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Přemysl Mladěnka, Eduard Jirkovský










Basic characteristics

• antibiotics with macrocyclic lactone ring (with 14-17 carbons)

• erythromycin - isolated in 1952 from Streptomyces erythreus

• spiramycin isolated from Streptomyces ambofaciens

• clarithromycin, roxithromycin, azithromycin and telithromycin are semisynthetic derivatives

Mechanism of action

• binding on 50S ribosomal subunits

• type of action - bacteriostatic at lower dose, but some representants are bactericidal to specific microbes at higher concentrations

Antibacterial spectrum

• very effective against G+ cocci and bacilli

➢ esp. the first generation accumulates in G+ bacteria as 100times more as in G- ones.

• sensitivity against G- microbes differs between representatives; the 2nd generations is more effective against selected G- microbes (ranked according the clinical importance):

Moraxella catharalis, Hemophilus influenzae, Neisseriae, Camphylobacter

➢ intracellular and atypical bacteria (Legionella, Brucella, Chlamydiae and Mycoplasma pneumoniae)1

• some species of Mycobacteriae and protozoans are also sensitive

mechanism of resistance

• active efflux of the drug from the cell

• changes in the target motive - mutation of 50S subunit or its methylation

• hydrolysis of the macrolides cycle

• cross-resistance between all macrolides, also often for penicillins


• absorption is not altered for clarithromycin and telithromycin, but is altered for spiramycin, roxitromycin and azitromycin

• good distribution

➢ accumulates in neutrophils and macrophages

➢ esp. azithromycin has extreme Vd (30 l/kg, Fig. 1B)

➢ generally small penetration to CSF

1 Mycoplasma, Legionella and Chlamydia are not sensitive to betalactam antibiotics.


• very variable plasma half-life within the group o short in erythromycin (2 hours)

o 5-10 hours in spiramycin, clarithromycin, roxitromycin and telithromycin o very long in azithromycin (40-70 hours) (Fig. 1A)

• variable plasma protein binding2

• all metabolized in the liver, excreted in the bile

• do not demand a dose reduction in renal failure cases

Fig. 1. Plasma half-life (A) and volume of distribution (B) of selected macrolides. Notice the exceptionality of azithromycin in comparison to other representatives. Data about roxithromycin volume of distribution are not available.

2 Clinically unimportant in general with exception of roxithromycin (96%).



Divisions according to chemical structure

C-14 ring: erythromycin, roxithromycin, clarithromycin, telithromycin

C-15 ring: azitromycin

C-16 ring: spiramycin

Macrolides of the 1


generation (natural)

• preferable for children, in pregnancy and breastfeeding

• erythromycin (currently only in topic preparations Zineryt®, Eryfluid®)

• spiramycin (Rovamycine® tbl) o dosing every 8-12 hours

Makrolides of the 2


generation (semisynthetic)

• preferable for Haemophilus infections

• better tissue distribution, esp. to lungs

• higher GIT tolerability

• administered orally 1-2x daily according to the drugs

• steep rise of their consumption leads to significant increase of the resistance

• clarithromycin (Fig. 2, CLA, Clarithromycin-Ratiopharm®, Clarithormycin-Teva®, Fromilid®, Klabax®, Klacid®, Klaritrhomycin Mylan®)

o 12-hour dosing

• roxithromycin (Roxithromycin Ratiopharm®) o 12-hour dosing

• azithromycin (AZI, Sumamed®, Apo-Azithromycin®, Azithromycin Actavis®, Azithromycin Mylan®, Azithromycin Sandoz®, Azitrox®, Azibiot®, Zetamoc®, Zitrocin®)

o 24-hour dosing

o very good tissue distribution, also cumulates in lysosomes, phagocytes, fibroblasts o tissue t1/2 is about 2-4 days, it makes plasma t1/2 about 40-70 hours -> shortening of the

duration of the treatment in many cases.

• telithromycin (Ketek®)

o lower risk of the resistance development

o significant safety concerns exist about drug-induced liver failure o dosing every 24 hours

o Sometimes is ranked among ketolides as a subgroup of macrolides


Fig. 2. Clarithromycin structure.

Adverse effects

• hypersensitive reaction are not common

• cholestatic hepatitis - esp. with ERY, rare in other macrolides excluded telithromycin (causing hepatotoxicity)

• GIT – often with ERY; AZI possess risk of pseudomembranous colitis

• prolongation of QT interval

• telithromycin caused accomodation disorders, deterioration of myastenia gravis


• ERY, CLA and telithromycin are inhibitors of CYP 450 and P-glycoprotein → risk of increase of effects (and toxicity ) of many drugs, e.g. theofylinu, amiodaronu, digoxinu, simvastatnu

• roxithromycin and AZI are more weaker inhibitors

• spiramycin probably does not possess such interaction potential


• infection of respiratory tract - especially for medium-grade pneumonia and atypical pneumonia caused by

Mycoplasma – macrolides or tetracycline

Legionella – AZI or fluorchinolone

Chlamydia - macrolides or doxycycline

➢ pertussis

• alternatives for penicillins and cephalosporins for treatment of

➢ infections of upper and lower respiratory tract

➢ syphilis, gonorrhea

Helicobacter pylori – CLA in combination of AMO

Mycobacterium avium-intracellulare3 – CLA or AZI in combination with other drugs

• some skin infections caused by Staphylococci or Streptococci

3 For treatment of Mycobacterium leprae – CLA + minocycline



currently only one medicinal preparative is available in CZ

chloramphenicol (Fig. 3, CMP, inj: Chloramfenikol Vuab®; gtt.oph:+dexamethanson-Spersadex®,+betamethason – Betabioptal®)

• only for treatment of life-threatening infections and only as the drug of last choice

• especially for treatment of meningitis and Richettsiae infections

• isolated in 1947 from Streptomyces venezuelae

Fig. 3. Chemical structure of chloramphenicol.

Mechanism of action

• inhibits protein synthesis due to binding to a 50S ribosomal subunit

• primary its action is bacteriostatic, but for some specific microbes is bactericidal

• easily cross through biological membranes

• may inhibit also mitochondrial protein synthesis in eukaryotic cells

Antimicrobial spectrum and resistant microbes

• broad spectrum → most of G+ and G-, and majority of anaerobe microbes

• effective even against Mycoplasma, Chlamydia and Rickettsia

• lower effect against Staphylococcus aureus

Salmonella, Shigella and Pseudomonas are resistant

Mechanism of resistance

• mostly due to acetylation of the parent compound

• decreased penetration into the microbes by induction of efflux mechanisms

• mutation of ribosomal binding site O Cl2





• fast absorption from GIT

• CMP-succinate is used for parenteral application

• very good distribution

• concentration in CSF reaches about 60 % of plasma cmax

• readily enters the breast milk, foetus and bile

• eliminated by liver glucuronidation (inactive metabolite) and excreted by urine

• plasma half-life: 3-4 hours

Adverse effects

• hypersensitive reaction - less common

• hematotoxicity – the most important AE, bone marrow is affected by two manners:

➢ dose-dependently – anaemia, leukopenia and thrombocytopenia

➢ dose-independently - idiosyncratic reaction - aplastic anaemia with incidence about 1:30,000

▪ in half of cases is reversible, additional risk of acute leukaemia after cure

▪ more common after longer therapy or after the repeated exposition

▪ probably matter of genetic predisposition

• "gray baby syndrome" (also termed "grey baby syndrome") - serious AE in newborn infants after use of excessive CMP dose

o newborn infants (esp. premature babies) have significantly reduced glucuronidase activity and renal excretion of CMP and its metabolites o due to the accumulation high plasma CMP levels blocks electron transport in

the liver, myocardium and skeletal muscles

o symptoms: ashen gray colour of the skin, cyanosis, irregular respiration, cardiovascular collapse, GIT symptoms etc.

• GIT symptoms – vommiting, diarrhea, loss of appetite, absominal distension etc.

• risk of developing candidiasis

Drug interaction

• CMP inhibits liver CYP450 and thus prolong half-time of some other drugs

• CMP plasma half-life is shorten due to glucuronidase induction by rifampicin and phenobarbital

Therapeutic Indications

• drug of the last choice for treatment of

➢ epidemic typhus (Rickettsia prowazekii) and typhoid fever (Salmonella typhi), cholera


➢ meningitis

➢ pertusiss (whooping cough), infections caused by anaerobes


Mechanism of action

• inhibition of proteosynthesis due to binding to 50S ribosomal subunit, binding site is similar to macrolides and CMP

• bacteriostatic antibiotic drugs

Antimicrobial spectrum

Streptococci sp., even against ones resistant to macrolides

Staphylococi sp. only those sensitive to methicillin

• anaerobic bacteria

• some protozoa4

• generally are ineffective against aerobic G- bacteria

Resistance development

• cross-resistance with macrolides can occur

• mutation of 50S binding site

• lincosamides are not substrate for efflux pump for macrolides


• lincomycin (Neloren® inj. i cps.)

o isolated from Streptomyces lincolnensis

• clindamycin (Fig. 4, p.o., i.v.: Dalacin C®, i.v.: Klimicin® )

o derived from lincomycin by replace of hydroxy group in pos. 7 with chloride o is more effective than lincomycin

4 Pneumocystis carini, Toxoplasma gondii and Plasmodium


Fig. 4. Structure of clindamycin.


• lincomycin has lower BAV (20-35 %) and food decrease absorption

• Clindamycin has higher BAV (90 %) and BAV is not affected by food

• good distribution to tissues and body fluids5, active trapping in leucocytes, accumulation in abscesses

➢ do not penetrate to CNS

➢ cross placental barrier

• biotransformation in liver, metabolites are excreted by urine and bile

→ presence of hepatic and/or renal failure require a dose reduction

• plasma half-life: 5 hours for lincomycin and 3 hours for clindamycin → administated each 6 - 8 hours

Adverse effects

• diarrhoea 2-20%

• pseudomembranous colitis – 0.01-10 %, can be of letal case

• skin hypersensitive reaction - up to 10 %

Therapeutic indications

• for treatment of severe infections clindamycin is used i.v. or i.m. as clindamycin phosphate

• they are used mainly for treatment of nosocomial staphylococcal or anaerobic infections

• for ambulatory care as an alternative for penicillins (hypersensitivity to penicillins) for treatment of skin and soft tissue infections

5 Vd of clindamycin is 1.1 L/kg



retapamulin (Fig. 5, Altargo ung.®)

• semisynthetic drug, derivatives of pleuromutilin (isolated from Clitopilus passackerianus in 1950’s)

• the only representative approved in humans (tiamulin approved in animals)

Mechanism of action

• inhibition of proteosynthesis due to binding to 50S ribosomal subunit, the binding site different from other drugs; prevent formation of 70S subunit

• bacteriostatic but become bactericidal in higher concentrations

Antibacterial spectrum and resistance

• Staphalococci (except of MRSA) and Streptococci

• Resistance is not crossed with any other known ATB!

Therapeutic indication

• Topic treatment of bacterial skin infections (mainly impetigo)

Fig. 5. Structure of retapamulin. From Čapková, 2008


Currently, linezolid is the only registered representative of this group in humans in CZ

Mechanism of action

• inhibition of proteosynthesis due to binding to 50S ribosomal subunit, the binding site different from other drugs; preventing formation of 70S subunit

• generally bacteriostatic for staphylococci and enterococci but bactericidal for streptococci


Antibacterial spectrum and resistance

• especially effective in treatment of G+ bacterial infections (also effective against vancomycin- resistant enterococci and MRSA)

Clostridium difficile is sensitive to linezolid in vitro

• modest activity against G- bacteria

• very low incidence of reistance


• rapid and complete absorption after p.o. administration (BAV 100 %)

• good and rapid distribution to all tissues, bronchial fluids, but lower in CSF

• plasma half-life: 5 hours in adults, 3 hours for children

• clearance decreases with age and in women

• metabolized in liver without involvement of CYP450

• metabolites are excreted mostly by urine

Adverse effects

• relatively safe in short-term use: AEs are mild (mainly diarrhoea, nausea and headache up to 10 %)

• in long-term use, bone marrow suppression (thrombocytopenia) and peripheral neuropathy could occur

• incidence of pseudomembranous colitis and Clostridium difficile-associated diarrhoea (CDAD) is similar with other ATB

• skin hypersensitive reaction - up to 10 %

Therapeutic indication

• treatment of resistant infection caused by sensitive microbes (mainly skin infections and pneumonia)

• may be an alternative for vancomycin for nosocomial pneumonia or as a drug of first-line (US guideline)

• linezolid (Fig. 6, Zyvoxid tbl i inf®)

Fig. 6. Structure of linezolid.



Currently, metronidazole is the only registered representative of this group in humans in CZ6

metronidazole (Fig. 7, p.o. tbl. et vag. tbl.: Entizol®; inj.: Efloran®, Metronidazol B.Braun®, Metronidazol-Serag®; miconazol → Klion-D 100®) – semisyntetic antibiotic and antiprotozoal agent

Fig. 7. Structure of metronidazole.

Mechanism of action

• interfere with energy metabolism only in anaerobic bacteria some protozoa

• bactericidal and amebicidal effects

Antimicrobial spectrum

• some protozoa: e.g. Giardia lamblia, Trichomonas vaginalis, Dracunculus medinensis, Entamoeba histolytica

• all obligatory anaerobic bacteria: e.g. Helicobacter pylori

• aerobic microorganisms are generally resistant


• fast and complete absorption (BAV 80 % p.o., 60-80 % per rectum, 20-25 % vaginal adm.)

• plasma half-life 8 hours

• distribution to all body water

➢ reaches effective therapeutic concentrations in saliva, milk, vaginal secret, seminal fluid as well as CSF

• plasma protein binding < 20 %

• metabolized in liver, excreated by kidney to urine

Adverse effects

• only seldom are so severe to discontinuation of the treatment is needed

mild but often AEs are headache, nausea, dry mouth, metallic taste and loss of appetite

• less often AE:

o vomiting, diarrhoea and abdominal pain

6ornidazole (ad us. vet) and tinidazol (nereg.) have longer half-life N





o risk of development of candidiasis

severe but less common AEs:

o peripheral neuropathy and CNS toxicity (vertigo, seizures, ataxia) → discontinuation of the treatment

o hypersensitive reaction (allergy) → discontinuation of the treatment

o disulfiram effect – inhibition of aldehyddehydrogenase, intolerance of alcohol o Steven-Johnson syndrome

• there are unsolved concerns about cancero- and mutagenesis

• chemical properties – brown colour of the urine

Drug interaction

• phenobarbital, prednisone, rifampicin and probably ethanol induce metabolism of metronidazole

• cimetidine decrease rate of metronidazole metabolism


• gravidity and breastfeeding

Therapeutic indications

• 90 % efficacy for treatment of vaginal trichomoniasis

o Used also in prevention of preterm delivery associated with bacterial vaginosis

• Treatment of amoebiasis, giardiasis, dracunculiasis etc.

• Drug of first choice in pseudomembranous colitis

• Along with beta-lactams for treatment of mixed anaerobic/aerobic infections



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