y Antibiotics (Greek anti, against; bios, life) are chemical

y

y y

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compounds used to kill or inhibit the growth of infectious organisms. Originally the term antibiotic referred only to organic compounds, produced by bacteria or molds, that are toxic to other microorganisms. The term is now used loosely to include synthetic and semisynthetic organic compounds . Antibiotic refers generally to antibacterials; however, because the term is loosely defined, it is preferable to specify compounds as being antimalarials, antivirals, or antiprotozoals. All antibiotics share the property of selective toxicity: They are more toxic to an invading organism than they are to an animal or human host

y The first observation of what would now be called an antibiotic effect was made in the 19th century by French Pasteur, chemist Louis Pasteur who discovered that certain saprophytic bacteria can kill anthrax bacilli y Penicillin, the archetype of antibiotics, is a derivative of tive the mold Penicillium notatum. Penicillin was discovered overed accidentally in 1928 by Fleming who showed its Fleming, effectiveness in laboratory cultures against many diseaseproducing bacteria y The first antibiotic to be used successfully in the treatment of human disease was tyrothricin, isolated from certain soil bacteria by American bacteriologist Rene Dubos in 1939.

y Antibiotics can be classified in several ways:

1. y y y

according to their action against the infecting organism organism: attack the cell wall some disrupt the cell membrane inhibit the synthesis of nucleic acids and proteins, the polymers that make up the bacterial cell. 2. according to which bacterial strains they affect: staphylococcus, streptococcus, or Escherichia coli 3. on the basis of chemical structure as penicillins, structure, cephalosporins, aminoglycosides, tetracyclines, macrolides, or sulfonamides, among others.

4. according to Cell Death and Growth Suppression Antibiotics may also be classed as a) bactericidal (killing bacteria) Antibiotics that damage the cell membrane cause the cell's metabolites to leak out, thus killing the (penicillins, cephalosporins) b) bacteriostatic (stopping bacterial growth and multiplication).those are nonetheless effective because bacteria that are prevented from growing will die off after a time or be killed by the defense mechanisms of the host( tetracyclines ,sulfonamides)

5. Antibacterials can be further subdivided according to their spectrum toy The narrow-spectrum act againist gram-positive bacteria (Penicillins) or act against many gram-negative as well as some gram-positive bacteria (Aminoglycosides,). y The broad-spectrum drugs are effective against both gram-positive and gram-negative bacteria (tetracyclines , chloramphenicols)

y Most antibiotics act by selectively interfering with the synthesis of one of the large-molecule constituents of the cell

1. Some act by disrupting the cell membrane (interfere with the synthesis of peptidoglycan). These drugs include the -lactam antibiotics, which are classified according to chemical structure into penicillins, cephalosporins, and carbapenemsThese antibiotics do not affect human cells because human cells do not have cell walls.

2. Nucleic-acid and protien synthesis: a) sulfonamides are indirectly interfere with nucleic acid synthesis b) inhibit the enzymes (DNA polymerase or RNA polymerase) eg;actinomycin, and rifampicin. c) inhibit synthesis of an enzyme responsible for the coiling and uncoiling of the chromosome(DNA replication and for transcription to m RNA) eg; quinolone antibiotics . d) affect the assembly of messenger RNA (protein products are mal/nonfunctional). Tetracyclines, aminoglycosides e) affect linking of amino acids to the growing protein chloramphenicol, puromycin.

y Penicillins are bactericidal, inhibiting formation of the cell

wall. There are four types of penicillins: 1. Natural penicillins 2. Aminopenicillins narrow-spectrumPenicillins 3. penicillinase-resistants. 4. antipseudomonal penicillins extended spectrum penicillinsy Side effects of the penicillins, while relatively rare, can include immediate

and delayed allergic reactionsspecifically, skin rashes, fever, and anaphylactic shock, which can be fatal.

Natural penicillins :They have narrow spectrum containing gram-positive and negative cocci (streptococci, pneumococci, enterococci, meningococci), grampositive bands (corynebacteria, L.monocytogenes), spirochetes (Leptospira sp., Treponema sp., Borrelia sp.), and most of anaerobes ( clostridial species, Actinomyces).1) penicillin G or benzylpenicillin y unstable in gastric acid juice, suitable only for intravenous administration y 1,000.000 units equals 625 mg of penicillin. 2) procain-penicillin y for intramuscular administration, usually once daily 3) penicillin V or phenoxymetylpenicillin y acid-stable form, for oral administration 4) benzathinpenicillin y depot form, creating stabile low level of antibiotic for 2-4 weeks y useful for prophylaxis of streptococcal reinfections.

Aminopenicillins :y The drugs spectrum similar to natural penicillin with extension against common gram-negative bacteria like E.coli, Salmonella enterica, Shigella sp., Proteus mirabilis, H. pylori, or H. influenzae. They are more effective than natural penicillin against enterococci and listeriae. y Ampicillin the basic representative of the subgroup, suitable for parenteral administration y Amoxicillin better absorption after oral administration y Remember: Patients with mononucleosis readily develop severe maculopapular exanthema even after a few tablets of aminopenicillin. This effect is caused by production of heterophile antibodies and should not be interpreted as true and lasting allergy.

y Because some gram-negative bacteria have become resistant due to plasmide-related production of betalactamase, new formulae were made containing the antibiotic together with a beta-lactamase inhibitor.

eg. amoxicillin + clavulanic acid y Aminopenicillins with or without beta-lactamase inhibitor are widely used in clinical practice. They are given in bacterial sinusitis, mesotitis and lower respiratory tract infections, urinary and hepatobiliary tract infections, purulent gynecological infections, and other communityacquired infections.

penicillinase-resistants(Anti-staphylococcal penicillins):

y They are resistant to staphylococcal beta-lactamase but not to other beta-lactamases produced by gram-negative microbes. y methicillin (only parenteral forms), oxacillin, cloxacillin, dicloxacillin y Remember: Methicillin-resistant strins of Staphylococcus aureus (MRSA) or Staphylococcus epidermidis (MRSE) are resistant to all beta-lactam antibiotics. Drug of choice in this situation is vancomycin.

Antipseudomonal penicillinsy effective against pseudomonas and other problematic gram-negative pathogens owing natural resistance y karbenicillin, ticarcillin, piperacillin. y These drugs are given in intensive care infections, according to the cultivation results. y The only route of administration is intravenous. y Combination of these antibiotics and beta-lactamase inhibitors were made as well:

ticarcillin + clavulanic acid piperacillin+ tazobactam

y Cephalosporin antibiotics are divided in four subgroups called generations. y The individual drugs are arranged into generations according their spectrum of antibacterial activity (including the susceptibility/resistance to beta-lactamases) not according to their date of synthesis or introducing to the market.

1st Generationy Effective against gram-positive cocci (streptococci and staphylococci). Their spectrum further includes corynabacteria, meningococci, and some gram-negative rods like E.coli or Proteus mirabilis. y cefalotin ,cefazolin (for parenteral administration) y cefalexin, cefadroxil, cefaclor* (for oral administration) *(cefaclor has moderate effect against Haemophilus, so it belongs to one-andhalf generation)

y The drugs are predominantly used for treatment skin and soft

tissue infections, and for prophylaxis in surgical procedures (except colorectal surgery and methicillin-resistant staphylococci)

2nd Generationy The drugs contain antibacterial activities of the 1st generation and extend to further community-acquired gram-negative bacteria like Haemophilus influenzae, Moraxella catarrhalis, E.coli y cefuroxim (for parenteral administration) y cefuroxim-axetil (for oral administration) The drugs are prescribed for treatment respiratory tract infections (bacterial sinusitis or mastoditis, pneumonia), and urinary and hepatobiliary tract infections. They can be used for prophylaxis in surgery as well. y Cefoxitin (only parenteral administration) has a good activity against relatively resistant anaerobe Bacteroides fragilis

3rd Generationy The drugs can be divided in two subgroups according to their

activity against Ps.aeruginosa: subgroup (A): consists of antibiotics of similar spectrum as 2nd generation but with enhanced activity against gram-negative bacteria and weaker effect against staphylococci. y cefotaxim, ceftriaxon (for parenteral administration) y These drugs are used for treatment of severe and lifethreatening infections caused by gram-negative pathogens like E.coli, H.influenzae, meningococci, salmonella . y Ceftriaxon is an antibiotic of extreme long half-time (8 hrs) in addition that allows once-daily administration. y cefpodoxim-proxetil, cefixim, (for oral administration)

subgroup (B) : included antibiotics effective against Ps. aeruginosa and other problematic gram-negative pathogens. However, the stronger is the anti-pseudomonadal effect, the weaker is the activity against staphylococci and other gram-positive microbes. y ceftazidim, cefoperazon (for parenteral administration) y These antibiotics are used in nosocomial infections/sepsis caused by gram-negative bacteria. y Ceftazidim is the strongest anti-pseudomonadal cephalosporin. y Cefoperazon s unique feature is predominant excretion via the bile: this advocates for its usage in hepatobiliary tract infections and in renal insufficiency.

4th Generationy Antibiotics of this group have a broad spectrum summarizing the 1st, 2nd and 3rd generation. They can resist some potent beta-lactamases. Nevertheless, their activity against staphylococci is not better than with cefalotin and activity against Ps.aeruginosa is not better than with ceftazidim. y cefpirom, cefepim (only parenteral administration) y These antibiotics are used in nosocomial infections or in nosocomial sepsis of unknown origin where covering the broad spectrum of pathogens is necessary (i.e. febrile neutropenia).

y They are very potent bacteriocidal antibiotics of extremely broad spectrum including majority of gram-positive and gram-negative pathogenes. These antibiotics resist effect of many beta-lactamases. y Imipenem, Meropenem (only parenteral administration) y These antibiotics are reserved for extreme resistant nosocomial infections/sepsis.

y They have strong and rapid bactericidal effect on bacteria.

(concentration-dependent)y They act in several sites of bacterial cell (outer membrane, ribosomes) y A very important feature of aminoglycosides is synergism with the

wall-affecting antibiotics (beta-lactams, glycopeptides). This synergism is expressed against some gram-positive (streptococci, enterococci) as well as gram-negative (E.coli, Pseudomonas) bacteria.y They are not absorbed from the gastrointestinal tract. Penetration

across biological barriers is poor. Volume of distribution correlates closely with the volume of extra-cellular fluid. The drugs are excreted unchanged by glomerular filtration.

y They are preferably used in combination with other antibiotics. Typical indications for usage aminoglycosides include:

a) severe infections or sepsis caused by gram-negative microbes, staphylococci, or M.tuberculosis (Amonoglycosidesare given especially at the onset of therapy, for rapid lowering of the massive bacterial load.)

b) severe infections caused by semi-resistant microbes when monotherapy is not bactericidal: In these situations, synergistic effect of aminoglycosides and wall-affecting antibiotics is often utilized. e.g: nosocomial infections caused by resistant gram-negative bacteria, infective endocarditis , enterococci, infections in immunocompromised patients in whom bactericidal activity of antibiotics is necessary.

Side effects 1. They can cause necrosis of the proximal tubular cells leading to reversible renal failure within several weeks or even days. 2. They can cause irreversible hearing loss (cochlear damage) and vestibular toxicity. 3. Neuromuscular blocade that can occur in predisposed patients (hypocalcemia, hypomagnesemia, myasthenia gravis) or in patients being treated with succinylcholin or other drug interfering with neuromuscular transmission.

In order to minimize the toxic effects, it is recommended :y to be careful of good water supply (daily diuresis 2 liters) y to prefer higher doses for few days at the onset of therapy y to respect a maximal treating period of 2-3 weeks, then a pause y y

y y

should follow of minimum 4-6 weeks to prefer once-daily administration (except infective endocarditis where multiple daily doses are preferred) while intravenous infusion, the time of administration should be 30-45 minutes (the period more then 1 hour enhances nephotoxicity, the period less then 20 minutes enhances the risk of neuromuscular blocade) to monitor renal and auditive functions three times weekly to measure serum levels of aminoglykosides (especially the minimum serum level)

Streptomyciny used in the treatment of tuberculosis. There are some more

indications for the very special situations

Gentamicin, Tobramycin.y Gentamicin is a standard and most widely used aminoglycoside y . Tobramycin is somewhat more effective against Pseudomonas.

Amikacin, Isepamiciny These antibiotics resist various bacterial destructive enzymes, so can

be used against some more resistant stems of nosocomial gramnegative pathogens. They do not work stronger than gentamicin but are somewhat less nephrotoxic.

y Remember: The nomenclature of aminoglycosides may be confusing.

The suffix -mycin is used for drugs produced by or derived from Streptomyces whereas -micin is reserved for drugs produced by or derived from other genus - Micromonospora.

y They are bactericidal antibiotics.(interfere with DNA y

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y y

metabolism). They are active mainly against gram-negative bacteria but the modern drugs are effective against gram-positive bacteria, intracellular pathogens, and even some anaerobes. Nalidix acid, The old quinolones without fluorine substituent on their ring, only oral preparations,absorb well from the GIT but achieve therapeutical concentration only in urine and partly in adjacent tissues like prostate. It can be used in lower urinary tract infections caused by E.coli and other enterobacteria, and in prostatitis. Norfloxacin, This drug is fluorinated and more effective but still has the same unfavourable pharmacokinetic profile.

y ciprofloxacin, ofloxacin, and pefloxacin consists of fluoroquinolones owing systemic effect. They spread well in the most tissues and penetrate into cells. Their spectrum is wider than in the former group: gram-negative bacteria including Pseudomonas aeruginosa ,staphylococci, chlamydiae, legionellae, and some mycobacteria. y They differ especially in their route of elimination:

- Ofloxacin is excreted almost entirely by the kidney. - Ciprofloxacin and pefloxacin are partly metabolized in the liver; and excreted via urine and feces. y These antibiotics are used in treatment of UTI, intestinal infections, biliary tract infections, bone and joint infections, many sexually transmitted infections .

y Adverse events in quinolone antibiotics are gastrointestinal disorders, allergy, leucopenia, thrombocytopenia, spasms, tendinitis, and even tendon ruptures. They affect pharmacokinetics of drugs metabolized in liver cytochrome P450 system. y Quinolones are not approved for gravid or breast feeding woman and children* until 18 years.

*This rule was changed

y They are static antibiotics reversibly inhibiting protein synthesis on ribosomal level of microorganisms. y Originally, they exhibited a broad-spectrum antibacterial activity involving gram-positive and gram-negative bacteria, anaerobes, spirochetes, and obligatory intracellular pathogens (chlamydiae, mycoplasmata).

y Erytromycin

The oldest macrolide. Its usage is associated with relatively frequent vomiting or reversible hepatic damage mainly in older preparations. y Claritromycin Modern macrolides and relatively strong. It was reported to interfere with angiogenesis and produce teratogenic effect in animals y Spiramycin They are especially suitable for infants and children or for long-time administration (therapy of toxoplasmosis in gravid women, long time prophylaxis of streptococcal infections in patients with allergy to beta-lactams). y Azitromycin. Similar to macrolides (azalides). It is active against sensitive gramnegative microbes and has very special farmakokinetic parameters: - very long half-time (2-4 days): a 3-day administration can make therapeutical levels in tissues for 7-14 days - the drug is transported to a locus of inflammation in leukocytes. Consequently, drug concentration in the site of inflammation is high, whereas serum concentration is extremely low.

y Sulfonamides were introduced before true antibiotics . Their usage as isolated drug is limited nowadays because of frequent side effects and increased resistance.

CO-TRIMOXAZOL : y it is a combination of two inhibitors of folic acid metabolism: sulfamethoxazole + trimethoprim y Both the sulfonamides and trimethoprim are static but the combination can have cidal effect against some bacteria.

y They penetrate across blood-brain barrier and placental barrier. The drugs are partly metabolized in the liver and excreted almost entirely through the kidney. y Adverse effect include allergy (erythema multiform including Stevens-Johnson syndrome, vasculitis and anaphylaxis), gastrointestinal disorders, headache, hematotoxicity (neutropenia, thrombocytopenia, anemia), nephrotoxicity. y Sulfonamides compete for bilirubin-binding sites on plasma albumin and may increase blood levels of unconjugated bilirubin. Therefore, co-trimoxazol can not be given to pregnant women or to newborns up to the age of 2 months.

y co-trimoxazol is rather a drug of second choice for most of these infections: severe diarrheal diseases with fever (salmonella), urinary tract infections, respiratory infections where pneumococcal or H.influenzae etiology can be expected (lobar pneumonia, sinusitis, otitis media). y Special indications include therapy or prophylaxis in HIV/AIDS patients (pneumocystosis, toxoplasmosis, isosporosis), nocardiosis, brucellosis, long-term treatment of staphylococcal osteomyelitis etc.

y They are static antibiotics reversibly inhibiting protein synthesis at bacterial ribosomes . y At present time, tetracyclines are used in treatment of various infections caused by non-pyogenic bacteria. Resistance within tetracycline family is completely crossed. y Adverse events: Gastrointestinal disorders; oral, intestinal, vaginal and skin dysmicrobia. In children, permanent teeth discoloration develops related to the total amount of absorbed tetracycline. Tetracyclines must not be prescribed for gravid and breast feeding women and for children until 8 years.

y Tetracycline and oxytetracycline are replaced with new tetracyclines doxycycline and minocycline which are better absorbed from gatrointestinal tract and have longer half-time (about 17 hours) allowing once-daily administration. They have substantially lower frequency of adverse events. y Doxycycline is excreted via intestinal secretion allowing treatment even in renal insufficiency

tetracyclines are used in: 1) Respiratory, genitourinary or occular infections caused by chlamydiae, mycoplasmata, and ureaplasmata. atypical pneumonia,acute and chronic urethritis and/or urethral syndrome, epididymitis, cervicitis, some of pelvic inflammatory diseases, inclusion conjuctivitis and trachoma. (Alternative drugs are macrolides.)

2) Rickettsial infections: Q fever, ehrlichiosis, typhus fever . (Alternative drug is chloramphenicol.) 3) Spirochetal infections: relapsing fever (Borrelia recurrentis), leptospirosis, syphilis and other treponemal infections. (Alternative drugs are penicillins, cephalosporines, macrolodes.) 4) Some other anthropozoonoses caused by non-pyogenic bacteria: brucellosis, campylobacteriosis,, plague, rat-bite fever. (Alternative drugs are fluoroquinolones.) 5) Mild to moderate infections caused by anaerobes: acne, actinomycosis, (Alternative drugs are other antibiotics effective against anaerobes.)

y The antibiotic posse bacteriostatic or cidal activity against a variety

of microbes including gram-positive and gram-negative bacteria, anaerobes, spirochetes, and obligatory intracellular pathogens (chlamydia, rickettsia, mycoplasma) by inhibiting protein synthesis on the ribosomal level. y its serum levels after oral and intravenous administration are equivalent. Chloramphenicol penetrates excellently across biological barriers including the blood/brain and blood/liquor barrier. It enters the cell compartment as well. y Chloramphenicol is metabolized in the liver and then excreted by the kidney.

y Adverse events: The most important undesirable effect of

chloramphenicol is its toxicity for bone marrow. It is manifested by anemia, leucocytopenia, thrombocytopenia, or any combination therefore Two forms of toxicity are distinguished: a) early toxicity occurring usually after 2 weeks of treatment. It is dose-dependent and reversible. b) delayed toxicity (aplastic anemia) that can develop several weeks or months after the cure. It is dose-independent and irreversible. The frequency of this event was estimated as 1:40.000 (range 1:20.000 to 1:200.000).y Chloramphenicol must not be prescribed for gravid women and

it is not advisable for newborns and sucklings: the liver can notmetabolize chloramphenicol sufficiently and the drug cumulates in tissues constituting so-called gray baby syndrome

y The acceptable indications are: 1. brain abscess and purulent meningitis (because of excellent penetration) 2. severe infections/sepsis caused by mixed aerobic and anaerobic flora (peritonitis, septic thrombophlebitis in abdominal area, severe forms of pelvic inflammatory disease, chest empyema caused by mixed flora) 3. severe rickettsial infections (Q fever, Rocky Mountains spotted fever, typhus)

* Former indications (typhoid fever, invasive Salmonella infections, pertussis, epiglotitis ) are left because cefalosporines of 2nd or 3rd generation or fluoroquinolones can be given instead

y bactericidal drugs inhibiting bacterial cell wall synthesis They

may also injure bacterial protoplasts or interfere with RNA synthesis. y their antibacterial spectrum is narrow and involves only grampositive microbes. y The drugs are not absorbed from the gastrointestinal tract. Penetration across biological barriers is poor. The drugs are excreted almost exclusively by glomerular filtration. y Reserve antibiotics for the treatment of serious gram-positive infections. They are used when beta-lactams can not be given. The typical indications are staphylococcal, enterococcal, or streptococcal infections: sepsis, endocarditis, joint infection, (nosocomial) pneumonia

vancomyciny Its usage requires special caution: The drug must be

administrated in a slow infusion ( 1 hour) and serum concentration should be measured. The dosage must be balanced very carefully because of significant nephrotoxicity and ototoxicity of the drug. y renal function should be monitored thrice or twice a week. y Adverse effects of vancomycin involve : 1. fever, chills, exanthema, and phlebitis at the site of infusion. 2. Reversible leukopenia, thrombocytopenia, or eosinophilia may develop . 3. Flushing and/or hypotension frequently occur after rapid intravenous administration. due to histamin release (red man syndrome) 4. Renal failure and hearing loss

y Vancomycin can also be given orally when pathogenicbacteria are localized in intestinal lumen. The typical example is colitis caused by Clostridium difficile. y Vancomycin is sometimes used in mixture with other nonabsorbable antibiotics for disinfecting of the gastrointestinal tract in neutropenic patients, in ICU patients requiring mechanical ventilation, or in patients preparing for great colic surgery.

y They are bactericidal narrow-spectrum antibiotics, effective

against most anaerobes and some protozoa (Trichomonas vaginalis, Entamoeba histiolytica, and Giardia lamblia). y This antibiotics interfere with electron transport in anaerobic metabolic pathways of bacterial or protozoal cells. y The drugs are very well absorbed from the gastrointestinal tract. After absorption, they posse excellent penetration across biological barriers including blood-brain and placental barrier. The drugs are metabolized in the liver by 40% and excreted mainly by the kidney

y Adverse events are usually mild and include gastrointestinal disorders (glossitis, metallic taste, dry mouth, nausea), allergy, headache, dizziness . y The drugs also inhibit the metabolism of oral anticoagulants. y Nitroimidazoles are not approved for gravid women. They and not advised for long treatment (polyneuropathy). y they are used in: 1. moderate to severe anaerobic infections including lifethreatening clostridial infections (gas gangrene) and pseudomembranous colitis caused by Cl.difficile, 2. mixed bacterial infections (in combination with other antibiotics), 3. above mentioned protozoal infections.

Metronidazoly It is the most widely used nitroimidazole because of persisting in prescription habits and low cost.

Ornidazole, Tinidazole y They have more advantageous phamacokinetic parameters (a half-time of 13 hours allowing once-daily administration) and less frequency of adverse events.

Clindamyciny bacteriostatic antibiotics reversibly inhibiting protein synthesis

on ribosomal level. y active only against gram-positive bacteria (mainly staphylococci and streptococci) and anaerobes. also active against some protozoa. y better absorbed when administered orally. it concentrates in phagocytic cells and achieve high levels in pus. It is partly metabolized in the liver and excreted in the bile and urine

lincomyciny It is somewhat weaker than clindamycin

y Bacteriocidal drug, nevertheless effective concentrations are reached only in urine. y excellent effect against enterococci y Adverse events: allergy, gastrointestinal disorders, neuropathy, autoimunne pneumonitis y The drug must not be used in gravid women y therapy and prophylaxis of urinary tract infections y Local administration: vaginal globule, paste for dermatological practices

WHAT DO WE NEED ATB FOR ?Kill the bacteria ?? Stop bacteria to grow ?? CIDAL: PNCs, CEFs -cell wall ATB: VAN AMG, COL Dilemma: -DNA/RNA metabolism: { FQ, RIF

STATIC:

-metabolic blocks:

{ SULF/TMP

- ribosomal dysfunction

(translation blocks): {ERY, LIN, TET,CMP

MAIN MISTAKES IN ATB TREATMENT:1) usage in diseases of non-bacterial origin(x non-antiinfective effect of ATB - macrolides!)

2) not taking material for cultivation before starting ATB treatment 3) not respecting individual pharmacokinetic parametersespecially in critical care patients where extreme changes of volume of distribution and of half-time (polyuria x oliguria) do occur

4) not requesting quantitative data of sensitivity in difficult-to-treat infectionsinfective endocarditis, osteomyelitis, sepsis in immunocompromised person

5) uncorrect interpreting ATB failure in outpatient s treatmentpatients compliance?

6) uncorrect answer to ATB failureearly change of ATB? prescribing a drug of the same spectrum ? cultivation attempts ?

7) blind confidence in various studies resultsy pharmaceutical companies influence ?