be administered IV or IM. • PNC V, amoxicillin, amoxicillin +clavulanic acid, indanyl carbenicillin -only as oral preparations. • Others are effective by the oral, IV, or IM routes. • b. Depot forms:Procaine PNC G and benzathine PNC G- administered IM Slowly absorbed, persist at low levels over a long time period.

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

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

5. Excretion: The primary route – renal tubular secretion and glomerular filtration. Patients with impaired renal function - adjust dosageregimens ! T1/2 of PNC G can (normal of 0.5-1.0 h) to 10 hours in renal failure. Probenecid inhibits the secretion of penicillins !! Nafcillin- eliminated primarily through the biliary route. [Also preferential route for the acylureido PNC in renal failure.] PNCs are also excreted into breast milk and into saliva.

E. Adverse reactions: • PNC -among the safest drugalthough adverse reactions do occur. • Hypersensitivity:The most important. The major cause is metabolite - penicilloic acid(it reacts with proteins and serves as a hapten). • Cca5% of patients have some kind of reaction (from urticaria to angioedema and anaphylaxis). • Cross-allergic reactions can occur among -lactam ATB ! • Diarrhea: • Disruption of the normal balance of GIT microorganism - common. Especially in agents thatare incompletely absorbed or with extended spectrum. • Alsopseudomembranous colitis may occur.

- Nephritis: Acute interstitial nephritis inhigh doses of methicillin. • Neurotoxicity:PNCs irritate neuronal tissue seizures if injected • intrathecally or in very high blood levels. Epileptics- especially at risk. • - Platelet dysfunction:»»»decreased agglutination (observed esp. with • the antipseudomonal PNCs - carbenicillin and ticarcillin). • Concern when patient is predisposed to hemorrhage or receiving • anticoagulants. • Cation toxicity:Generally administered as the Na or K salt. Toxicity • by large quantities of ions. • - Hoigné syndrom (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)

Clinical uses of penicillins • Given p.o. - in more severe cases i.v.; often in combination with other ATB. • Uses include: • ― bacterial meningitis (e.g. by N. meningitidis, S. pneumoniae): benzylPNC, high doses i.v. • ―bone and joint infections (e.g. S. aureus): f\ucloxacillin • ― skin and soft tissue infections (e.g. Streptococcus pyogenes or S. • aureus): benzylPNC, flucloxacillin; animal bites: co-amoxiclav • ―pharyngitis (from S. pyogenes): phenoxylmethylPNC • ―otitis media (S. pyogenes, H. influenzae): amoxicillin • ― bronchitis (mixed infections common): amoxicillin • ― pneumonia: amoxicillin • ― urinary tract infections (e.g. with E. coIl): amoxicillin • ― gonorrhea: amoxicillin (+ probenecid) • ― syphilis: procaine benzylPNC • ― endocarditis (e.g. with Streptococcus viridans or Enterococcus faecalis) • ― serious infections with Pseudomonas aeruginosa: piperacillin. • This list is not exhaustive !!!

CEPHALOSPORINS b-Iactam ATB; closely structurally and functionally related to PNC. Mostly produced semisynthetically. The same mode of action as PNCs, the same resistance mechanisms. However, they are more resistant than the PNCs to b-Iactamases. A. Antibacterial spectrum Classified as first, second, third, or fourth generation, based on their bacterial susceptibility patterns and resistance to b-Iactamases. Ineffective against MRSA, L. monocytogenes, Clostridium difficile, and enterococci.

1st generation: Act as PNC G -resistant to the Staphylo.penicillinase; also activity against Proteus mirabilis, E. coli, and Klebsiella Pneumoniae (the acronym PEcK). E.g., cephalexin, cephalotin, cefazolin 2nd generation: Greater activity against 3 additional G- organisms: H. influenzae, Enterobacter aerogenes, some Neisseria species(HENPEcK); E.g., cefuroxime, cefamandol, cefaclor Activity against G+ organisms is weaker. The exceptions - related cephamycins -cefoxitin and cefotetan - little activity against H. influenzae. Effective against Bacteroides fragilis; cefoxitin is the most potent.

3rd generation: Inferior to 1st-gen.against G+ cocci -enhanced activity against G- bacilli and most other enteric organisms and Serratia marcescens. Ceftriaxone or cefotaxime- agents of choice in the treatment of meningitis. Ceftazidime- against Pseudomonas aeruginosa. 4th generation: Cefepime, Cefpirom Wide antibacterial spectrum - active against streptococci and staphylococci (but only those that are methicillin-susceptible). Also effective against aerobic G- organisms(enterobacter, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa).

B. Resistance Mechanisms - the same as inPNCs. (Though not susceptible to the staphylococcal penicillinase, they may besusceptible to extended spectrum b-Iactamases.) C. Pharmacokinetics - Administration: Some – orally. Most of cephalosporins must be admin. IV or IM (poor oral absorption).

- Distribution:All very well into body fluids.All cross the placenta. However, adequate therapeutic levels in the CSF (regardless of inflammation) - only the 3rd generation (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- useful in orthopedic surgery. - Fate: Biotransformation is not clinically important. Elimination: renal tubular secretion and/or glomerular filtration adjust doses in severe renal failure !!! Cefoperazone, cefamandole andceftriaxone - excreted in bile into the fecesemployed in patients with renal insufficiency.

D. Adverse effects - Allergy:Patients with an anaphylactic response to PNCs should not receive cephalosporins. To be avoided or used with caution in individuals 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: If cefamandole, cefotetan, or cefoperazone is ingested with alcohol or alcohol-containing medications. They block the 2nd step in alcohol oxidationaccumulation of acetaldehyde.(Due to the presence of the methylthiotetrazole group). - Bleeding:hypoprothrombinemia (associated with MTT group–e.g.cefamandole, cefoperazone)  treatment with vitamin K - Nephrotoxicity, diarrhea. - Phlebitisafter i.v. - Blood countchanges

Clinical uses of the cephalosphorins • Septicaemia (e.g. cefuroxime, cefotaxime) • Pneumonia caused by susceptible organisms • Meningitis (e.g. cefriaxone, cefotaxime) • Biliary tract infection • Urinary tract infection (especially in pregnancy, or in patients unresponsive to other drugs) • Sinusitis (e.g. cefadroxil).

ANTIMICROBIAL THERAPY V. Geršl According to: