Table of contents :

Novel strategies in antibacterial drug development^ref :

• antivirulence-directed therapy
• target virulent bacteria
• requires discovery of a lethal target present only in virulent bacteria
• vaccination directed against virulence determinants has also been proposed
• this approach would prevent acquisition of antibiotic resistance genes by non-pathogenic bacteria
• genomics : new targets for inhibiting bacterial growth and variability : block vital metabolic pathway, efflux pump inhibitors, quorum-sensing signalling systems, hoped that mutations in the targeted gene that may occur through drug pressure will not be compatible with viability. Identify target gene => clone gene, express, purify and crystallize => identify active site and screen molecule against site => test in whole bacteria. 200-400 bacterial genes are essential genes and are a priori candidates for killing sites by inhibitors. Comparative bacterial genomics allows further prioritization of ORFs that are conserved in pathogens but absent in higher eukaryotes, and for which a function can often be predicted by bioinformatics. There are several cases in which additional knowledge is likely to increase markedly the probability of finding new macromolecular targets. An under-explored target is the transglycosylase step of peptidoglycan assembly in the cell wall, in which the chemo-enzymatic synthesis of the complex lipoglycopeptide substrate, lipid II, now enables modern configurations of high-throughput assays. In Gram-positive bacteria, it has been known for some time that cell-surface proteins can covalently attach to peptidoglycan. Bacterial genomic analyses have identified multiple sortases in different pathogens. Deciphering the selectivity of sortases for groups of proteins that end up at the cell surface might be a prelude to the screening or design of inhibitors. Sortases should be readily accessible to ligands, and therefore good drug targets, but it remains to be proven how responsive they will be for bacteriostatic or bacteriocidal action. A final example is the non-classical pathway of isoprenoid synthesis. In contrast to the classical mevalonate pathway found in eukaryotes, many bacteria, including clinically important pathogens, have recently been found to contain the genes that encode a separate pathway that has deoxyxylulose-5-phosphate as an intermediate rather than mevalonate. The 7 enzymes of the deoxyxylulose-5-phosphate pathway are not present in humans; these enzymes are essential for lipid I and II biosynthesis as key intermediates in peptidoglycan assembly.
• tageting non-multiplying bacteria (antibiotic kills the multiplying bacteria) : combination strategies. When antibiotic dose decreases below a threshold, metabolism in non-multiplying bacteria starts and some of them begin to multiply, becoming susceptible to the next dose of antibiotic
• overcoming resistance : strategies to combat efflux pumps-mediated drug resistance
• apramycin, which mimics a short section of RNA, interrupts the plasmid's replication by sticking to RNA strands that carry its genetic information. This 'blocks' the strands, at which point the host bacterium categorizes the plasmid as a foreign body and ejects it. Apramycin is not likely to be used in clinical trials, because it is quite toxic. But now that the chemists have proved how it works, they are looking for other molecules that could do the same job without causing problems for the patient.

phenol

Woods-Fildes theory : the theory that the antibacterial activity of at least some chemotherapeutic drugs (especially the sulfonamides) is a consequence of a competitive inhibition of essential metabolic reactions of the microorganism.

• antibacterial interfering with cell-wall biosynthesis (absent in cell wall-less Bacteria and L forms) : bactericidal
• nicotinic acid derivatives :
• isoniazid / isoniazide (INH) / isonicotinic acid hydrazide (INAH^®, Nydrazid^®, Rifamate^®, ...) is a pro-drug, which, after activation by the mycobacterial katG-encoded catalase peroxidase, reacts nonenzymatically with NAD⁺ and NADP⁺ to generate several isonicotinoyl adducts of these pyridine nucleotides :
• the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. It inhibits pyridoxal phosphorylation to vitamin B₆ (Mycobacteria cells contain low levels of such a kinase) : so pyridoxine-dependent reactions are inhibited (e.g. enoyl-ACP reductase of fatty acid synthase (FAS) II, which converts D²-unsaturated to saturated fatty acids on the pathway to mycolic acid biosynthesis). It should be co-administered with vitamin B₆ / pyridoxine to minimize adverse side effects from pyridoxal kinase inhibition.
• the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosisdihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc2155 protects cells against growth inhibition by isoniazid by sequestering the drug^ref.
• ethionamide (Trecator-SC^®) inhibits the acetylation of isoniazid in vitro.
• prothionamide
• pyrazinamide (PZA) (pyrazine analog of nicotinamide) inhibits mycobacterial fatty acid synthase (FAS) I, involved in mycolic acid biosynthesis.
• D-ethambutol hydrochloride (Myambutol^®). It blocks arabinosyl transferases involved in synthesis of lipoarabinomannan (LAM) and mycolic acids. It is the only chemotherapeutical effective on Mycobacterium marinum. Side effects : visual disturbances
• lipopeptides :
• acid lipopeptides inhibit LTA synthesis
• daptomycin (Cidecin^®, Cubicin^®) : rapdily bactericidal, i.v. only, may cause myalgia, efficacy for bacteremia/endocarditis not demonstrated
• riminophenazines :
• B663 / clofazimine / clofazamine (Lamprene^®) inhibits Na⁺/K⁺ ATPase and acts as an immunosuppressor
• B669
• b-lactams have been introduced in 1940 :
• penicillins : tetrahydrothiazole-containing (penem group) compounds that irreversibly inhibit the transpeptidase activity of penicillin-binding protein (PBP) 3. 1 international unit of penicillin : the specific penicillin activity contained in 0.6 mg of the international standard sodium salt of penicillin II or G.
• natural penicillins(Gram +ve Bacteria and Neisseria gonorrhoeae). Resistance to penicillin today occurs in as many as 80% of all strains of Staphylococcus aureus : surprisingly, Streptococcus pyogenes has never fully developed resistance to penicillin !
• benzylpenicillin (Benpen^®)
• penicillin G (benzathine, potassium, procaine) (Bicillin^® C-R/L-A, Penicillin G^®, Pfizerpen^®, Wycillin^®)
• penicillin V (Pen-Veek^®, Beepen-VK^®)
Side effects : drug-triggered pemphigus
• biosynthetic penicillins (a-aryloxyalkylpenicillins)
• pheneticillin
• propicillin
• fenbenicillin
• chlomethocillin
• azidocillin (acid-resistant => PO)
• semisynthetic penicillins (Gram -ve rods). A mold produces the main part of the molecule (6-aminopenicillanic acid) which can be modified chemically by the addition of side shains. Resistant to b-lactamase.
• dihydropenicillin F
• a-aminopenicillins / 2nd generation
• amoxicillin (Amoxil^®, Hiconcil^®; Pulsys^® is a once-daily formulation; Flumox^® in combination with flucloxacillin)
• ampicillin (Omnipen^®, Polycillin^®, Pentrexyl^®, Servicillin^®, ...) is effective orally (prodrugs : bacampicillin (Penglobe^®, Spectrobid^®), etacillin, pivampicillin (Pondocillin^®), talampicillin and metampicillin)
• cyclacillin (Cyclapen-W^®)
• epicillin
Side effects : Steven-Johnsons's syndrome
• anti-Pseudomonas aeruginosa penicillins :
• a-carboxypenicillins (decreased effect on Gram +ve)
• carbenicillin indanyl sodium (Pyopen^®, Geogen^®, Geocillin^®)
• carfecillin
• ticarcillin (Ticar^®)
• ureidopenicillins or N-acylpenicillins
• apalcillin
• azlocillin
• furbenicillin
• guanylureidopenicillin
• mezlocillin sodium (Mezlin^®)
• piperacillin (Avocin^®, Pipracil^®)
• pirbenicillin
• thymoxycillin
• a-sulphoxypenicillins
• sulbenicillin (Lilacillin^®)
• suncillin
• b-lactamase resistant penicillins
• isoxazolpenicillins
• cloxacillin (Prostaphylin-A^®)
• dicloxacillin (Dycill^®, Diclocil^®, Dynapen^®, Pathocil^®, ...)
• flucloxacillin / floxacillin (Floxapen^®; Flumox^® in combination with amoxicillin)
• oxacillin (Prostaphilin^®, Bactocil^®)
• methicillin (Staphcillin^®) binds PBP2.
• nafcillin (Unipen^®, Nallpen^®, Nafcil^®...)
• 6a-methoxypenicillins (6a-methoxyphenem)
• temocillin (Temopen^®)
• amidinopenicillins
• mecillinam (Coactin^®)
• pivmecillinam (Alexid^®, Selexid^®)
• amidinopentanoic acids
• amdinocillin (prodrugs : pivamdinocillin, bacamdinocillin)
Side effects : type I, type II, type III and type IV hypersensitivities. Before the initiation of cephalosporin therapy, skin testing should be performed for patients with a suspected history of IgE-mediated reactions to penicillins^ref. The rate of cross-reactivity of > 10% between penicillins and cephalosporins has not been well established. 3 retrospective clinical studies reported rates of reaction to carbapenems of 9 to 11% among inpatients with a reported penicillin allergy^{ref1, ref2, ref3}. An earlier study reported that of 20 subjects with a positive penicillin skin test, 10 reacted to an imipenem reagent^ref.
• oxacephems (oxacephem group) : effective against Gram +ve and Gram -ve Bacteria, penicillinase-resistant.
• latamoxef
• moxalactam (Moxam^®)
• cephalosporins (Gram +ve and Gram -ve Bacteria) (from 7-aminocephalosporanic acid). Cephem group. They tend to be resistant to b-lactamases/penicillinases from S. aureus. They bind PBP3.
• cephalosporin C (Cefamezine^®)
• 1^st generation cephalosporins
• cefacetryl
• cefadroxil (orally active) (Duricef^®, Ultracef^®)
• cefalexin / cephalexin (orally active) (Cefanox^®, Ceforex^®, Cilex^®, Ibilex^®, Keflex^®, Keftal^®, Keftabs^®, Ulex^®). Side effect : drug-triggered pemphigus
• cephaloridine
• cephalotin (Keflin^®, Seffin^®)
• cephapirin (Cefadyl^®)
• cephatrizin (orally active)
• cefazolin (Ancef^®, Kefzol^®, Zolicef^®,...) : i.v.
• cephradine (Askacef^®, Velocef^®) (orally active)
• cephtezol
• 2^nd generation cephalosporins (cephamycins)
• axetil (acetoxyetyl) cefuroxime (Ceftil^®) (b-lactamase resistant)
• cefaclor (Ceclor^®, Ceclor CD^®, Keflor^®, Varcef^®) (orally active)
• cefamandole (Mandol^®)
• cefmetazole (Cefmetazon^®)
• cefocinid (Monocid^®)
• ceforanide (Precef^®)
• cefotetan disodium (Apatef^®, Cefotan^®)
• cefotiam (Pansporine^®, Pansporin T^®)
• cefoxitin (Mefoxin^®) (b-lactamase resistant)
• cefprozil (Cefzil^®)
• ceftmetazole (Zefazone^®)
• cefuroxime (Kefurox^®, Zinacef^®) : i.v.
• loracarbef (Lorabid^®)
• 3^rd generation cephalosporins
• cefdinir (Omnicef^®)
• cefetamet pivoxil
• cefixime (Suprax^®)
• cefmenoxime (Bestcall^®)
• cefodizim (Timecef^®)
• cefoperazone (Cefobid^®)
• cefotaxime (Claforan^®) : i.v.
• cefpodoxime proxetil (Orelox^®, Vantin^®)
• cefsulodin (Takesulin^®)
• ceftazidime (CAZ) (Ceptaz^®, Fortaz^®, Fortum^®, Tanicef^®, Tazidime^®,...) (P.aeruginosa)
• ceftibuten (Cedax^®, Seftem^®)
• ceftizoxime (Cefizox^®, Eposerin^®)
• ceftriaxone (Rocephin^®)
• moxalactam (Moxam^®)
• 4^th generation cephalosporins (oxacephamycin)
• cefditoren pivoxil (Meiact^®)
• cefepime (Maxipime^®) : i.v. (P.aeruginosa)
• cefetecol
• cefozopran (Firstcin^®)
• cefpirome (Cefrem^®) : i.v.
• flomoxef (Flumarin^®)
• 5ht generation cephalosporins (P.aeruginosa)
• ceftobiprole medocaril / BAL 5788 / RO 65-5788 / JNJ 30982081 is the water-soluble prodrug of the pyrrolidinone cephalosporin, ceftobiprole / BAL 9141 / RO 63-9141, which has activity against P.aeruginosa^ref
• ceftarolime (Cerexa^®)
• CB-181963 (CAB-175) (i.v.)
Side effects : Steven-Johnsons's syndrome
• carbapenems (Gram +ve cocci and Gram -ve rods, P.aeruginosa, anaerobes, Enterococci) (the N atom in the penem group of penicillin is substitued by a C atom => carbopenem group). They arise from modifications of the chemically unstable thienamycin. Parenteral administration.
• group 1 : no activity against nonfermenting bacteria
• tebipenem / ME121 (Japan)
• panipenem + betamipron (PAPM/BP) (Carbenin^® + betamipron) : to inhibit panipenem uptake into the renal tubule and prevent nephrotoxicity
• group 2 : activity against nonfermentating bacteria
• imipenem (IPM) / MK 0787 / N-formimidoiyl thienamycin + cilastatin (IPM/CS) (an inhibitor of renal dihydropeptidase I (DHP-I)-mediated hydrolysis in proximal renal tubule) (Imipem^®, Primaxin^®, Tienem^®). As it is a zwitterion it can penetrates the outer membrane in Gram -ve Bacteria. The trans-hydroxyethil side chain differs from the cis-aminoacyl  side chain in penicillins and so this molecule is not a substrate for b-lactamase. It binds PBP a/Ib.
• meropenem (EMPM) (Merrem IV^®) is a dimethylcarbamoyl pyrodinyl derivative of thienamycin and is not hydrolized by dipeptidase I
• doripenem^ref
• biapenem (BIPM) (Japan) is more stable than imipenem, meropenem and panipenem to hydrolysis by human renal DHP-I, and therefore does not require the coadministration of a DHP-I inhibitor.
• group 3 : tomopenem
• ertapenem (Invanz^®) is a once-daily parenteral group 1 carbapenem antibiotic used in the treatment of complicated intraabdominal infection^{ref1, ref2, ref3}. Several characteristics of ertapenem make its use attractive as a potential preoperative antimicrobial agent in elective colorectal surgery, since it is characterized by rapid intravenous administration, appropriate coverage against potential pathogens, a long half-life (so it does not require a second administration during most surgeries), and a safety profile similar to that of other commonly used antibiotics^{ref1, ref2, ref3, ref4}
• faropenem daloxate (Farom^®), a new oral penem
• RO4908463 / CS-023
• olivanic acids / olivanates
• MM4550
• MM13902
• MM17880
• MM22380
• MM22381
• MM22382
• MM22383
In recent years, the number of class D beta-lactamases with carbapenem-hydrolysing properties has increased substantially. Based on amino acid sequence identities, these class D or OXA-type carbapenemases are divided into eight distantly related groups, and they are only remotely related to other class D beta-lactamases. A putative ancestor to one of the plasmid-encoded OXA-type carbapenemases has been found. OXA-type carbapenemases are not integrated into integrons as gene cassettes like many class D oxacillinases, but most of the OXA-type carbapenemases are instead encoded by chromosomal genes. Some of these OXA-type carbapenemases are widely dispersed in Pseudomonas aeruginosa and especially in Acinetobacter baumannii. Although most of the OXA-type carbapenemases show only weak carbapenemase activity, carbapenem resistance may result from a combined action an OXA-type carbapenemase and a secondary resistance mechanism such as porin deficiencies or overexpressed efflux pumps. This article reviews the phylogeny and the genetic environments of the encoding genes and kinetic properties of the OXA-type carbapenemases^ref
• monocyclic b-lactams / monobactams (aerobic Gram -ve Bacteria)
• aztreonam (Azactam^®) : penicillinase-resistant, used against Pseudomonas aeruginosa
• carumonam (Amasulin^®)
• tigemonam
• b-lactamase / penicillinase competitive irreversible inhibitors (they are effective only if coupled to a penicillin whose pharmacokinetics is identical) :
• 6b-iodopenicillanic acid
• 6b-bromopenicillanic acid
• olivanic acids / olivanates
• BRL42715
• oxapenems
• clavulanic acid (clavam group) in combination with ...
• amoxicillin : clavamox (Augmentin^® / Clavucid^®)
• ticarcillin : co-amoxiclav (Timentin^®)
• penem sulfones
• sulbactam, a penicillanic acid sulfone in combination with ...
• ampicillin (Unasyn^®)
• piperacillin
• tazobactam (in combination with piperacillin in TAZ/PIPC or Tazocin^® / Zosyn^®)
• glycopeptides (heptapeptide-attached sugars) have been introduced in 1958 (Gram +ve Bacteria)
• vancomycin group
• vancomycin hydrochloride (Lyphocin^®, Vancocin^®, Vancoled^®) inhibits both transglycosylation and transpeptidation reactions during peptidoglycan assembly: it makes 5 hydrogen bonds to the -D-Ala-D-Ala dipeptide terminus of each uncrosslinked peptidoglycan side chain, inhibiting both the transglycosilase and transpeptidase activity of PBPs. Nowadays vancomycin-resistant Enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) (MBC > 32 mg/mL) appeared thanks to a plasmid-coded enzyme that creates -D-Ala-D-lactate termini, resulting in the loss of 1 hydrogen bond that significantly reduces the binding constant ! The VanA strains are resistant to both vancomycin and teicoplanin, while the VanB strains are resistant to vancomycin only.

Side effects : nephrotoxicity, histamine-mediate "red-man syndrome" (anaphylactoid reaction). Cross-resistance to glycopeptides can arise from use of avoparcin as growth promoter in animal feeding.
• oritavancin / LY333328
• teicoplanin group : N-methylLeu in 1 and Lys in 3 are replaced by substituted phenylGlys
• teicoplanin (Targocid^®, Targosid^®) (a lipoglycopeptide less toxic than vancomycin)
• telavancin
• ristocetin (it also binds to vWF (which in fact is a.k.a. ristocetin cofactor) causing human platelets aggregation)
• dalbavancin (Pfizer) : a new milestone of outpatient antimicrobial therapy (OPAT) ? One-shot schedule (1-week half-life; 60% accumulates in bone)
• eremomycin
• BRL 47761
• ramoplanin (a glycolipodepsipeptide consisting of 17 amino acids cyclized to a macrolactone) inhibits transpeptidase activity of PBPs
• fosfomycin trometamol (Monural^®, Monuril^®) (broad spectrum) (from Streptomyces gradiae) inhibits PEP transferase
• bacitracin zinc (AK-Tracin^®, Baci-IM^®, Baciferm^®; Polysporin^® in combination with polymixin B; Bimixin^® in combination with neomycin; Neosporin^® in combination with both neomycin and polymixin B) (Gram +ve Bacteria) needs a divalent cation (Mg²⁺, Zn²⁺, Co²⁺, Ni²⁺ or Cu²⁺) to bind the undecaprenol-P-P and preventing it from being dephosphorylated by a membrane pyrophosphatase. It has a high kidney toxicity which precludes its systemic use. It is present in many topical antibiotic preparations, and since it is not absorbed by the gut, it is given to "sterilize" the bowel prior to surgery.
• D-cycloserine (Seromycin^®) (Gram -ve and Gram +ve Bacteria) (from Streptomyces orchidaceous) enters bacterial cells by means of an active transport system for Gly and can reach a relatively high intracellular concentration inhibiting Ala racemase and D-Ala-D-Ala synthetase. Side effects : as it is fairly toxic (NMDA-R partial agonist) it has limited use as a secondary drug for TBC.
• spirocyclohexene
• griseofulvin inhibits microtubule formation in mitotic spindle. It may act as a photosensitizer.
• antibacterial interfering with cell membrane integrity : these antibiotics disorganize the structure or inhibit the function of bacterial membranes. However, due to the similarities in phospholipids in eubacterial and eukaryotic membranes, this action is rarely specific enough to permit these compounds to be used systemically.
• cyclic polypeptides
• polymyxin. Effective mainly against Gram -ve Bacteria : usage is usually limited to topical usage and is occasionally given for UTIs caused by Pseudomonas strains that are gentamicin-, carbenicillin- and tobramycin-resistant. The balance between effectiveness and damage to the kidney and other organs is dangerously close, and the drug should only be given under close supervision in the hospital.
• polymixin B sulfate (a mixture of polymixin B₁ and B₂) (Aerospin^®; Polysporin^® in combination with bacitracin; Neosporin^® in combination with bacitracin and neomycin; Neosporin^® in combination with gramicidin and neomycin; Polytrim^® in combination with trimethoprim) binds to the lipid-A portion (the hyppo) of LPS^ref
• polymixin E / colistin (Acetylcolistin^®, Colisticina^®, Colistin-600^®, Colimicin^®, Coly-Mycin-S^®, Multimycine^®) (bactericidal) from Aerobacillus colistinus
• amoxicillin + colistin (Amoxycol^®, Potencil^®)
• ampicillin + colistin (Entercol^®)
• erythromycin + colistin (Erythrostine^®)
• flumestine + colistin (Flumestin^®)
• erythromycin + trimethoprim + colistin (Mycoplasmin^®)
• oxytetracycline + colistin (Colicyclin^®)
• colistin  + vitamins + amino acids (Colistin-80^®)
• colistin sulfate + neomycin sulfate + thonzonium bromide + hydrocortisone acetate (Coly-Mycin S^®)
• colistemethate (Coly-Mycin^®) M & S; Colbiocin^® in combination with rolitetracycline and chloramphenicol
• tyrothricin
• polyene : inhibits sterols present in cell wall-less Bacteria, but they are mainly used as antifungal agents.
• platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. This anti-bacterial effect is exerted through the selective targeting of b-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including MRSA, VISA and VRE. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity^ref.
• antibacterial interfering with protein synthesis
• impairing 50S subunit => prevents translation => bacteriostatic
• oligosaccharides
• evernimomycin / evernimoicin / evernimycin / SCH27899 (Ziradin^®)
• macrolides have been introduced in 1952 (against most Bacteria ; bactericidal for a few Gram +ve Bacteria) : macrocylic (12÷22 carbon atoms) lactones linked through glycoside bonds with amino sugars. Binding to the rRNA 23S (P8 protein ?) in the 50S ribosomal subunit inhibits elongation of the protein by peptidyl transferase or prevents translocation of the ribosome or both.
• dirithromycin (Dynabac^®)
• fluritromicin
• midecamicin
• rokitamycin
• 14 carbons
• clarithromycin (Biaxin Filmtabs^®, Biaxin XL Filmtabs^®, Biaxin^®, Klacid^®, Klaricid^®) : agonist on MTLR1.
• erythromycin base (E-Mycin^®, Ilotycin^®,  ...), estolate (Ilosone^®), gluceptate (Ilotycin Gluceptate^®), ethylsuccinate (E.E.S.^®, ...) + sulfisoxazole or lactobionate (Erythrocyn Lactobionate-I.V.^®) ; Benzamycin^®, Persa-Gel^®, ... in combination with benzoyl peroxide. From Streptomyces erythreus : not effective against Enterobacteriaceae. Bactericidal in vitro at high concentrations.

Side effect : vomiting and infantile hypertrophic pyloric stenosis (IHPS) due to action as agonist on MTLR1 (33%)

• dirithromycin
• flurithromycin
• oleandomycin : agonist on MTLR1.
• troleandomicin (Tao^®)
• roxithromycin (Rulide^®, Rulid-D^®)
• 15 carbons (2nd generation)
• azithromycin (Zithromax^®) : agonist on MTLR1.
• 16 carbons
• josamycin (Josalid^®)
• miocamycin (Miocamen^®)
• midecamicin
• rokitamycin
• rosaramycin
• spiramycin (Rovamycine^®, Ulcar^®) for treatment of toxoplasmosis and cryptosporidiosis
Cross-resistance to macrolides can arise from use of tylosin and virginiamycin as additives in animal feeding.
• third-generation macrolides / 3-ketolides (a 3-keto group replacesL-cladinose group of macrolides)
• telithromycin (Ketek^®) is 99% effective in vitro against Streptococcus pneumoniae. i.v. only, may cause nausea and vomiting, and acute hepatitis^ref. It inhibits secretion of IL-1b and TNF-a^ref
Inhibit catabolism of warfarin, triazolam, valproate, cyclosporine, ....
• lincosamides
• lincomycin hydrocloride (Lincocin^®)
• clindamycin (Cleocin^®, Dalacin C^®) pediatric (Cleocin Pediatric^®), topical (Cleocin T^®) or topical phosphate (Cleocin Phosphate^®, Actiza^®) is 7-chloro-7-deoxylincomycin, effective against Gram +ve Bacteria and Gram -ve Neisseria, Hemophilus influenzae, Bacteroides spp.). Velac^® in combination with tretinoin.
Cross-resistance to lincosamides can arise from use of tylosin and virginiamycin as additives in animal feeding.
• streptogramins (introduced in 1962) bind 50S impairing both early peptide chain elongation and late peptide chain extrusion => bacteriostatic. They are a mix of :
• A (macrolide)
• dalfopristin
• B (cyclic peptide)
• quinupristin
• pristinamycin / RP 59500 = quinupristin + dalfopristin (Q/D) (Synercid^®) : they are semisynthetic derivatives of pristinamycins. i.v. only, not active against E.faecalis, efficacy for bacteremia/endocarditis not demonstrated
Cross-resistance to streptogramins can arise from use of tylosin and virginiamycin as additives in animal feeding.
• fusidic acid (against Gram +ve Bacteria; bactericidal in vitro at high concentrations) (from Fusidium coccineum) inhibits EF-G
• ramycin inhibits EF-G
• viomycin (Viocin^®) : a basic polypeptide antibiotic administered intramuscularly (along with other drugs) in the treatment of Mycobacterium tuberculosis. May cause ototoxicity
• phenicols / phenyl propanoids have been introduced in 1949: effective against Gram +ve and Gram -ve cocchi and Salmonella typhi
• chloramphenicol (currently it is produced entirely by chemical synthesis) (AK-Chlor^®, Chloromycetin^®, Chloroptic^®, Ocu-Chlor^®; Colbiocin^® in combination with rolitetracycline and sodium colistimetate) inhibits the bacterial enzyme peptidyl transferase in the 50S subunit

Side effects : since mitochondria probably originated from prokaryotic cells and have 70S ribosomes, they are subject to inhibition. The eukaryotic cells most likely to be inhibited by chloramphenicol are those undergoing rapid multiplication, thereby rapidly multiplying mitochondria.
• such cells include the blood forming cells of the bone marrow, the inhibition of which could present as acquired aplastic anemia in 1:50,000. Bone marrow toxicity was recognized to be associated with chloramphenicol in 2 ways:
• a dose-dependent reversible marrow depression that disappears when the drug is stopped
• an idiosyncratic reaction that causes irreversible marrow failure (albeit quite rarely) that is not dose-dependent and may occur at quite low drug levels. It should be noted that cases of the idiosyncratic reaction have been described following the use of chloramphenicol eye drops
• in newborns it may cause gray syndrome (a potentially fatal condition seen in neonates, particularly premature infants, characterized by an ashen gray cyanosis, listlessness, weakness, and gray syndrome,   a potentially fatal condition seen in neonates, particularly premature infants, due to a reaction to chloramphenicol, characterized by an ashen gray cyanosis, listlessness, weakness, and systemic arterial hypotension) due to inadequate glucuronidation with drug accumulation.
Chloramphenicol was a commonly used antibacterial agent in the 1950s and, like other antimicrobials in use today, was commonly used in situations where no specific antibiotic is required (such as in a viral respiratory infection). Now it is seldom used in human medicine except in life-threatening situations (e.g. typhoid fever). R plasmid-encoded resistance gene = chloramphenicol acetyltransferase (CAT). The only antimicrobial whose enteric absorption (palmitate) is better than parenteral absorption (succinate)
In Jan 2002, chloramphenicol was detected in animal feed in Europe. This contamination was traced to fish/seafood products coming from the Far East. A commentary from the Chinese  Ministry of Agriculture on the "Draft Report for the Residue Control in Live Animals and Animal Products by EC Inspection Mission to China"^ref mentions that chloramphenicol was discontinued from the Chinese Veterinary Pharmarcopoeia in 2000. An investigation into the contamination of shrimp revealed that 'the prawn-peeling workers had not worn protective gloves in the past, causing an itchy  symptom on their hands, so some of the workers used chloromycetin (chloramphenicol) to treat their hands in order to avoid the itching, and, as a result, the prawns were polluted". The 2002 FDA report regarding chloramphenicol testing in imported seafood^ref contains this discussion: "Until recently, the sensitivity of the methodology to detect chloramphenicol in shrimp could find the drug down to 5 parts per billion (ppb). Recently, Canada, and the European Union (EU), have refined their methods to detect even lower levels, and, have taken action on food products from China and Viet Nam found to be contaminated by chloramphenicol. The FDA has modified its methodology to confirm chloramphenicol levels in shrimp and crayfish to 1ppb and is further modifying the methods to detect 0.3 ppb, which will place the U.S. methodology in line with Canada and the EU. The new methodology for testing for chloramphenicol to the level of 1 ppb will be used to test imported shrimp and crayfish that are suspected to contain chloramphenicol. FDA will detain, and refuse entry to, any product it identifies, and confirms, as containing chloramphenicol". On 5-6 Jun 2002, a senior delegation of Chinese officials met with the FDA to discuss the issue of chloramphenicol residues in shrimp and crayfish. The delegation informed the FDA that, on 5 Mar 2002, China banned the use
of chloramphenicol in animals and animal feeds. They also informed the FDA that they are initiating testing of shrimp, crayfish, and other animal-derived foods intended for export, to ensure the absence of chloramphenicol and other drug residues. The FDA and China exchanged information on testing methodologies. The FDA informed the Chinese officials that the Agency would take enforcement action against products found to be in violation.
• tiamphenicol
• florfenicol (Aquaflor^® and Nuflor^®)
• pleuromutilin (Econor^®) : a natural antibiotic diterpene that  binds to the ribosomal peptidyl transferase centre (PTC) of the 50S ribosomal subunit with its tricyclic mutilin core positioned in a tight pocket at the A-tRNA binding site^ref and interacts with domain V of 23S RNA^ref. It is effective against resistant mycoplasma infection in immunocompromised patients^ref
• azamulin [14-O-(5-(2-amino-1,3,4-triazolyl)thioacetyl)-dihydromutilin] is an azole derivative^ref
• tiamulin / 81.723 HFU is used in the control and treatment of veterinary gram-positive and gram-negative pathogens, with a particular emphasis on infections in swine^ref. It has exceptional activity (MIC < 1 µg/ml) against anaerobic bacterial species, intestinal spirochetes, and Mycoplasma spp^ref
• valnemulin
• 4-methoxybenzoylcarbamate / SB-222734^ref
• nocathiacins are cyclic thiazolyl peptides with inhibitory activity against gram-positive bacteria
• BMS-249524 (nocathiacin I), identified from screening a library of compounds against a multiply antibiotic-resistant Enterococcus faecium strain, was used as a lead chemotype to obtain additional structurally related compounds
• 2 more water-soluble derivatives, BMS-411886 and BMS-461996^ref
The 23S rRNA A2058G alteration mediates macrolide, lincosamide, and streptogramin B resistance in the bacterial domain and determines the selectivity of macrolide antibiotics for eubacterial ribosomes, as opposed to eukaryotic ribosomes. However, this mutation is associated with a disparate resistance phenotype: it confers high-level resistance to ketolides in mycobacteria but only marginally affects ketolide susceptibility in streptococci. Mutational alteration of the polymorphic 2057-2611 base pair from A-U to G-C in isogenic mutants of Mycobacterium smegmatis significantly affects susceptibility to ketolides but does not influence susceptibility to other macrolide antibiotics. In addition, the 2057-2611 polymorphism determines the fitness cost of the 23S rRNA A2058G resistance mutation. Polymorphic nucleotides mediate the disparate phenotype of genotypically identical resistance mutations and provide an explanation for the large species differences in the epidemiology of defined drug resistance mutations^ref.
• impairing 30S subunit => wrong translation => toxic alterated proteins => bactericidal
• tetracyclines (bacteriostatic) : products of the aromatic poliketide biosynthetic pathway in Streptomyces, act by binding the 30S subunit and blocking the binding of aminoacyl tRNA to the A site on the ribosome. As most Bacteria possess an active transport system for tetracycline that allows intracellular accumulation of the antibiotic at concentrations 50 times as great as that in the medium, a blood level which is harmless to animal tissues can halt protein synthesis in invading Bacteria.
• chlortetracycline (Aureomycin^®)
• demeclocycline (Declomycin^®)
• meclocycline (Meclan^®)
• doxycycline / doxycyclin (Bassado^®, Doxymycin^®, Doryx^®, Vibra^®, Vibra-Tabs™, Vibramycin^®,; low-dose oral formulation for dermatology : Oracea^®) does not cause the photosensitizing reaction that may occur with conventional tetracycline. Divalent cations, gluten products, and calcium do not materially interfere with its absorption. Since doxycycline is a highly lipid-soluble antimicrobial, a loading dose is necessary for optimal results. Therefore, for moderate or severe infections, the usual dose, given intravenously or orally, should be doubled for 72 hours and then reduced to the usual dose (ie, 200 mg every 12 hours reduced to 100 mg every 12 hours). The entire dose (intravenous or oral) may be given once daily. Doxycycline should be taken with food and should not be given to pregnant patients or young children
• lymecycline (Tetralysal^®)
• methacycline (Rondomycin^®)
• minocycline (Minocin^®, ...) is 10-folds more lipid-soluble than conventional tetracycline whereas doxycycline is only 5-folds more lipid-soluble. The clinical importance of this characteristic is that minocycline has particularly good tissue penetration and excellent CNS penetration. It is effective also against MRSA. Food and divalent cations interfere minimally or not at all with oral absorption, and photosensitizing reactions are rare. Because of its high lipid-solubility, the drug is maintained in high concentrations in middle ear fluid; thus, it has been implicated in vestibular side effects. It should not be given to pregnant patients or young children. Minocycline-induced hyperpigmentation can be severely disfiguring and is more likely to occur in certain populations of patients (e.g., those with pemphigus, pemphigoid, or atopic dermatitis). It is important to recognize this condition early and offer an alternative treatment, since symptoms can take months to years to resolve once the drug is withdrawn. There are 4 types of minocycline-induced cutaneous hyperpigmentation^ref:
• type I occurs on the face within inflammatory tissue
• type II occurs on the arms and legs in a circumscribed distribution
• type III appears diffusely muddy-brown on sun-exposed skin
• type IV occurs on the thorax within scar tissue
• oxytetracycline (Terramycin^®, ...)
• rolitetracycline
• rolitetracycline + betamethasone disodium phosphate + chloramphenicol + colisti methate sodium (Eubetal Antibiotico^®)
• Colbiocin^® in combination with chloramphenicol and sodium colistimethate
• tetracycline (Achromycin^®, ...)
Some newly discovered members of the tetracycline family (e.g. chelocardin) have been shown to act by inserting into the bacterial membrane, not by inhibiting protein synthesis.
Side effects : contraindicated during pregnancy and before age 8; renal toxicity (75%), hepatotoxicity, neurotoxicity, systemic arterial hypertension, hirsutism, gingival hyperplasia, GI toxicity, Steven-Johnsons's syndrome
• glycylcyclines are tetracycline derivatives
• tigecycline / GAR936 : not transported by the tetracycline efflux pumps (Staphylococcus aureus, including MSSA, GISA, MRSA, Streptococcus pneumoniae, includnig PRSP, VRE, Acinetobacter, Bacteroides fragilis, Acinetobacter, Enterobacter; inactive against Proteus spp. and P.aeruginosa). Serum levels sometimes lower than the MIC, but high tissue distribution far above the MIC, low inhibitory quotient in the blood but a high inhibitory quotient in tissue. Nausea and vomiting is the most commonly reported adverse event^ref.
Appropriate targets :
• peritonitis, but in combination therapy if suspicion of Pseudomonas involvement (e.g. postoperative peritonitis, peritonitis treated with antibiotics before surgery)
• nosocomial pneumonia (post-operative pneumonia, early-onset VAP, VAP due to Enterobacter, Acinetobacter)
• severe community-acquired pneumonia
• complicated skin and skin tissue infections (postoperative cellulitis)
• infections with resistant Gram-positive pathogens (VRE, MRSA, GISA, VRSA)
• infections with resistant Gram-negative pathogens (Enterobacter, Acinetobacter)
• catheter-related bacteremia ?
• endocarditis ?
• aminoglycosides have been introduced in 1950 (against Gram -ve Bacteria and just a little Gram +ve Bacteria). They bind to the S12 (a.k.a. P10) protein in the 30S subunit of the bacterial ribosome blocking the binding of initiator N-fMet- tRNA^Met to the ribosome and preventing the normal dissociation of ribosomes into their subunits, leaving them mainly in their 70S form, impairing polysomes formation. It stabilizes aa-tRNA on the ribosome both with a cognate and with a near-cognate codon in the A site by altering the rates of GTP hydrolysis by elongation factor Tu (EF-Tu), resulting in almost identical rates of GTP hydrolysis and virtually complete loss of selectivity. The difference in spelling (-micin or -mycin) reflects the isolation from Streptomyces spp. or Micromonospora spp., respectively. They can be classified according to their aminocyclitol :
• streptidin-containing
• streptomycin (Streptomycin^®) : restricted spectrum, but effective even against Mycobacterium tuberculosis
• 2-deoxystreptamine-containing
• gentamicin sulfate (Gentalyn^®, Garamycin^®, Genoptic^®, Gent-AK^®, Gentacidin^®, ...) : broad spectrum. Gentamicin surgical implant is a biodegradable leave-behind implant impregnated with gentamicin, and is indicated as an adjunct to systemic antibiotic therapy for the treatment and prevention of post-surgical acquired infection in both hard and soft tissues. The product was developed using Innocoll's proprietary collagen-based technology, CollaRx^®, and has been approved in 49 countries. It is marketed under the following different trade names: Collatamp^® G, Collatamp^® EG, Sulmycin^® Implant, Garamycin^® Schwamm, Duracol^®, Duracoll^®, Gentacol^®, Gentacoll^®, Garacol^®, Garacoll^® and Cronocol^® in Europe, Central and South America, Middle East, Africa and Asia
• only topical PO use before GI tract surgery (no if hemorrhages are suspected !) : very toxic when administered IV !
• kanamycin sulfate (Kantrex^®) : restricted spectrum, but if given IV it is effective even against Staphyloccous aureus
• intermediate spectrum
• neomycin sulfate (Mycifradin^®, Neo-Fradin^®; Neosporin G.U. Irrigant^® in combination with polymixin B; Neosporin^® in combination with bacitracin and polymixin B; Neosporin^® in combination with gramicidin and polymixin B) or undecylenate
• paramomycin (Humatin^®) : effective even against Staphyloccous aureus
• broad spectrum
• amikacin / BBK8 (Amikin^®)
• netilmicin (Netromycin^®) : semisynthetic
• sisomicin / thiostrepton (Siomycin^®) derived from Micromonospora inyoensis, closely related to the C_1a component of the gentamicin complex; it is bactericidal for many gram-negative and some gram-positive organisms, having a range of activity similar to that of gentamicin.
• sisomicin sulfate : the sulfate salt of sisomicin, used in the treatment of infections caused by susceptible gram-negative organisms; administered intravenously or intramuscularly.
• nystatin + neomycin sulfate + thiostrepton + triamcinolone acetonide (Animax^®)
• tobramycin (Aktob^®, Tobral^®, Tobrex^®, Nebcin^®; ZyLet^® in combination with loteprednol)
• apramycin
• arbekacin (Habekacin^®)
• bambermycins
• bekanamycin
• butirosin
• dibekacin
• framicetin (topical use)
• isepamicin (Exacin^®)
• ribostamycin
• bacteriostatic
• kasugamicin (Kasumin^®)
• spectinomycin (Trobicin^®)
Resistance genes : aminoglycoside acetylases (AAC), adenylylases (AAD), and phosphorylases (APH).
Side effects :
• reversible acute renal failure lasting up to 20 days after suspension (evaluate [Ala-aminopeptidase]_urine]
• damage to the vestibulocochleary (auditory) nerves => permanent deafness and/or temporaneous dizziness lasting 2-6 months. gentamicin-induced hearing loss averages 8% for a short course of therapy^ref but may be higher in developing countries, where aminoglycosides are frequently the only affordable antibiotics and are sold over the counter. No therapy presently exists to prevent ototoxicity. Animal models suggest that ototoxicity is caused by reactive oxygen species and is attenuated by antioxidants^ref. Salicylate is a clinically promising antidote^ref that can be administered as aspirin. 195 patients received 80 to 160 mg of gentamicin twice daily by intravenous infusion (generally for 5 to 7 days) and were randomly assigned to receive 14 days of supplementation either with 3 g of aspirin per day, divided into 3 doses (89 patients), or with placebo. The incidence of hearing loss in the placebo group was within the anticipated range (13%) but was significantly lower in the aspirin group (3%). The efficacy of the gentamicin therapy was not affected by the administration of aspirin. However, gastric symptoms were more common in the aspirin group^ref.
• oxazolidinones (introduced in 2000) inhibit the bacterial pre-translational initiation complex formation => bacteriostatic
• linezolid (Zyvox^®) i.v. and p.o. Side effects : thrombocytopenia, hyperlactatemia, metabolic acidosis, and peripheral neuropathy are adverse effects related to the drug's capacity for interference with mitochondrial function^ref; efficacy for bacteremia/endocarditis not demonstrated
• AZD2563
• PNU288234
• ranbezolid
• DA7687
• mupirocin (Bactroban^®) inhibits Ile-tRNA synthetase
• puromycin / stylomycin
• sparsomicin (Sparsomycin^®)
• pulvomicin
• kirromicin
• hexamethylenamine / hexamine / methenamine mandelate and hippurate (Urex^®, Hiprex^®, Mandelamine^®) : the compound decomposes in water at acidic pH according to the following reaction :

NH₄(CH₂)₆ + 6H₂O + 4H⁺ => 4NH₄⁺ + 6HCHO
• nitrofurans
• nifurfolin
• nifuroxazide (Antinal^®)
• nifuroxima
• nifurzide
• nitrofurantoin (Furadantin^®, Macrobid^®, Macrodantin^®, ...)
• nitrofurazone (Furacin^®)
• antibacterial interfering with DNA replication and repair
• clofazimine (Lamprene^®) preferentially binds to GC-rich mycobacterial DNA.
• metronidazole / 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (bactericidal) (Flagyl^®, Metrocream^®, Metrogel^®, Noritate^®, Protostat^®)
• quinolones have been introduced in 1962 (bactericidal against Gram -ve Bacteria) at low doses inhibit the religation of the doubly cleaved DNA whose 5' ends are tethered on 2 Tyr residues in type II bacterial topoisomerases [both DNA gyrase (1 Tyr per GyrA subunit in the active (GyrA)₂(GyrB)₂ tetramer) and DNA topoisomerase IV], while at high doses (e.g. those present in urine) inhibit N-methyltransferase
• 1^st generation quinolones : urinary antiseptic, uneffective against Pseudomonas aeruginosa
• nalidixic acid (NegGram^®). Side effects : Steven-Johnsons's syndrome
• oxolinic acid
• piromidic acid
• 2^nd generation quinolones : urinary antiseptic, effective even against Pseudomonas aeruginosa
• cinoxacin (Cinobac^®, Cinoxacin^®)
• flumequine
• novobiocin (Albamycin^®) binds the B subunit of DNA gyrase inhibiting ATP hydrolysis
• pipemidic acid (Dolcol^®, Pipram^®)
• rosoxacin (Eradacil^®)
• 3^rd generation / 6-fluoroquinolones (FQ) : systemic distribution (expecially used against bacterial respiratory and UTIs, prostatitis, osteomyelitis, and Salmonella typhi). Fluoroquinolones, broad-spectrum antibiotics that are widely perceived to have favorable adverse-effect profiles, have become the most prescribed antibiotics in the USA^ref. From 1995 to 2002, the number of fluoroquinolone prescriptions in the USA increased by a factor > 3, reaching about 22 million prescriptions per year^ref. The available fluoroquinolones have well-established differences in antimicrobial activity, but their disparate adverse-effect profiles are increasingly being recognized. Serious adverse events have led to the withdrawal or restriction of several fluoroquinolones in recent years^ref
• broad spectrum
• enoxacin (Penetrex^®)
• norfloxacin (Chibroxin^®, Noroxin^®, Noxacin^®, Utinor^®)
• very broad spectrum
• ciprofloxacin (Ciloxan^®, Cipro^®, Ciproxin^®) : PO, i.v.. In European ICUs it is effective against 89% of MSSA, 7% of MRSA, 92% of E.coli, 78% of Enterobacter spp., and 73% of P.aeruginosa^ref. Ciprofloxacin is absorbed from the gastro-intestinal tract. Oral bioavailability is approximately 70% and a peak plasma concentration is achieved 0,5 to 2 hours after oral dosing. Absorption may be delayed by the presence of food, but is not substantially affected overall. The plasma half-life is about 3,5 to 4,5 hours and there is evidence of moderate accumulation. Half-life may be prolonged in severe renal failure and to some extent in the elderly. Plasma protein binding ranges from 20 to 40%. Ciprofloxacin is widely distributed in the body and tissue penetration is extensive. It appears in the cerebrospinal fluid, but the concentrations are only about 10% of those in the plasma when the meninges are not inflamed. Ciprofloxacin crosses the placenta, and is distributed into the breast milk. High concentrations are achieved in the bile. Ciprofloxacin is eliminated principally by urinary excretion, but non-renal clearance may account for about a third of elimination and includes hepatic metabolism, biliary excretion, and possibly transluminal secretion across the intestinal mucosa. Urinary excretion is by active tubular secretion as well as glomerular filtration and is virtually complete within 24 hours. About 40 to 50% of an oral dose is excreted unchanged in the urine and about 15% as metabolites Faecal excretion over 5 days has accounted for 20 to 35% of an oral dose. At least 4 active metabolites have been identified. Oxociprofloxacin appears to be the major urinary metabolite, and sulphociprofloxacin is the primary faecal metabolite. Only small amounts of ciprofloxacin are removed by haemodialysis or peritoneal dialysis. Polymorphism of the mexR gene which is involved in the resistance to drugs like ciprofloxacin. Mutations in mexR result in increased resistance to multiple antibiotics due to overexpression of this efflux system. The MexR product contains 147 amino acids with a molecular mass of 16,964 Da.
• ofloxacin (Floxin^®, Ocuflox^®, Tarivid^®)
• long-acting (1 / die) and broad spectrum
• fleroxacin (Megalone^®)
• lomefloxacin (Maxaquin^®)
• pefloxacin (Peflocin^®)
• temafloxacin (Omniflox^®), recalled because of hemolysis, renal failure, and hypoglycemia^ref (Rubinstein E. History of quinolones and their side effects. Chemotherapy 2001;47:Suppl 3:3-8, 44)
• uvofloxacin
• clinafloxacin
• difloxacin (Dicural^®)
• enrofloxacin for veterinary use
• garenofloxacin
• gatifloxacin (Tequin^®) : limited data suggest that as compared with other currently available fluoroquinolones, gatifloxacin (Tequin, Bristol-Myers Squibb) may be uniquely associated with increased risks of both hypoglycemia and hyperglycemia^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12, ref13, ref14, ref15} (Tailor SA, Simor AE, Cornish W, Phillips E, Knowles S, Rachlis A. Analysis of spontaneous report of hypoglycemia and hyperglycemia associated with marketed systemic fluoroquinolones made to the Canadian Adverse Drug Reaction Monitoring Program. Can J Hosp Pharm 2004;57:12-17; Frothingham R. Gatifloxacin associated with a 56-fold higher rate of glucose homeostasis abnormalities than comparator quinolones in FDA Spontaneous Reporting Database. In: Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., October 30–November 2, 2004. Washington, D.C.: American Society for Microbiology, 2004:19; Létourneau G, Morrison H, McMorran M. Gatifloxacin: hypoglycemia and hyperglycemia. Can Adverse React Newsl 2003;13(3):1-2). Although the mechanism of these apparently competing adverse effects is not fully understood, studies in animals suggest that although gatifloxacin can promote insulin release and hypoglycemia by blocking the ATP-sensitive potassium channels of pancreatic islet cells, it can also trigger the vacuolation of pancreatic b cells, leading to reduced insulin levels and hyperglycemia^{ref1, ref2, ref3, ref4}. Evidence that gatifloxacin causes dysglycemic effects in humans consists of data from case reports, small studies in healthy volunteers or hospital inpatients, and one small post-marketing study^{ref1, ref2, ref3, ref4, ref5} (Grasela DM, Lacreta F, Kollia G, Randall D, Stoltz R, Berger S. Lack of effect of multiple-dose gatifloxacin (GAT) on oral glucose tolerance (OGTT), glucose and insulin homeostasis, and glyburide pharmacokinetics (PK) in patients with type II non-insulin-dependent diabetes mellitus (NIDDM). In: Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 26–29, 1999. Washington, D.C.: American Society for Microbiology, 1999:11; Schwarzbard L, Lodise TP, Lomaestro BM, Smith R. Comparison of glucose intolerance (GI) between gatifloxacin (G) and levofloxacin (L) in elderly, hospitalized patients. In: Program and abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., December 16–19, 2005. Washington, D.C.: American Society for Microbiology, 2005:463). These studies yielded conflicting conclusions regarding the effects of gatifloxacin on blood glucose levels, but some reports strongly suggest the existence of a causal relation^ref. For example, one recent report described two patients in whom profound hyperglycemia (glucose, 942 to 1456 mg/dl) developed shortly after gatifloxacin therapy but who had no subsequent evidence of diabetes^ref. The use of gatifloxacin among outpatients is associated with an increased risk of in-hospital treatment for both hypoglycemia and hyperglycemia : so it should not be used in diabetics and other high risk patients)^ref
• gemifloxacin mesylate (Factive^®)
• grepafloxacin (Raxar^®) : recalled because of QT-interval prolongation^{ref1, ref2} (Rubinstein E. History of quinolones and their side effects. Chemotherapy 2001;47:Suppl 3:3-8, 44)
• levofloxacin (Levaquin^®, Quixin^®, Tavanic^® in Europe, Cravit^® in Asia) (i.v.)
• marbofloxacin for veterinary use
• moxifloxacin (Avelox^®, Avalox^®) (i.v.) has recently shown promise in a murine model of Mycobacterium tuberculosis^ref
• pazufloxacin mesilate
• thiazeto-quinolines :
• prulifloxacin / NM441 (Quisnon^®) (lipophilic prodrug) => ulifloxacin / NM394
• rufloxacin
• sitafloxacin
• sparfloxacin (Spara^®, Zagam^®) : recalled because of QT-interval prolongation^{ref1, ref2} (Rubinstein E. History of quinolones and their side effects. Chemotherapy 2001;47:Suppl 3:3-8, 44)
• tosufloxacin
• trovafloxacin (Trovan^®) : recalled because of hepatotoxicity^{ref1, ref2}.
• ABT-492
Side effects :
• fluoride causes cartilage alterations (use is forbidden during pregnancy and in children) => bilateral acute or chronic Achilles calcaneal tendinitis => tendon rupture, more common in patients over 60 years of age. The latency period between the start of treatment and the appearance of the first symptoms range from 1 to 510 days with a median of 6 days. Most patients recover within 2 months after cessation of therapy, but 26% have not yet recovered at followup.
• relapse in patients who suffered juvenile epilepsy
• photosensitivity (use sunglasses)
• neurologic impairment
• incidence of convulsions and anxiety due to action as GABA_A antagonists
• nausea and vomiting
Simultaneous administration of antacids containing magnesium or aluminium and ciprofloxacin or other quinolones decreases the gastrointestinal absorption of those antibacterial agents due to drug-cation chelation^ref.
• antibacterial interfering with transcription
• ansamycins (bactericidal) inhibit bacterial RNA polymerase (RNAP)
• rifamycins (RIF)
• rifampin (Rifadin^®, Rimactane^®) is a semisynthetic derivative of rifamycin B active against Gram +ve Bacteria, Mycobacterium tuberculosis and some Gram -ve Bacteria. Rifampicin acts quite specifically against the b subunit of the bacterial RNA polymerase and apparently blocks the entry of the first nucleotide which is necessary to activate the polymerase. It is effective orally and crosses the blood-brain barrier, so it is useful for treatment of bacterial meningitis.

Side effect : drug-triggered pemphigus, orange urines, increased catabolism of cyclosporine, oral antidiabetics, GR agonists, and quinidine
• rifabutin (Mycobutin^®)
• rifapentine (Priftin^®)
• rifaximin (Flonorm^®, Lumenax^®, Normix^®, RedActiv^®, Rifacol^®) is a non-absorbed (<0.5%), broad-spectrum, gastrointestinal-specific, oral antibiotic for treatment of hepatic encephalopathy, Clostridium difficile-associated diarrhea, travellers' diarrhea, colonic diverticular disease and Crohn's disease
• streptoovaricins
• CBR703 series compounds inhibit known catalytic activities of RNAP (nucleotide addition, pyrophosphorolysis, and Gre-stimulated transcript cleavage) but not translocation of RNA or DNA when translocation is uncoupled from catalysis.
• xenobiotics interfering with energy metabolism
• proton pump of bacterial ATP synthase inhibitors : compound J / R207910 (source : Johnson & Johnson) moves easily to the lungs and kills Mycobacterium tuberculosis.


While screening for a new broad-spectrum antibiotic, J&J researchers discovered that a class of compounds called diarylquinolines worked against Mycobacteria smegmatis : chemical tinkering led them to the even more potent R207910. It potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (MIC 0.06 µg/ml). In mice, R207910 exceeds the bactericidal activities of isoniazid and rifampin by at least 1 log. As expected, resistance to R207910 developed when given to mice as a monotherapy, but the J&J team's experiments with mice have convinced leading TB researchers that swapping the drug for 1 of the 3 in the most popular triple-drug combination now used would delay development of resistant strains. Substitution of drugs included in the WHO's first-line tuberculosis treatment regimen (rifampin, isoniazid and pyrazinamide) with R207910 accelerates bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations, about half the time it takes using the standard treatmen. A single dose of R207910 inhibits mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice are well tolerated in healthy human volunteers^ref. Human versions of the synthase are not affected by the drug and initial studies in humans show that injections are safe, at least for short periods of time. Trials in people who are actively sick are now under way, although it will be many years before the drug makes it to the market. One of the drugs in the standard tuberculosis cocktail does not mix well with many HIV drugs, but a regimen with compound J would be fine. Another potential bonus is that the compound may be useful against latent tuberculosis, as it kills even when the bacteria are not actively reproducing. Although the outbreaks of multidrug-resistant tuberculosis (MDR-TB) that afflicted New York City in the 1990s were relatively minor when compared to the burden of global tuberculosis [HN1]^{ref1, ref2}, they served to raise public and political awareness. The result was that for the first time TB control was included on the agenda of the G8 economic summit meetings. The world's leaders lent their support to that of nongovernmental organizations, such as the Global Alliance for TB Drug Development (GATDD) and the WHO, by encouraging industry and academia to engage in the development of new drugs to treat this chronic respiratory disease. This was a crucial event given that TB claims up to 2 million lives annually worldwide, blights myriad communities principally in developing countries, and that no new TB drugs have been discovered in the past 40 years^ref. The current treatment for TB recommended by WHO--known as directly observed therapy short-course (DOTS)--requires patients to adhere to a 3- or 4-drug regimen comprising isoniazid, rifampin, pyrazinamide, and/or ethambutol for a minimum of 6 months. Many patients fail to complete therapy because of drug side effects and the complicated drug regimen, resulting in relapse--often in the form of MDR-TB, which is even more difficult to treat. An ideal new TB drug should be highly active, so that treatment duration can be reduced to <3 months; it should kill the persistent bacilli that might otherwise reactivate later in life; and it must show activity against MDR-TB strains. Optimally, a new therapeutic agent would be specific for Mycobacterium tuberculosis and also compatible with existing TB drugs, because combination therapy will remain mandatory to combat this major killer^ref. Its lead compound was identified by adopting a medium-throughput screening approach using live mycobacteria rather than the more popular target-based, high-throughput screening that uses robotics to screen millions of compounds for inhibitors of critical functions such as key enzyme activities. This proved a very astute decision because it avoided problems with drug permeability (which always affect the target-based screens at a later stage) by identifying active compounds that freely entered the mycobacteria. After optimization by synthetic chemistry, the investigators were left with 20 interesting drug candidates; of these, R207910 showed the best activity profile. R207910 is bactericidal and exquisitely active against a broad range of mycobacteria [HN11], displaying little or no activity against the other microorganisms tested. Crucially, R207910 is active against both the drug-sensitive and drug-resistant forms of M. tuberculosis. This organic compound of 555.51 daltons, which contains both planar hydrophobic moieties and hydrogen-bonding acceptor and donor groups, displays perfect drug-like features that satisfy most of Lipinski's rules for good drug candidates^ref. Pharmacokinetic and pharmacodynamic studies in different animal models have confirmed the excellent drug-like properties of diarylquinolines. To identify the target of R207910, mutants of M. tuberculosis were isolated and the related faster-growing organism M. smegmatis that were resistant to R207910, and characterized by whole-genome sequencing. 2 different missense mutations in the atpE gene, which encodes the C subunit of ATP synthase, the enzyme that uses the transmembrane proton-motive force to generate ATP for the cell^ref. 
Model of the mycobacterial ATP synthase showing the position of mutations that confer resistance to the diarylquinoline drug R207910^ref. ATP synthase has 2 major structural domains, F₀ and F₁, that act as a biological rotary motor^ref. F₁ is composed of 9 subunits (a₃, b₃, g, d, e) and is located in the cytoplasm, where it generates ATP. F₀ spans the cytoplasmic membrane and contains 13 to 15 subunits (a, b₂, c_9-12) arranged as a symmetrical disc. The F₀ and F₁ domains are linked by subunits g, e, d, and b₂. Rotation of the transmembrane disc and the central stalk is driven by the proton-motive force. The c subunit is an a-helical hairpin structure with a short connecting loop. Notably, the A63P mutation is very near E60, the glutamic acid residue whose carboxyl group is protonated during proton translocation. The proton-motive force fuels the rotation of the transmembrane disk and the central stalk, which in turn modulates the nucleotide affinity in the catalytic b subunit, leading to the production of ATP. The c subunit has a hairpin structure with 2 a helices and a short connecting loop. The 2 mutations affect the membrane-spanning a helices of the ATP synthase c subunit and may restrict binding of R207910 to the enzyme. Although biochemical confirmation is now required, it is possible that the drug impedes assembly of the mobile disk or interferes with its rotational properties, leading to inadequate synthesis of ATP. A puzzling feature of R207910 is its exceptional specificity for mycobacteria. ATP synthase is a ubiquitous enzyme found in most living organisms, including humans. There is very limited sequence similarity between the mycobacterial and human AtpE proteins, which bodes well for the safety of the compound, as borne out by the phase I study in human volunteers. The mycobacteria-specific activity of R207910^ref may also be the consequence of limited sequence similarity among bacterial AtpE proteins. However, those antitubercular agents that show highly restricted activity (such as isoniazid, ethionamide, and pyrazinamide) are all prodrugs requiring activation by a mycobacterial enzyme^ref. Although its chemical structure gives no clues to potential activation sites, R207910 may also prove to be a prodrug. Mouse studies already show that this compound can greatly shorten the duration of therapy, both alone and in association with current antitubercular agents. Furthermore, the equally remarkable activity of R207910 against M. ulcerans--the agent of an emerging human disease called Buruli ulcer^ref, for which surgery is the only cure--also raises expectations for a safer treatment for this disfiguring affliction^ref.
• anti-pathogenic drugs :
• quorum sensing inhibitors (QSI)^{ref1, ref2}
• N-acyl homoserine lactones (AHL) analogues
• xenobiotics interfering with intermediate metabolism (anti-metabolites or growth factor analogs)
• inhibitors of dihydropteroate synthetase required for the synthesis of tetrahydrofolic acid (THF) as they are structurally similar to p-aminobenzoic acid (PABA).
• sulfones
• dapsone / 4,4'-diaminodiphenylsulfone
• dapsone + pyrimethamine (Maloprim^®, Deltaprim^®)
• sulfoxone / aldesulfone sodium (Diasone sodium^®)
Side effects : Steven-Johnsons's syndrome
• sulfonamides (bacteriostatic). They were introduced as chemotherapeutic agents by Domagk, Mietsch and Klarer in 1935, who showed that one of these compounds (the substituted sulfanilamide ...


... derived from the intracellular degradation of the bacterial stain 4-sulfonamide-2',4'-diaminobenzol or red Prontosil ...

 ...) had the effect of curing mice with infections caused by b-hemolytic Streptococcus spp.. Chemical modifications of the compound sulfanilamide gave compounds with even higher and broader antibacterial activity. Bacteria which are almost always sensitive to the sulfonamides include Gram +ve Streptococci (b-hemolytic Streptococci and Streptococcus pneumoniae (even if some Streptococci can assume folate from the environment, bypassing the synthesis blockage)) and Gram -ve Bacteria (E. coli, Neisseria meningitidis). They cross the blood-brain barrier.
• rapidly absorbed and rapidly eliminated sulfonamides
• sulfisoxazole diolamine (Gantrisin^®, ...; Pediazole^® in combination with erythromycin ethylsuccinate for otitis media; ? in combination with phenazopyridine for UTIs)
• sulfamethoxazole (Gantanol^®)
• sulfadiazine (Silvadene^®, SSD^®)
• hydrophylic (poorly absorbed) sulfonamides => p.o. intestinal antisepticals
• phtalylsulfacetamide / phthalylsulfonazole
• phtalylsulfathiazole
• sulfasalazine (Azaline^®, Azulfidine^®, Sulfasalazine^®)
• sulfoguanidine
• sulfonamides for topical use
• sulfacetamide (AK-Sulf^®, Bleph-10^®, Cetamide^®, Isopto Cetamide^®, Klaron^®, Sebizon^®, Sodium Sulamyd^®, Sulf-10^®, Sultrim^®... ; Sulfacet-R^® in combination with sulfur)
• silver sulfadiazine (SSD) (SSD^®, Silvadene^®, ...)is the most commonly used topical antibacterial agent for the treatment of burn wounds. It has many clinical advantages, including a broad spectrum of antimicrobial activity, low toxicity, and minimal pain on application. The current formulation of silver sulfadiazine contains a lipid soluble carrier, polypropylene glycol, that has certain disadvantages, including pseudo-eschar formation and the need for twice daily application. A new formulation of silver sulfadiazine in a water soluble gel, poloxamer 188, can be applied once a day and its water solubility allow easy application and removal. Silver compounds are used widely as effective antimicrobial agents to combat pathogens (bacteria, viruses and eukaryotic microorganisms) in the clinic and for public health hygiene. Silver cations (Ag⁺) are microcidal at low concentrations and used to treat burns, wounds and ulcers. Ag is used to coat catheters to retard microbial biofilm development. Ag is used in hygiene products including face creams, "alternative medicine" health supplements, supermarket products for washing vegetables, and water filtration cartridges. Ag is generally without adverse effects for humans, and argyria  is rare and mostly of cosmetic concern.Resistance to silver compounds as determined by bacterial plasmids and genes has been defined by molecular genetics. Silver resistance conferred by the Salmonella plasmid pMGH100 involves nine genes in three transcription units. A sensor/responder (SilRS) two-component transcriptional regulatory system governs synthesis of a periplasmic Ag(I)-binding protein (SilE) and two efflux pumps (a P-type ATPase (SilP) plus a 3-protein chemiosmotic RND Ag(I)/H+ exchange system (SilCBA)). The same genes were identified on five of 19 additional IncH incompatibility class plasmids but thus far not on other plasmids. Of 70 random enteric isolates from a local hospital, isolates from catheters and other Ag-exposed sites, and total genomes of enteric bacteria, 10 have recognizable sil genes. The centrally located 6 genes are found and functional in the chromosome of Escherichia coliK-12, and also occur on the genome of E. coli O157:H7. The use of molecular epidemiological tools will establish the range and diversity of such resistance systems in clinical and non-clinical sources
• mafenide (a-amino-p-toluene-sulfonamide) acetate (Sulfamylon^®)
• long-acting sulfonamides
• sulfadoxine (Fansidar^® in combination with pyrimethamine)
• sulfamazole
• sulfamazone
• sulfamethizole (Thiosulfil Forte^®)
• sulfametopirazine
• sulfametoxypiridazine
• sulfametrol
• succinylsulfathiazole
Side effects : renal and hepatic toxicity (they may cause kernicterus in newborns by displacing bilirubin from plasma proteins in the face of increased bilirubin production from fetal erythrocyte turnover, decreased bilirubin conjugation, acidosis, and decreased blood-brain barrier), agranulocytosis, thrombocytopenia, acquired aplastic anemia, hemolytic anemia in G6PD^- patients, GI toxicity, Steven-Johnsons's syndrome =>