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antibacterial drugs By Dechang Zhang Department of Pharmacology, School of Basic Medicine, Peking Union Medical College History of antimicrobial therapy Early The first recorded successful use of antimicrobial 17th therapy involving the use of an extract from cinchona century bark for the treatment of malaria. 1909 Paul Ehrlich's quest for a "magic bullet" that would bind specifically to particular sites on parasitic organisms leads to an arsenic derivative, salvarsan, with modest activity against syphilis. He also suggested that antimicrobial drugs would be most useful if the sites of action were not present in the organs and tissues of the human host. 1929 Alexander Fleming discovers penicillin. 1935 Discovery of prontosil, a forerunner of sulfonamides. 1940 Florey and Chain first use penicillin clinically. Principles of antimicrobial use 12 Factors to consider when selecting antimicrobial agents for therapy in patients 1. Is an antimicrobial agent necessary? 2. Identification of the pathogen 3. Empiric versus directed therapy 4. Susceptibility of infecting microorganism 12 Factors to consider when selecting antimicrobial agents for therapy in patients 5. Need for bactericidal versus bacteriostatic agent 6. Pharmacokinetic and pharmacodynamic factors 7. Anatomical site of infection 8. Cost 9. Toxicity 12 Factors to consider when selecting antimicrobial agents for therapy in patients 10. Host factors Allergy history Age Renal function Hepatic function Pregnancy status Genetic or metabolic abnormalities Host defenses function 12 Factors to consider when selecting antimicrobial agents for therapy in patients 11. Need for combination therapy 12. Antibiotic resistance concerns 1. Is an antimicrobial agent necessary? • viral infections that do not respond to antibiotics • noninfectious processes mimicking a bacterial infection • culture isolation of an organism that is colonizing an anatomical site and not causing an infection In general, the clinician should resist temptation to begin antimicrobial therapy unless there is a reasonable probability that a bacterial infection is present. When the downside risk of withholding therapy is great, such as with bacterial meningitis or in clinically unstable patients, therapy should be started without delay even when the presence of a bacterial infection is uncertain. Another indication for antimicrobials is prophylactic therapy, which is intended to prevent illness in someone at risk of infection. 2. Identification of the pathogen Characterization of the organism is central to selection of the proper drug. Presence and morphologic features of microoganisms in body fluids that are normally sterile. Culture the infective organism to arrive at a conclusive diagnosis and to determine the susceptibility of antimicrobial agents. 3.Empiric versus directed therapy The acutely ill patient with infections of unknown origin a neutropenic patient a patient with severe headache, a rigid neck, and sensitivity to bright lights(meeningitis) Therapy is initiated after specimens for laboratory analysis have been obtained but before the results of the culture are available. The choice of drug in the absence of susceptibility data the site of infection the patient's history Broad-spectrum therapy may be needed initially for serious infections when the identity of the organism is unknown or the site makes a polymicrobial infection likely. A gram-positive coccus in the spinal fluid A newborn infant most likely to be Group B Streptococcus. sensitive to penicillin G. A forty-year old patient most likely to be S. pneumoniae. frequently resistant to penicillin G, sensitive to a third-generation cephalosporin or vancomycin. 4.Need for bactericidal versus bacteriostatic agent Bacteristatic drugs arrest the growth and replication of bacteria at serum levels achievable in the patient, thus limiting the spread of infection while the body’s immune system attachs, immoblilizes, and eliminates the pathogens. Bactericidal drugs kill bacteria at drug serum levels achievable in the patient. They are more aggressive compare with bicteriostatic antimicrobial drugs . A given agent may show bactericidal actions under certain conditions but bacteriostatic actions under others, depending on the concentration of drug and the target bacteria. A bacteriostatic agent often is adequate in uncomplicated infections because the host defenses will help eradicate the microorganism. Bactericidal agents are required for management of infections in areas "protected" from host immune responses, such as endocarditic vegetations and cerebrospinal fluid (CSF). 5. Determination of antimicrobial susceptibility of infective organisms In the laboratory, susceptibility is most often measured using a disk diffusion test Stokes controlled sensitivity test . In the Stokes controlled sensitivity test, a control organism is inoculated on part of a plate and the test organism is plated on the remainder. Disks are placed at the interface and the zones of inhibition are compared. The use of a sensitive control shows that the antibiotic is active, so that if the test organism grows up to the disk it may safely be assumed that the test organism is resistant to that drug. An alternative measure of susceptibility is to determine the Minimum Inhibitory Concentration (MIC) and the Minimum Bactericidal Concentration (MBC) of a drug. A series of broths are mixed with serially diluted antibiotic solutions and a standard inoculum is applied. After incubation, the MIC is the first broth in which growth of the organism has been inhibited. The more resistant an organism is, then the higher will be the MIC. The MBC is measured by inoculating the broths used for MIC determinations onto drug-free medium. The MBC is the first dilution at which no growth is observed. Cidal drugs have MBC values that are close to the MIC value for particular organisms. With static agents, the MIC is much lower than the MBC. The MIC/MBC test of a moderately resistant bacteriostatic drug. Note that once the bacteria are removed from the drug they can grow on drug free medium at most concentrations. The MIC/MBC test of a moderately resistant bactericidal drug. The bacteria removed from the drug cannot grow on drug free medium. One tube difference is allowed in this test. 6. Pharmacokinetic and pharmacodynamic factors Oral peak concentrations : 1 to 2 hours may be delayed by food or delayed intestinal transit vary widely in their oral bioavailability Most life-threatening infections are treated, at least initially, with IV agents. Parenteral therapy ensures adequate serum levels, and, for many agents, higher drug levels can be achieved when administered IV. The amount of drug that reaches the extravascular tissues and fluids depends on : ● the concentration gradient between plasma and target tissue, degree of drug binding to plasma and tissue proteins, molecular size, ● degree of ionization and lipid solubility of the drug, ● its rate of elimination or metabolism. ● concentration-dependent killing Fluoroquinolones and aminoglycosides kill bacteria faster at higher concentrations. Post-antibiotic effect (PAE) These agents also continue to inhibit growth of bacteria for several hours after the concentrations of the drug fall below the MIC in the serum. The Post-Antibiotic Effect (PAE) shows the capacity of an antimicrobial drug to inhibit the growth of bacteria after removal of the drug from the culture. To determine the PAE a liquid culture with an initial count of 106 to 107 colony forming units (CFU) per ml is exposed to a certain concentration of the drug for a certain time. A control group is left untreated. After the given time, drug of the treated culture is removed, e.g., by dilution 1:1000 in fresh, drug-free medium. The same procedure is applied to the untreated control. The time it takes for both colonies to increase their CFU by 1 log10 is measured. PAE is defined as the time needed by a culture that was treated with an antibiotic to increase in number (CFU) by 1 log10 compared to untreated controls, and is usually given in hours. The PAE provides additional time for the immune system to remove bacteria that might have survived antibiotic treatment before they can eventually regrow after removal of the drug from the animal's organism. A longer PAE can therefore influence the clinical outcome of antimicrobial therapy. Most β-lactam agents do not exhibit concentrationdependent killing nor do they have a prolonged post-antibiotic effect. 7. Anatomical site of infection The site of infection often influences not only the agent used but also the dose, route, and duration of administration. The desired peak concentration of drug at the site of infection should be at least 4 times the MIC. However, if host defenses are adequate, peak oncentrations may be much lower and even be equal to the MIC and still be effective. When host defenses are absent or inoperative, peak concentrations 8- to 16-fold greater than the MIC may be required. Blood-Brain Barrier 1.Lipid solubility (quinolones vs penicillin) 2.Molecular weight (vancomycin) 3.Protein binding Readily Enter CSF Chloramphenicol Sulfonamides Trimethoprim 甲氧苄氨嘧啶 Rifampin 利福平 Metronidazole 甲硝唑 Enter CSF When Inflammation Present Penicillin G Ampicillin氨苄西林 Piperacillin哌拉西林 Oxacillin苯唑西林 Nafcillin萘夫西林 Cefuroxime头孢呋辛 Cefotaxime头孢噻肟 Ceftriaxone 头孢曲松 Ceftazidime头孢他定 Aztreonam氨曲南 Ciprofloxacin环丙沙星 Vancomycin万古霉素 Meropenem美罗培南 Cefepime头孢平 Do Not Enter CSF Adequately to Treat Infection Cefazolin 头孢唑啉 Cefoxitin头孢西丁 Erythromycin乙琥红霉素 Clindamycin克林霉素 Tetracycline 四环素 Gentamicin庆大霉素 Tobramycin 妥布霉素 Amikacin阿米卡星 Endocarditis Meningitis Osteomyelitis foreign body abscesses organisms that can survive within phagocytic cells (Mycobacterium, Salmonella) 8. Cost 9. Toxicity Because of nephrotoxicity and ototoxicity, aminoglycoside use has decreased with the development of β-lactams and fluoroquinolones with broad gram-negative activity. 10. Host factors Allergy history Significant allergy appears to be more common with β-lactams, particularly penicillins, and sulfonamides. In anaphylactic reactions to penicillins, the IgE antibody is usually directed at the penicillin nucleus, so the potential for allergic reactions to other penicillins is high. Age Renal function Antimicrobial agents that require dosage adjustment include aminoglycosides, vancomycin, certain penicillins, most cephalosporins, carbapenems(碳青霉烯类), and quinolones. Failure to adjust dosage can lead to ototoxicity from aminoglycosides and neurotoxicity from penicillins, imipenem, or quinolones. Aminoglycosides can cause renal toxicity and should be used with caution in patients with preexisting renal insufficiency. aminoglycosides vancomycin certain penicillins most cephalosporins carbapenems 碳青霉烯类 quinolones Hepatic function Antimicrobials metabolized in the liver include chloramphenicol, erythromycin, clarithromycin, rifampin, nitroimidazoles, and some of the quinolones. Pregnancy status Agent Potential Toxicity Sulfonamides Hemolysis in newborn with glucose-6-phosphate dehydrogenase deficiency; Tetracyclines Trimethoprim Limb abnormalities, dental staining, inhibition of bone growth Altered folate metabolism Quinolones Abnormalities of cartilage Vancomycin Possible auditory toxicity Agent Aminoglycosides Potential Toxicity Eighth nerve damage Chloramphenicol Gray baby syndrome Erythromycin estolate Cholestatic hepatitis (胆汁 淤积性肝炎) in mother Metronidazole Possible teratogenicity 致 畸性 Nitrofurantoin Hemolytic anemia Genetic or metabolic abnormalities Genetic abnormalities of enzyme function may alter the toxicity of certain agents. hemolysis in glucose-6phosphate dehydrogenasedeficient people can be provoked by sulfonamides, nitrofurantoin, pyrimethamine (乙胺嘧啶), sulfones(砜), and chloramphenicol. Host defenses function An absence of white blood cells predisposes a patient to serious bacterial infection, and bacteriostatic agents are often ineffective in treating serious infections in neutropenic hosts. The critical white blood cell count is between 500 and 1000 mature polymorphonuclear 3 cells/mm . 11. Antimicrobial combinations To treat a life-threatening infection To treat a polymicrobial infection Empiric therapy when no one agent is active against potential pathogens To achieve synergy (obtain enhanced antibacterial activity) To prevent the emergence of resistant bacteria To permit the use of a lower dose of one of the antimicrobial agents Box 44-3 Reasons for concurrent use of more than one antimicrobial agent in a patient indifferent effects The combined activity equals the sum of the separate activities. Synergism ( 协同) is present if the activity of the combined antimicrobial agents is greater than the sum of the independent activities. Combinations of antibiotics are antagonistic when the activity of the combination is less than could be achieved by using the agents separately. The combination of an inhibitor of cell-wall synthesis with an aminoglycoside antibiotic The combination of agents acting on sequential steps in a metabolic pathway The combination of agents in which one (such as an inhibitor of β-lactamases) inhibits an enzyme that inactivates the other compound, such as clavulanate with amoxicillin Antibiotic decision making after therapy has started Infection Duration (days) Streptococcal pharyngitis 10 Otitis media 中耳炎 5-10 Sinusitis 鼻窦炎 10 Uncomplicated urinary tract infection 3 Pyelonephritis 肾盂肾炎 14 Cellulitis 蜂窝织炎 3 days after inflammation resolves Infection Pneumococcal pneumonia Other pneumonia Duration (days) 3-5 days after fever resolves variable, often 14 Bacteremia variable, often 10-14 days without endocarditis 28-42 7-14 42 21 Endocarditis Meningitis Osteomyelitis Septic arthritis 12. Antibiotic resistance concerns Prevalence of antibiotic resistant bacteria Resistance in nosocomial (医院) infections • Nowadays, About 70 percent of the bacteria that cause infections in hospitals are resistant to at least one of the drugs most commonly used for treatment Resistance in nosocomial (医院)infections • Some organisms are resistant to all approved antibiotics and can only be treated with experimental and potentially toxic drugs (e.g. MRSA耐甲氧金葡, Pseudomonas 假单胞) Resistance in community acquired infections • Staphylococci - up to 60% MRSA (Methicillin Resistant Staph Aureus) Resistance in community acquired infections • Pneumococci (Streptococcus pneumoniae) - 25% resistant to penicillin, while a further 25% are resistant to more than one antibiotic Resistance in community acquired infections • Mycobacterium tuberculosis 5% are multiple drug resistant (MDR) 杨晓霞事件 1994年右手拇指局部感染抗生素治疗无效。 反复转院多次抗生素治疗,病情逐渐恶化直 至右手坏死3个月后截肢。创面继续感染。此 后,经首都13家医院的50 名中西医专家先后 两次会诊。几十次的细菌培养试验,伤口上 分离出12种细菌并且这些细菌已经对大多数 的抗生素产生了耐药性。其中有一种细菌对 59种药物和21种抗生素具有耐药性。 泰能 泰能含有两种成分:亚胺培南是新 型的β-内酰胺抗菌素-硫霉素,其特 性是杀菌谱较其它抗菌素广泛;西 司他丁钠盐为特异性酶抑制剂,它 可阻断亚胺培南在肾脏的代谢,继 而增加尿道中未经改变的亚胺培南 的浓度,本制剂之亚胺培南与西司 他丁钠盐的重量比率为1:1。 Antibiotic resistance can be intrinsic or acquired. Pseudomonas aeruginosa outer membrane Acquired resistance can be due to mutation of existing genetic information or acquisition of new genes. Spontaneous mutation • mutation and selection of antibiotic resistant mutants in the presence of the antibiotic • “vertical gene transfer” to progeny results during normal cell division Lateral or horizontal gene transfer (HGT) • genetic material contained in small packets of DNA can be transferred between individual bacteria of the same species or of different species • Three mechanisms of HGT Conjugation 接合 Transformation 转化 Transduction 转导 Conjugation: occurs when there is direct cell-cell contact between two bacteria and transfer of small pieces of DNA called plasmids takes place Transformation: pieces of DNA are taken up from the external environment Transduction: bacteria-specific viruses (bacteriophages) transfer DNA between two closely related bacteria Mechanisms of bacterial resistance to antibiotics reduced uptake into cell 1. Reduced uptake into cell 2. Active efflux of antibiotic from the cell 3. Eliminate or reduce binding of antibiotic to cell target 4. Enzymatic cleavage or chemical modification inactivates antibiotic molecule 5. Metabolic bypass of inhibited reaction 6. Overproduction of antibiotic target Reduced uptake into cell • Antibiotic must be transported by cell.A mutation in the transport system gene could eliminate uptake. Decreased uptake has been described for aminoglycosides, some β-lactams, tetracyclines, and others. Active efflux of antibiotic from the cell • Antibiotic is pumped out of the cell at a rate equal to the rate of entry Efflux pumps are the main mechanism of resistance for tetracyclines and have also been described for quinolones. Eliminate or reduce binding of antibiotic to cell target • Antibiotic must be bound to cell surface before transport. Mutation in the binding protein gene reduces ability of antibiotic to bind to cell surface Enzymatic cleavage or chemical modification inactivates antibiotic molecule • Antibiotic is degraded or chemically modified in some way losing functionality β-lactamases catalyze the hydrolysis of penicillins, cephalosporins, and other βlactams. When hydrolyzed, the βlactam is unable to bind to bacterial transpeptidases and other enzymes needed for cell wall synthesis and repair. Many enzymes have been described that inactivate aminoglycosides. Metabolic bypass of inhibited pathway • Bacterium develops a new pathway which bypasses the inhibited reaction(s) Some thymidine-requiring streptococci are not inhibited by trimethoprim and sulfonamides. because the resistant bacteria produce adequate concentrations of thymidine nucleotides by an alternative pathway and as a result survive exposure to these drugs. exposed to these agents. Overproduction of antibiotic target • Bacterium speeds up the inhibited reaction or produces excessive amount of the antibiotic’s target, thereby “mopping up” the antibiotic and allowing the uninhibited reaction to proceed Combating Antibiotic Resistance Defining the Problem • Not enough new antibiotics to cope with the development of resistance to “old” antibiotics Defining the Problem • Widespread misuse of antibiotics in agriculture and by patients and health care workers in med/vet situations e.g.use of antibiotics as feed additives given to farm animals topromote growth unnecessary antibiotic prescriptions Solving the problem • Pharmaceutical companies need new, less costly strategies to develop antimicrobials Solving the problem • Regulate use of antibiotics as feed additives promote growth Solving the problem • Stop administration and uses of antibiotics for viral infections or nonmedical purposes Antimicrobial prophylaxis in surgery. Medical Lett 2001; 43:92. Gold HS, Moellering RC Jr. Antimicrobialdrug resistance. N Engl J Med 1996; 335:1445-1453. Steinberg JP, Blass MA. Non-surgical antibiotic prophylaxis. In Schlossberg D: Current therapy of infectious diseases, Philadelphia, Mosby-Harcourt Health Sciences, 2000.