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Home , Aminopenicillin, Penamecillin

Projekt „Zvýšení kvality vzdělávání na UK a jeho relevance pro potřeby trhu práce-ESF Reg. č. CZ.02.2.69/0.0/0.0/16_015/0002362“, je financován z programu OP VVV

BETA-LACTAM Eduard Jirkovský, Přemysl Mladěnka

Content

BETA-LACTAMS ...... 2

PENICILLINS ...... 2

CLASSIFICATION OF ...... 3

GENERAL ASPECTS OF PENICILLINS’ PHARMACOKINETIC ...... 4

NATURAL PENICILLINS ...... 4

ANTISTAPHYLOCOCCAL PENICILLINS ...... 6

AMINOPENICILLINS ...... 8

ANTIPSEUDOMONAL PENICILLINS ...... 9

ADVERSE EFFECTS OF ALL PENICILLINS ...... 10

INTERACTION OF PENICILLINS ...... 11

USE IN PREGNANCY AND BREASTFEEDING ...... 11

CEPHALOSPORINS ...... 12

CARBAPENEMS ...... 16

MONOBACTAMS ...... 18

REFERENCES ...... 19

Projekt „Zvýšení kvality vzdělávání na UK a jeho relevance pro potřeby trhu práce-ESF Reg. č. CZ.02.2.69/0.0/0.0/16_015/0002362“, je financován z programu OP VVV

Beta-lactams • the name of this group of ATBs is based on their common chemical structure (Fig. 1) • all members of this group are bacteriocidal

O O S R N R N H H N N O S O H O CO O H 3 penicillines

O S HO R1 N H R2 S R N O N O C O O H C O O H

Fig. 1. Chemical structure of β-lactam ATBs.

PENICILLINS • the first antibiotics discovered (1928, A. Flemming; isolatated from a mould of the genus Penicillium spp. – originally Penicillium chrysogenum, syn. P. notatum) • naturally occurring penicillins currently used in clinics are G and penicillin V • currently broadly used against sensitive microbes • all penicillins have short post- effect • very good safety profile – they are often drug of choice for many infections • world-wide the most used antibiotic drugs

Mechanism of action • primary target – PBP – penicillin binding proteins o i.e. enzymes with transpeptidase activity o the individual microbes differ in structure and affinity to the given compound o mutation in PBP leads to ATB resistance • thus their main effect is to inhibit formation of chains by preventing formation of the crosslinks due to inhibition of final transpeptidation reaction

Projekt „Zvýšení kvality vzdělávání na UK a jeho relevance pro potřeby trhu práce-ESF Reg. č. CZ.02.2.69/0.0/0.0/16_015/0002362“, je financován z programu OP VVV

Mechanism of ATB resistence • enzymatic degradation by ß-lactamases (penicillinases, cephalosporinases etc.) • structure modification of penicillin-binding protein (PBP) → lower affinity of PBP to ATB • presence of efflux system or inability of ATB to penetrate to PBP

Inhibitiors of ß-lactamase as a tool for limiting the resistance • drugs with no antimicrobial activity • binds to the active site of ß-lactamase and irreversibly inactivate the enzyme (Fig. 2) • effective mainly against ß-lactamases encoded in plasmids • PK parameters are similar to the active ATB which they are used with • - produced by produkována Streptomyces clavuligerus; currently combined with o certain risk of hepatotoxicity (e.g. transient increase of transaminases, (prolonged) cholestatic hepatitis; mid-to-moderate severity, self-limiting) • - combined with and • – combined with and ceftolozane • – does not contain ß-lactam moiety, approved by FDA in 2015, combined with

O O S O O S O N OH O N O O N N COOH COOH COOH N A B C N

Fig. 2. Chemical structures of selected inhibitors of ß-lactamases: A: clavulanic acid, B: sulbactam, C: tazobactam

Classification of penicillins • natural penicillins – narrow antimicrobial spectrum, easily hydrolyzed by penicillinases • antistaphylococcal penicillins – naturally resistant to penicillinases produced by staphylococci • extended-spectrum penicillins ➢ – slightly extended antimicrobial spectrum ➢ antipseudomonal penicillins – very extended antimicrobial spectrum, count for and group

Projekt „Zvýšení kvality vzdělávání na UK a jeho relevance pro potřeby trhu práce-ESF Reg. č. CZ.02.2.69/0.0/0.0/16_015/0002362“, je financován z programu OP VVV

General aspects of penicillins’ pharmacokinetic • food decrease the absorption of penicillins (except for amoxicillin)

• Vd = 0.25 – 0.35 L/kg → do not penetrate into fagocyte cells → they are not effective on strictly intracellular patogens • HEB cross only in case of meningitis, final concentration in the liquor represents ≈ 5 % of plasma concentrations

• t1/2 30 – 90 min • main route of elimination is tubular secretion, partially also glomerular filtration • high concentrations is urine

• during renal failure is t1/2 prolonged almost to 10 hours • probenecid should be used for decrease of tubular secretion of penicillin

O O S S N N H H N O N O O O O COOH A C O

O N O H2N S N O O H D N O COOH H H N N B E

Fig. 3. Chemical structures of natural penicillins (A-C), procaine (D) and benzathine (E). A: penicillin G, B: penicillin V a C: . Differences between penicillin G and V are marked in red.

Natural penicillins Classification according to rout of administration (Fig. 3) • for parenteral administration – (PEN G) and tis depot formulations • for p.o. administration – (PEN V) and penamecillin

Antimicrobial spectrum of natural penicillins • primary to G+ bacteria, from G- bacteria are/were sensitive only G- cocci • G+ cocci ➢ Streptococcus pyogenes – 100 % sensitivity ➢ Streptococcus pneumoniae – “good” sensitivity in Czech Republic ➢ Staphylococcus aureus – 90 % sensitivity

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➢ Enterococus sp. are resistant • G- cocci ➢ Neisseria meningitis - sensitive ➢ Neisseria gonorrhoeae – occasionally resistant • G+ endospore-forming rods (Bacillus antracis, genus Clostridium) • G+ non-endospore-forming rods (Corynebacterium diphteriae) • spirochaetes (Treponema pallidum is still very sensitive, Borrelia burgdorferi) • some anaerobes • none of penicillins or other β-lactames are not active against mycobacteria and intracellular patogenes (rickettsie, chlamydie, mycoplasmy, legionely), fungi, viruses and protozoans

Therapeutic use of natural penicillins • infection caused by “streptococcus” (S. pyogenes) – drug of choice • meningitis caused by “meningococcus” (N. meningitis) and infection caused by S.pneumoniae – high-dose PEN G i.v. is still the first therapeutic choice • syphilis – still very good sensitivity to PEN G, administration along with probenecid is preferable • eradication of carriage state in patients (diphtheria, anthrax, clostridial infections)

Non-depot formulation of natural penicillins penicillin G (Fig. 3A, Penicilin G Biotika®) • also known as benzylpenicillin • instable in acidic pH, BAV only 1/3 → only IV administration penicillin V (Fig. 3B, V-penicilin Slovakofarma®, Penbene®, Ospen®) • also known as phenoxymethylpenicillin

• stable in acidic pH, cplasma 2-5 times higher than for penicillin G, administered p.o. • Common dosing schedule is 750 mg every 8 hours, event.. 500-750 mg every 6 hours penamecillin (Fig. 3C, withdrawn from market) • acetoxymethylester of penicillin G • dosing interval 8 hours

Generally, for the β-lactams ATB, in order to be effectiveness at least on 90 % of the microbial population, the concentration in a specific compartment must be above the minimal inhibition concentration (MIC) for at least 40–50 % of the dosing interval. MIC for streptococci is relatively low, therefore the concentrations of PEN V are above the MIC for about 4 hours after administration of normal dose → dosing interval each 8 hours is sufficient for treatment of streptococci infections.

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Depot formulation of penicillins • used for poorly soluble PEN G • suspensions, strictly for i.m. administration; slow diffuse of both drugs from the salt complex and absorption to the circulation forming sustained blood concentration • drug of choice in cases if good patient’s compliance is necessary or is expected to be inadequate (p.o. administration in children, treatment of VTD) • Hoigne’s syndrome – occasionally after i.m. application o embolic toxic reactions possibly due to vascular occlusion by large crystals of the penicillin salts o symptoms are short-lasting and self-limiting: severe agitation with confusion, visual and auditory hallucinations and dire fear (death anxiety) o it is not case of alleric reaction! procaine-penicillin G (Prokain penicilin G Biotika®) • a choice for acute infections • therapeutic concentration of PEN G is stable for 24 hours → dosing once daily i.m. • i.m. application is painless due to the local anesthetic effect of procaine AE: allergic reaction could occur also to procaine; be aware of high procaine plasma concentrations after (accidental) rapid absorption of high dose of procaine-penicillin G. benzathin-penicillin G (Retarpen inj plv sus.) also as bicillin • maintain therapeutic concentration of PEN G 2-4 weeks • a choice for profylaxis and aftertreatment and eradication of carriage of certain infections (e.g. rheumatic fever and erysipel caused by β-hemolytic streptococci; acute and latent syphilis) • similar local anesthetic properties like procaine • benzathin-penicillin G is also used p.o. administered preparations (e.g. Ospen) – in this case the PK is equal like for phenoxymethylpenicillin combination of both depot preparations, similar indication as benzathin-penicillin (Pendepon ® compositum inj.sic. , currently not registred)

antistaphylococcal penicillins • penicillins naturally resistant against staphylococcal penicillinases • drug of choice for staphylococcal infections due to their low toxicity • in comparison to natural penicillins, antimicrobial activity against other non-staphylococcal bacteria is lower • specific properties of this group is high bound to plasma albumin

Projekt „Zvýšení kvality vzdělávání na UK a jeho relevance pro potřeby trhu práce-ESF Reg. č. CZ.02.2.69/0.0/0.0/16_015/0002362“, je financován z programu OP VVV

Methicillin-Resistent Staphylococcus Aureus (MRSA) • a strain of Staphylococcus aureus which is resistant not only to and other antistaphylococcal penicillins, but also to other penicillins and cephalosporins. • These strains are often resistant to aminoglycosides, tetracyclines, macrolides and linkosamides (particular sensitivity need to be tested). • methicillin was never marketed in this region, but was (and still is clinically used) → in this region you should also found ORSA (oxacilin-resistant….) in the literature methicillin (Fig. 4A, never registered in CZ) • the first (prototype) drug of these class • does not associated with risk of hepatotoxicity like oxacillin and other former members of this group oxacillin (Fig. 4B, Prostaphlin inj.®) • effective also against majority of G+ cocci, β-hemolytic streptococci, pneumococci • certain risk of idiosyncratic hepatotoxicity, e.g. transient increase of transaminases, (prolonged) cholestatic hepatitis; mid-to-moderate severity, self-limiting naficillin (not registered in CZ but in US) • similar with oxacillin

O C O A H N O S 2 S N N H H N N O O COOH O COOH

O B D O S H N O N 2 S N H N N H O COOH N HO O COOH

O O E S N N N N H H N O O O COOH

Fig. 4. Antistaphylococcal (A-B) and extended-spectrum penicillins (C-E) with marked typical structure motive. A: methicillin, B: oxacillin, C: ampicillin, D: amoxicillin a E: piperacillin.

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Extended-spectrum penicillins

aminopenicillins antimicrobial spectrum of aminopenicillins • good antimicrobial effect also against G- bacteria, clinically important is their effect against Hemophilus influenzae, Escherichia coli1 • covers also Enterococcus faecalis, Listeria monocytogenes. • main route of resistance or acquired resistance is production of β-lactamases • primary resistant are Pseudomonas spp., Mycoplasma spp., Serratia spp., Enterobacter spp., and Mycobacteria spp. • primary resistant but sensitive with a β-lactamase inhibitor – Shigella spp. o Klebsiella pneumoniae – special case, currently present nosocomial strains produced β-lactamases to majority of used inhibitors (the sensitivity need to be tested) • preparations with addition of β-lactamase inhibitor ➢ stabilization of primary sensitive bacteria to aminopenicillins (e.g. β-lactamase-producing strains of Hemophillus influenzae) ➢ extension of the spectrum to β-lactamase-producing bacteria (e.g. Moraxella catarralis, some strains of Klebsiella pneumoniae) ➢ disadvantage of these preparations are higher incidence of GIT-related adverse effects due to stronger infliction against bacterial microflora

ampicillin (Fig. 4C, AMP, separate only for i.v. Ampicilin Biotika®) • stable in acidic pH • p.o. BAV is low • undergo enterohepatic circulation (→ high concentration in the bile), excreted also in faeces ampicillin + sulbactam (Unasyn® , Bitammon®) • for i.v. preparations combined in ratio 2:1 (AMP:sulbactam) • for p.o. preparations is used (codrug/mutual prodrug) – ester of ampicillin and sulbactam (ratio 1:1) o used every 12 hours, food does not change the absorption amoxicillin (Fig. 4D, Duomox®, Ospamox®) • only for p.o. use • stable in acidic pH • BAV is almost complete

1 Hemophilus influenzae belongs along with S. pneumoniae to the most common cause of bacterial pneumonia and other respiratory infections, Escherichia coli is the most common cause of urinary tract infections.

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• food does not change the absorption amoxicillin + clavulanic acid (Augmentin®, Amoksiklav®, Curam®, Medoclav®, Megamox®) • marketed preparations are in ration 7:1 (amoxicillin:clavulanic ac.) • food does not change the absorption • is currently the most common cause of drug induced liver disease in most large case series from the United States and Europe

Therapeutic use of aminopenicillins • infection of upper and lower respiratory tract, mainly in combination with β-lactamase inhibitor ➢ sinusitis ➢ “angina” (i.e. sore throat or angina tonsillaris) should be cured by PEN V or PEN G! ➢ ambulant treatment of community acquired pneumonia, in severe cases in combination with other ATB • infection of urogenital tract – initial treatment of pyelonephritis (usefulis combination with the β-lactamase inhibitors) • meningitis, also caused by Listeria monocytogenes • part of the “triple-combination” for eradication of Helicobacter pylori

Adverse Effects of • besides AE common for PEN in general, the incidence of exanthems (hives) are more often • Amoxicillin and other aminopenicillins have been linked with idiosyncratic liver injury, but only rarely and in isolated case reports

Contraindication of aminopenicillins: • sore throat (“angina”) - clinical manifestation of sore throat and infection mononucleosis is very difficult to distinguished → generalized itchy maculopapular rash occurs in almost all patients received aminopenicillin - unknown association with classic allergic rash after aminopenicillins (i.e. occurrence of this symptom does not imply sensitization to these drugs in future)

Antipseudomonal penicillins Antimicrobial spectrum • Very broad, G+ and G- including those resistant in other lower generations of penicillins (e.g. Pseudomonas spp., resistant strain of Klebsiella pneumoniae)

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• they are sensitive to action of β-lactamases, therefore they are always used along with the inhibitors of β-lactamases

Therapeutic use of antipseudomonal penicillins • parenteral treatment of life-threatening infections • drug of choice for pseudomonal infections, eventually in combination with aminoglycosides

Drugs • these class was originally formed by group of carboxypenicillins2 and ureidopenicillins, but currently is registered for human use only one drug from ureidopenicillins class - piperacillin piperacillin (Fig. 4A) in a combination with tazobactam (Fig. 2C) inj: Tazocin®, Tazip®) • it has the most extended spectrum from all penicillins (n.b. also resistant strains of Klebsiella spp.) • it has high portion of biliary excretion in comparison to other penicillins

Adverse effects of all penicillins • overall lower toxicity and more safe than other ATB • majority of AE are based on idiosyncratic hypersensitivity reactions ➢ represent the most AE in PEN treatment (incidence 0.7-4 %) ➢ all four degree of allergic reaction should developed (from rash manifested as hives to anaphylactoid reactions) ➢ all members have similar probability to induce allergic reaction ➢ should develop also after lower doses ➢ penicillins and their metabolic products are haptens (esp. penicillin fragment) ➢ allergy for one penicillin is often crossed to other penicillins. Cross-reactivity to cephalosporins in 7 % of cases. ➢ most threatening is angioedema and anaphylactoid reaction. If developed, cross-reactivity with all penicillins. ➢ idiosyncratic hypersensitive reaction is not always based on allergic/immunological background, e.g.:

2 The first antipseudomonal penicillin was . in a combination with clavulanic acid was recently withdrawn from the market due to rising resistance. Ticarcillin is still available in some countries for veterinary use in horses.

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o idiosyncratic hepatoxicity of aminopenicillins and antistaphylococcal penicillins manifested as transient subclinical elevation of plasma hepatic enzymes and (prolonged) cholestasis. Range of symptoms after clinical manifestation are from fever, nausea, abdominal pain, pruritus and jaundice. Fatal states are very rare and always attributed to other comorbidities. ▪ preparations with clavulanate have more higher incidence than respective separate penicillins o itchy maculopapular rash after aminopenicillins misused for treatment of infection mononucleosis • dyspeptic symptoms • Hoigne’s syndrome

Interaction of penicillins • extended-spectrum penicillins negatively inflict gut bacterial microflora and therefore could inhibit: ➢ vitamin K synthesis by saprophytic strains → increase of the warfarine effects ➢ bacterial decomposition of estrogen conjugates → decrease effect of oral contraceptives

Use in pregnancy and breastfeeding • pregnancy category B. • ß-lactams (and inhibitors of β-lactamases) cross the placental barrier but teratogenic or mutagenic potential was not observed nor in animal, neither in humans. They are also excreted to the milk. • β-lactams are drug of choice during pregnancy and breastfeeding if clinicall yindicated. After normal dose, they should not influence the fetus and infants. However, after higher and longer treatment were sporadically observed necrotizing enterocolitis after prophylactic treatment of placental rupture in preterm delivery. • they could inflict gut bacterial microflora in infants.

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CEPHALOSPORINS Mechanism of action: the same as penicillins, binding to PBP Resistance: the same mechanism as for penicillins (the inability to penetrate to the target structure, modification of PBPs, production of the β-lactamases) Classification of cephalosporins (see Table 1)

Table 1. Classification of cephalosporins

Resistance to CSF Gen. Sensitivity of G+ Sensitivity of G- β-lactamases penetration

limited (but Klebsiella, 1st very good Moraxella and Proteus could be small do not cross sensitive)

extended (Proteus, Klebsiella, 2nd very good more stable ≈ 10 % c Hemophilus, Moraxella) plasma

very good (including good, not against 3rd weak Enterobacteriaceae), some also mostly good AmpC & ESBL for Pseudomonas

good, in vitro also 4th very good very good good against ESBL

like 4th good, not against 5th similar like 3rd generation* ?+ plus MRSA ESBL*

ESBL: broad-spectrum β-lactamases; AmpC: AmpC type β-lactamases; *: variable effect against AmpC → spectrum could be even broader; +: penetration probably should be sufficient for treatment of meningitis, but it has weak clinical evidence yet

Pharmacokinetic of cephalosporins • BAV is not significantly changed by food in case of parent drug x prodrug as esterified ( axetil) has higher BAV with food! • they are primary excreted by kidney (exception of cefoperazone)

• t1/2 is short, usually 1-2 hours (exception of )

• Vd similar to penicillins • cephalosporins also cross placenta

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Drugs 1st generation

• (Vulmizolin®, Cefazolin Sandoz®, Cefazoline Panpharma®) o for i.v. administration, stable against staphylococcal ß-lactamase • (Fig. 5A, Biodroxil®, Duracef®) o mostly for treatment of urinary tract infections, dosing twice a day • (not in CZ, FDA red. Keflin®, in EU for veterinary use) o known for it nefrotoxicity

2nd generation

• cefuroxime (Axetine®; Zinacef®) o for i.v. administration in form of natrium salt o in CSF reaches concentrations about 10% of plasmatic concentrations • cefuroxime-axetil (Fig. 5C,Zinnat®, Cefuroxim Teva®, Medoxin®, Xorimax®) o prodrug, acetyloxyethyl ester of cefuroxime o for p.o. use only, dosing twice a day • (Cefzil®) o p.o., dosing according to type of infection (every 12-24 hours)

3rd generation

• (Ceftax®, Cefotaxime Lek®, Cefotak®) o i.v., drug of choice for infection meningitis • ceftriaxone (Fig. 5B,Samixon®, Ceftriaxon Sandoz®, Ceftriaxon Kabi®) o i.v., drug of choice against gonorrhea • cefixim ( innfarm®) o p.o.; for non-complicated infection of urinary and respiratory tract 3rd generation - antipseudomonal • used for meningitis, skin and joint infections, infection of respiratory and urogenital tract, sepsis etc. caused also by S. pneumonie, S. aureus, H. influenza • cefoperazone (Fig. 5D,Cefobid®; + sulbactam → Sulperazon® ) o i.v., sold also as a co-formulation with sulbactam o its elimination is exception between cephalosporins – only 25 % is excreted by urine o contain N-methylthiotetrazole side chain (N-MTT) which is responsible for its specific adverse effect – MTT is inhibitor of: ▪ vitamin K epoxide reductase → causes hypoprothrombinemia ▪ aldehyde dehydrogenase → causes disulfiram-like effect (similar to Antabus)

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• ceftazidime (Fortum®, Ceftazidim Stragen®, Ceftazidim Mylan®, + avibaktam - Zavicefta inf®) o i.v., sold also as a co-formulation with avibactam (non-β-lactam containing inhibitor of β-lactamases) → effective on majority of resistant strains producing β-lactamases

4th generation

• (Fig. 5E,Naxipime®) o i.v., highly resistant to β-lactamases – generally higher activity than in 3rd generation o used also for nosocomial pneumonia (P. aeruginosa)

5th generation – na meticilin rezistentní stafylokoky

• ceftaroline (Zinforo®) o i.v., active against MRSA – used also for community-acquired pneumonia • (not registered in CZ, but EMA, FDA… approved it Zevtera®, Mabelio®) o same as ceftaroline

O O S N S HO N H N 2 N N H H N OH NH2 N S N N O O S O N O A COOH B COOH O S O O N O S H N N N N N N H H N O O NH O N N O 2 O COO O O S N N COOH O C O D OH

O N S O H N N + H2N N 2 H N S S N N NH N S H O N N N O H N O H COO- O O E F COOH

Fig. 5. Representatives of five generations of cephalosporins. A: cefadroxil, B: ceftriazone, C: cefuroxime-axetil, D: cefoperazone, E: cefepime, F: ceftobiprole (5. generace). MTT fragment marked in red.

Adverse effects of cephalosporins • like penicillins, the most common AE is hypersensitivity

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• rare AE is nefrotoxicity (esp. for cefaloridine & cefalotin which are now minimally used, prior was withdrawn) o more common in combination with aminoglycosides (caused probably due to AMG) • post-antibiotic diarrhea, risk of pseudomembranous colitis and superinfection is rare • cefoperazone (drug containing MTT structure fragment): disulfiram-like reaction, bleeding due to hypoprothrombinemia, thrombocytopenia, platelet dysfunction

Therapeutic use • all cephalosporins have short post-antibiotic effect • 1st generation is suitable for treatment of non-complicated infections caused by S. aureus and S. pyogenes which are not producing β-lactamases; not suitable for infection caused by G- bacteria • 2nd generation – infections of respiratory tract not caused by P. aeruginosa • 3rd generation – initial therapy of meningitis and gonorrhea • 3rd generation antipseudomonal – an alternative to piperacillin in treatment of staphylococcal infections • 4th generation – nosocomial infections caused by G- bacteria producing non-ESBL β- lactamases (not for MRSA) • 5th generation – currently introducing to clinics, “drug of last resort” , effective against MRSA and PRSP (penicillin-resistent Streptococcus pyogenes)

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CARBAPENEMS • all belong to group of “drug of last resort” used for treatment of severe life-threatening nosocomial infections (i.e. hospital- and community-acquired infections) X a susceptibility to MRSA is uncertain in monotherapy • they have the most extended spectrum from all β-lactams ATB • basic structure was isolated from Streptomyces cattleya, currently used drugs are its derivatives • all carbapenems could cause superinfections and pseudomembranous collitis

Mechanism of action • carbapenems like other β-lactams bind to PBP

Mechanism of resistance • they are stable to majority of β-lactamases • however, some strains produce carbapenemases • resistance is relatively less common but would be important clinically

Antimicrobial spectrum and indications • in fact all G+ and G-, aerobic and anaerobic ones, including strains producing extended-spectrum β-lactamases and chromosomal-coding β-lactamaes → nosocomial infections • between clinically important susceptible pathogens belong: ➢ Streptococci, incl. PRSP ➢ resistant strains of G- bacilli ▪ enterobacteriaceae ▪ pseudomonas → not for monotherapy, big difference between individual carbapenems ➢ sensitivity of MRSA is uncertain ➢ P. aeruginosa – and are the most effective ATB against this pathogen Pharmacokinetic of carbapenems • only for IV administration

• t1/2 about 1 hour • imipenem is hydrolyzed in kidney by dehydrodipeptidases 1 (DHP-1) to inactive metabolite → therefore is co-administered with selective reversible inhibitor of DHP-1 - cilastatin (Fig. 6C) • usually administered every 6-8 hours

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• main route of excretion is into the urine

Drugs imipenem (Fig. 6A, + cilastatin → Tienam® , Imipenem/Cilastatin Hospira®)

Adverse effects of imipenem ➢ the most often is nausea and vomitingnejčastěji (1-20 %) ➢ convulsions (paroxysmal epilepsy in high doses) and vertigo by 1.5 % of patients ➢ hypersensitive reaction would be crossed with other β-lactams ➢ hypotension would occurs during IV administration meropenem (Fig. 6B, Meronem®, Menoinfex®, Meropenem Kabi®; Meropenem Hospira® Meropenem Ranbaxy®) ▪ is not hydrolyzed by DHP-1 ▪ spectrum of AE is similar to imipenem

HO HO H S N NH S N N S N N H O COOH O O COOH N COOH O H NH2 COOH A B C

Fig. 6. Chemical structures of the most often used carbapenems (A-B) and the inhibitor of dehydrodipeptidase 1 cilastatinu (C). A: impipenem a B: meropenem

Following carbapenems are currently minimally used: (Invaz ®) ▪ is not hydrolyzed by DHP-1 (not registered in CZ, Finibax® and Doribax® in Japan and US) ▪ is hydrolyzed by DHP-1 to inactive metabolite pivoxil (not registerd in CZ, Orapenem ® in US) ▪ prodrug, the only orally administered

Projekt „Zvýšení kvality vzdělávání na UK a jeho relevance pro potřeby trhu práce-ESF Reg. č. CZ.02.2.69/0.0/0.0/16_015/0002362“, je financován z programu OP VVV

MONOBACTAMS This class contains only one drug, . aztreonam (Fig. 7, Cayston® for inhalation) ▪ Isolated from Chromobacterium violaceum Mechanism of action ▪ binding to PBP-3 Antimicrobial spectrum ▪ its spectrum covers G- aerobic microbes (enterobacteriaceae, Pseudomonas) ▪ G+ bacteria and anaerobic ones are primary resistant ▪ formerly was declared as extremely resistant to β-lactamases, but currently it is not true

Pharmacokinetic of aztreonam ▪ currently is available only in preparation for inhalation, otherwise it is available also for IV administration

▪ t1/2 = 1.7 hours ▪ excretion mainly in unchanged form by urine

Adverse effects of aztreonam ▪ generally well-tolerated drug ▪ allergic reactions are usually manifested only as rash/hives ▪ risk of superinfections and pseudomembranous colitis

S O

NH + N N 3 H N N O SO H O 3 HOOC

Fig. 7. Chemical structure of aztreonam.

Projekt „Zvýšení kvality vzdělávání na UK a jeho relevance pro potřeby trhu práce-ESF Reg. č. CZ.02.2.69/0.0/0.0/16_015/0002362“, je financován z programu OP VVV

REFERENCES Arancibia A, Guttmann J, González G, González C. Absorption and disposition kinetics of amoxicillin in normal human subjects. Antimicrob Agents Chemother1980;17(2):199-202. Brayfield A et al. Martindale The complete drug reference. 38th edition. Pharmaceutical press: London, 2014 Brunton L, Chabner B & Knollman B. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition. Mc Graw-Hill: New York, 2011. Jindrák V, Hedlová, Urbášová P et al. Antibiotická politika a prevence infekcí v nemocnici. Mladá fronta:Praha, 2014. Kinzig M, Sörgel F, Brismar B, Nord CE. Pharmacokinetics and tissue penetration of tazobactam and piperacillin in patients undergoing colorectal surgery. Antimicrob Agents Chemother. 1992;36(9):1997-2004 Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology 7th edition. Churchill Livingstone: Edinburgh, 2012. Katzung BG, Masters SB, Trevor AJ. Basic & Clinical Pharmacology 12th ed.. McGraw-Hill Medical: New York/London (2012) Web pages of FDA, EMA and SUKL, Micromedex (2018)