antibacterial drugantibacterial drugssBy

Dechang ZhangDepartment of Pharmacology, School of Basic Medicine, Peking Union Medi

cal College

History of antimicrobial therapyHistory of antimicrobial therapy

Early Early 1717thth centurcenturyy

The first recorded successful use of The first recorded successful use of antimicrobial therapy involving the use of an antimicrobial therapy involving the use of an extract from cinchona bark for the treatment extract from cinchona bark for the treatment of malaria.of malaria.

19091909 Paul Ehrlich's quest for a "magic bullet" that would biPaul Ehrlich's quest for a "magic bullet" that would bind specifically to particular sites on parasitic organismnd specifically to particular sites on parasitic organisms leads to an arsenic derivative, salvarsan, with modess leads to an arsenic derivative, salvarsan, with modest activity against syphilis. He also suggested that antit activity against syphilis. He also suggested that antimicrobial drugs would be most useful if the sites of actmicrobial drugs would be most useful if the sites of action were not present in the organs and tissues of the hion were not present in the organs and tissues of the human host.uman host.

19291929 Alexander Fleming discovers penicillin.Alexander Fleming discovers penicillin.

19351935 Discovery of prontosil, a forerunner of sulfonamides.Discovery of prontosil, a forerunner of sulfonamides.19401940 Florey and Chain first use penicillin clinically.Florey and Chain first use penicillin clinically.

Principles of Principles of antimicrobial useantimicrobial use

12 Factors to consider when selecting 12 Factors to consider when selecting antimicrobial agents for therapy in antimicrobial agents for therapy in patientspatients

1. Is an antimicrobial agent 1. Is an antimicrobial agent necessary? necessary? 2. Identification of the pathogen 2. Identification of the pathogen 3. Empiric versus directed therapy 3. Empiric versus directed therapy 4. Susceptibility of infecting 4. Susceptibility of infecting microorganism microorganism

12 Factors to consider when selecting an12 Factors to consider when selecting antimicrobial agents for therapy in patientstimicrobial agents for therapy in patients

5. Need for bactericidal versus 5. Need for bactericidal versus bacteriostatic agent bacteriostatic agent 6. Pharmacokinetic and 6. Pharmacokinetic and pharmacodynamic factors pharmacodynamic factors 7. Anatomical site of infection 7. Anatomical site of infection 8. Cost 8. Cost 9. Toxicity9. Toxicity

12 Factors to consider when selecting 12 Factors to consider when selecting antimicrobial agents for therapy in antimicrobial agents for therapy in patientspatients

10. Host factors 10. Host factors

Allergy history Age Allergy history Age Renal function Hepatic function Renal function Hepatic function Pregnancy status Pregnancy status Genetic or metabolic abnormalities Genetic or metabolic abnormalities Host defenses functionHost defenses function

12 Factors to consider when selecting 12 Factors to consider when selecting antimicrobial agents for therapy in antimicrobial agents for therapy in patientspatients

11. Need for combination therapy 11. Need for combination therapy 12. Antibiotic resistance concerns12. Antibiotic resistance concerns

1. Is an 1. Is an antimicrobial antimicrobial agent agent necessary?necessary?

• • viral infections that do not viral infections that do not respond to antibiotics respond to antibiotics • • noninfectious processes noninfectious processes mimicking a bacterial infection mimicking a bacterial infection • • culture isolation of an culture isolation of an organism that is colonizing organism that is colonizing an anatomical site and not an anatomical site and not causing an infection causing an infection

In general, the clinician In general, the clinician should resist temptation to should resist temptation to begin antimicrobial therapy begin antimicrobial therapy unless there is a reasonable unless there is a reasonable probability that a bacterial probability that a bacterial infection is present.infection is present.

When the downside risk of When the downside risk of withholding therapy is great, withholding therapy is great, such as with bacterial meningitis such as with bacterial meningitis or in clinically unstable patients, or in clinically unstable patients, therapy should be started therapy should be started without delay even when the without delay even when the presence of a bacterial infection presence of a bacterial infection is uncertain.is uncertain.

Another indication for Another indication for antimicrobials is prophylactic antimicrobials is prophylactic therapy, which is intended to therapy, which is intended to prevent illness in someone at prevent illness in someone at risk of infection. risk of infection.

2.2. Identification Identification

of the of the pathogenpathogen

Characterization of Characterization of the organism is the organism is central to selection central to selection of the proper drug. of the proper drug.

Presence and mPresence and morphologic featuorphologic features of microoganres of microoganisms in body fluiisms in body fluids that are normds that are normally sterile.ally sterile.

Culture the infective Culture the infective organism to arrive organism to arrive at a conclusive at a conclusive diagnosis and to diagnosis and to determine the determine the susceptibility of susceptibility of antimicrobial antimicrobial agents.agents.

3.3.Empiric versus Empiric versus directed therapy directed therapy

The acutely ill patient with infections The acutely ill patient with infections of unknown originof unknown origin

a neutropenic patienta neutropenic patienta patient with severe headache, a ria patient with severe headache, a rigid neck, and sensitivity to bright liggid neck, and sensitivity to bright lights(meeningitis)hts(meeningitis)

Therapy is initiated Therapy is initiated afterafter specimens for laboratory specimens for laboratory analysis have been analysis have been obtained obtained but beforebut before the the results of the culture are results of the culture are available.available.

The choice of drug in the The choice of drug in the absence of susceptibility absence of susceptibility data data the site of infection the site of infection the patient's historythe patient's history

Broad-spectrum therapy mBroad-spectrum therapy may be needed initially for seay be needed initially for serious infections when the irious infections when the identity of the organism is udentity of the organism is unknown or the site makes a nknown or the site makes a polymicrobialpolymicrobialinfection likely.infection likely.

A gram-positive coccus in the spinal fluidA gram-positive coccus in the spinal fluid

A newborn infant most likely to be Group B A newborn infant most likely to be Group B Streptococcus. Streptococcus. sensitive to penicillin G. sensitive to penicillin G.

A forty-year old patient most likely to be S. A forty-year old patient most likely to be S. pneumoniae. pneumoniae. frequently resistant to penicillin G, sensitive tfrequently resistant to penicillin G, sensitive to a third-generation cephalosporin or vancoo a third-generation cephalosporin or vanco

mycin.mycin.

4.Need for bactericidal 4.Need for bactericidal versus versus bacteriostatic agent bacteriostatic agent

Bacteristatic drugs arrest the Bacteristatic drugs arrest the growth and replication of bactgrowth and replication of bacteria at serum levels achievableria at serum levels achievable in the patient, thus limiting te in the patient, thus limiting the spread of infection while thhe spread of infection while the body’s immune system attace body’s immune system attachs, immoblilizes, and eliminaths, immoblilizes, and eliminates the pathogens.es the pathogens.

Bactericidal drugs kill bBactericidal drugs kill bacteria at drug serum leacteria at drug serum levels achievable in the pvels achievable in the patient. They are more agatient. They are more aggressive compare with gressive compare with bicteriostatic antimicrobbicteriostatic antimicrobial drugsial drugs . .

A given agent may show baA given agent may show bactericidal actions under cerctericidal actions under certain conditions but bacteriotain conditions but bacteriostatic actions under others, static actions under others, depending on the concentrdepending on the concentration of drug and the target ation of drug and the target bacteria.bacteria.

A bacteriostatic agent often iA bacteriostatic agent often is adequate in uncomplicated s adequate in uncomplicated infections because the host dinfections because the host defenses will help eradicate thefenses will help eradicate the microorganism.e microorganism.

Bactericidal agents are Bactericidal agents are required for management of required for management of infections in areas infections in areas "protected" from host immune "protected" from host immune responses, such as responses, such as endocarditic vegetations and endocarditic vegetations and cerebrospinal fluid (CSF).cerebrospinal fluid (CSF).

5. Determination of 5. Determination of antimicrobial antimicrobial susceptibility of susceptibility of infective organisms infective organisms

In the In the laboratory, laboratory, susceptibility susceptibility is most often is most often measured measured using a using a disk disk diffusion diffusion testtest

Stokes controlled sensitivity testStokes controlled sensitivity test

.

In the In the Stokes controlled Stokes controlled sensitivity testsensitivity test, a control , a control organism is inoculated on part organism is inoculated on part of a plate and the test organism of a plate and the test organism is plated on the remainder. is plated on the remainder. Disks are placed at the Disks are placed at the interface and the zones of interface and the zones of inhibition are compared.inhibition are compared.

The use of a sensitive control The use of a sensitive control shows that the antibiotic is shows that the antibiotic is active, so that if the test active, so that if the test organism grows up to the organism grows up to the disk it may safely be disk it may safely be assumed that the test assumed that the test organism is resistant to that organism is resistant to that drug.drug.

An alternative measure of An alternative measure of susceptibility is to determine susceptibility is to determine the the Minimum Inhibitory Minimum Inhibitory Concentration (MIC)Concentration (MIC) and and the the Minimum Bactericidal Minimum Bactericidal Concentration (MBC)Concentration (MBC) of a of a drug.drug.

A series of broths are A series of broths are mixed with serially dilutmixed with serially diluted antibiotic solutions ed antibiotic solutions and a standard inoculuand a standard inoculum is applied. After incum is applied. After incubation, the MIC is the firbation, the MIC is the first broth in which growtst broth in which growth of the organism has bh of the organism has been inhibited.een inhibited.

The more resistant The more resistant an organism is, an organism is, then the higher will then the higher will be the MIC.be the MIC.

The MBC is measured by The MBC is measured by inoculating the broths used inoculating the broths used for MIC determinations for MIC determinations onto drug-free medium. onto drug-free medium. The MBC is the first dilution The MBC is the first dilution at which no growth is at which no growth is observed.observed.

CidalCidal drugs have drugs have MBCMBC valu values that are es that are close toclose to the the MIMICC value for particular organi value for particular organisms. With sms. With static agentsstatic agents, th, the e MICMIC is is much lower much lower than tthan the he MBCMBC. .

The MIC/MBC test of a moderately resiThe MIC/MBC test of a moderately resistant bacteriostant bacteriostaticstatic drug. drug. Note that once the bacteria are removed fNote that once the bacteria are removed from the drug they can grow on drug free rom the drug they can grow on drug free medium at most concentrations.medium at most concentrations.

The MIC/MBC test of a moderately The MIC/MBC test of a moderately resistant bacteriresistant bactericidalcidal drug. drug. The bacteria removed from the drug cannot The bacteria removed from the drug cannot grow on drug free medium. grow on drug free medium. One tube difference is allowed in this test.One tube difference is allowed in this test.

6. Pharmacokinetic and 6. Pharmacokinetic and

pharmacodynamic pharmacodynamic factors factors

Oral Oral

peak concentrations :peak concentrations :1 to 2 hours may be delayed 1 to 2 hours may be delayed by food or delayed intestinal by food or delayed intestinal transit vary widely in their oral transit vary widely in their oral bioavailabilitybioavailability

Most life-threatening Most life-threatening infections are treated, at infections are treated, at least initially, with IV agents.least initially, with IV agents.

Parenteral therapy ensures Parenteral therapy ensures adequate serum levels, and, adequate serum levels, and, for many agents, higher drufor many agents, higher drug levels can be achieved whg levels can be achieved when administered IV. en administered IV.

The amount of drug that reacThe amount of drug that reaches the extravascular tissues hes the extravascular tissues and fluids depends onand fluids depends on : :

● ● the concentration gradient the concentration gradient between plasma and target between plasma and target tissue, tissue,

●● degree of drug binding to degree of drug binding to plasma and tissue proteins, plasma and tissue proteins, molecular size, molecular size,

●● degree of ionization and degree of ionization and lipid solubility of the drug, lipid solubility of the drug,

●● its rate of elimination or its rate of elimination or metabolism.metabolism.

concentration-dependent killconcentration-dependent killing ing

Fluoroquinolones and aminoglFluoroquinolones and aminoglycosides kill bacteria faster at ycosides kill bacteria faster at higher concentrations. higher concentrations.

Post-antibiotic effect (PAE) Post-antibiotic effect (PAE)

These agents also continue These agents also continue to inhibit growth of bacteria to inhibit growth of bacteria for several hours after the for several hours after the concentrations of the drug concentrations of the drug fall below the MIC in the fall below the MIC in the serum.serum.

The Post-Antibiotic Effect The Post-Antibiotic Effect (PAE) shows the capacity of (PAE) shows the capacity of an antimicrobial drug to inhibit an antimicrobial drug to inhibit the growth of bacteria after the growth of bacteria after removal of the drug from the removal of the drug from the culture.culture.

To To determine the PAEdetermine the PAE a liquid a liquid culture with an initial count of culture with an initial count of 101066 to 10 to 107 7 colony forming units colony forming units (CFU) per ml is exposed to a (CFU) per ml is exposed to a certain concentration of the certain concentration of the drug for a certain time. A drug for a certain time. A control group is left untreated.control group is left untreated.

After the given time, drug of the After the given time, drug of the treated culture is removed, e.g., by treated culture is removed, e.g., by dilution 1:1000 in fresh, drug-free dilution 1:1000 in fresh, drug-free medium. The same procedure is medium. The same procedure is applied to the untreated control. The applied to the untreated control. The time it takes for both colonies to time it takes for both colonies to increase their CFU by 1 logincrease their CFU by 1 log1010 is is

measured.measured.

PAE is defined as the time PAE is defined as the time needed by a culture that was needed by a culture that was treated with an antibiotic to treated with an antibiotic to increase in number (CFU) by 1 increase in number (CFU) by 1 loglog1010 compared to untreated compared to untreated

controls, and is usually given in controls, and is usually given in hours.hours.

The PAE provides additional tiThe PAE provides additional time for the immune system to reme for the immune system to remove bacteria that might have smove bacteria that might have survived antibiotic treatment befourvived antibiotic treatment before they can eventually regrow afre they can eventually regrow after removal of the drug from the ter removal of the drug from the

animal's organism. animal's organism.

A longer PAE can therefore A longer PAE can therefore influence the clinical influence the clinical outcome of antimicrobial outcome of antimicrobial therapy.therapy.

Most β-lactam agents do Most β-lactam agents do not exhibit concentration-not exhibit concentration-dependent killing nor do tdependent killing nor do they have a prolonged poshey have a prolonged post-antibiotic effect.t-antibiotic effect.

7. 7. Anatomical site Anatomical site of infection of infection

The site of infection often The site of infection often influences not only the influences not only the agent used but also the agent used but also the dose, route, and duration dose, route, and duration of administration.of administration.

The desired peak The desired peak concentration of drug at the concentration of drug at the site of infection should be at site of infection should be at least 4 times the MIC.least 4 times the MIC.

However, if host defenses are However, if host defenses are adequate, peak oncentrations adequate, peak oncentrations may be much lower and even may be much lower and even be equal to the MIC and still bbe equal to the MIC and still be effective. e effective.

When host defenses are When host defenses are absent or inoperative, peak absent or inoperative, peak concentrations 8- to 16-fold concentrations 8- to 16-fold greater than the MIC may be greater than the MIC may be required.required.

Blood-Brain Blood-Brain BarrierBarrier

1.Lipid solubility (quinolo1.Lipid solubility (quinolones vs penicillin)nes vs penicillin)2.Molecular weight (vanc2.Molecular weight (vancomycin)omycin)3.Protein binding 3.Protein binding

Readily Enter CSFReadily Enter CSF

ChloramphenicolChloramphenicolSulfonamidesSulfonamidesTrimethoprim Trimethoprim 甲氧苄氨嘧啶甲氧苄氨嘧啶 Rifampin Rifampin 利福平利福平 Metronidazole Metronidazole 甲硝唑甲硝唑

Enter CSF When Inflammation PresentEnter CSF When Inflammation Present

Penicillin G AmpicillinPenicillin G Ampicillin 氨苄西林氨苄西林

PiperacillinPiperacillin 哌拉西林 哌拉西林 OxacillinOxacillin 苯唑西林苯唑西林

NafcillinNafcillin 萘夫西林 萘夫西林 CefuroximeCefuroxime 头孢呋辛头孢呋辛

CefotaximeCefotaxime 头孢噻肟 头孢噻肟 Ceftriaxone Ceftriaxone 头孢曲松头孢曲松

CeftazidimeCeftazidime 头孢他定 头孢他定 AztreonamAztreonam 氨曲南氨曲南

CiprofloxacinCiprofloxacin 环丙沙星 环丙沙星 VancomycinVancomycin 万古霉素万古霉素

MeropenemMeropenem 美罗培南美罗培南

CefepimeCefepime 头孢平头孢平

Do Not Enter CSF Adequately to Do Not Enter CSF Adequately to

Treat InfectionTreat Infection

Cefazolin Cefazolin 头孢唑啉 头孢唑啉 CefoxitinCefoxitin 头孢西丁 头孢西丁 ErythromycinErythromycin 乙琥红霉素 乙琥红霉素 ClindamycinClindamycin 克林霉素 克林霉素 Tetracycline Tetracycline 四环素四环素 GentamicinGentamicin 庆大霉素 庆大霉素 Tobramycin Tobramycin 妥布霉素 妥布霉素 AmikacinAmikacin 阿米卡星阿米卡星

Endocarditis MeningitisEndocarditis MeningitisOsteomyelitis Osteomyelitis foreign body foreign body abscesses abscesses organisms that can survive withiorganisms that can survive within phagocytic cells (n phagocytic cells (MycobacteriuMycobacterium, Salmonella)m, Salmonella)

8.8. Cost Cost

9. Toxicity9. Toxicity

Because of nephrotoxicity Because of nephrotoxicity and ototoxicity, aminoglycoand ototoxicity, aminoglycoside use has decreased witside use has decreased with the development of β-lacth the development of β-lactams and fluoroquinolones ams and fluoroquinolones with broad gram-negative awith broad gram-negative activity.ctivity.

10. Host factors10. Host factors

Allergy historyAllergy history

Significant allergy appearSignificant allergy appears to be more common wits to be more common with β-lactams, particularly ph β-lactams, particularly penicillins, and sulfonamideenicillins, and sulfonamides.s.

In anaphylactic reactions to pIn anaphylactic reactions to penicillins, the IgE antibody is enicillins, the IgE antibody is usually directed at the penicillusually directed at the penicillin nucleus, so the potential foin nucleus, so the potential for allergic reactions to other per allergic reactions to other penicillins is high.nicillins is high.

Age Age

Renal functionRenal function

Antimicrobial agents that require Antimicrobial agents that require dosage adjustment include amindosage adjustment include aminoglycosides, vancomycin, certaioglycosides, vancomycin, certain penicillins, most cephalosporin penicillins, most cephalosporins, carbapenems(ns, carbapenems( 碳青霉烯类碳青霉烯类 )), a, and quinolones. nd quinolones.

Failure to adjust dosage can leaFailure to adjust dosage can lead to ototoxicity from aminoglycod to ototoxicity from aminoglycosides and neurotoxicity from pensides and neurotoxicity from penicillins, imipenem, or quinolones. icillins, imipenem, or quinolones.

Aminoglycosides can cause renAminoglycosides can cause renal toxicity and should be used al toxicity and should be used with caution in patients with prewith caution in patients with preexisting renal insufficiency. existing renal insufficiency.

aminoglycosides aminoglycosides vancomycin vancomycin certain penicillins certain penicillins most cephalosporins carbapenemost cephalosporins carbapenems ms 碳青霉烯类碳青霉烯类 quinolones quinolones

Hepatic functionHepatic function

Antimicrobials metabolized in thAntimicrobials metabolized in the liver include chloramphenicol, e liver include chloramphenicol, erythromycin, clarithromycin, riferythromycin, clarithromycin, rifampin, nitroimidazoles, and soampin, nitroimidazoles, and some of the quinolones. me of the quinolones.

Pregnancy statusPregnancy status

Agent Potential Toxicity

Sulfonamides Hemolysis in newborn with glucose-6-phosphate dehydrogenase deficiency;

Tetracyclines Limb abnormalities, dental staining, inhibition of bone growth

Trimethoprim Altered folate metabolism

Quinolones Abnormalities of cartilage

Vancomycin Possible auditory toxicity

AgentAgent Potential ToxicityPotential Toxicity

AminoglycosidesAminoglycosides Eighth nerve damageEighth nerve damage

ChloramphenicoChloramphenicoll

Gray baby syndromeGray baby syndrome

Erythromycin estErythromycin estolateolate

Cholestatic hepatitis (Cholestatic hepatitis ( 胆胆汁淤积性肝炎汁淤积性肝炎 )) in mother in mother

MetronidazoleMetronidazole Possible teratogenicity Possible teratogenicity 致畸性致畸性

NitrofurantoinNitrofurantoin Hemolytic anemiaHemolytic anemia

Genetic or Genetic or metabolic metabolic abnormalitiesabnormalities

Genetic abnormalities of Genetic abnormalities of enzyme function may alter enzyme function may alter the toxicity of certain agents.the toxicity of certain agents.

hemolysis in glucose-6-phosphhemolysis in glucose-6-phosphate dehydrogenase-deficient pate dehydrogenase-deficient people can be provoked by sulfoeople can be provoked by sulfonamides, nitrofurantoin, pyrimenamides, nitrofurantoin, pyrimethamine thamine (( 乙胺嘧啶乙胺嘧啶 ),), sulfones sulfones(( 砜砜 ),), and chlo and chloramphenicol. ramphenicol.

Host defenses Host defenses functionfunction

An absence of white blood cells An absence of white blood cells predisposes a patient to serious predisposes a patient to serious bacterial infection, and bacteriobacterial infection, and bacteriostatic agents are often ineffectivstatic agents are often ineffective in treating serious infections ie in treating serious infections in neutropenic hosts. n neutropenic hosts.

The critical white blood cell couThe critical white blood cell count is between 500 and 1000 matnt is between 500 and 1000 mature polymorphonuclear cells/mure polymorphonuclear cells/mmm33. .

11. Antimicrobial 11. Antimicrobial combinationscombinations

Box 44-3 Reasons for concurrent use of more than one antimicrobial agent in a patient

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

indifferentindifferent effects effects The combined activity equals The combined activity equals the sum of the separate the sum of the separate activities. activities.

Synergism (Synergism ( 协同协同 ) is present if ) is present if the activity of the combined antithe activity of the combined antimicrobial agents is greater than microbial agents is greater than the sum of the independent activthe sum of the independent activities. ities.

Combinations of antibiotics are Combinations of antibiotics are antagonisticantagonistic when the activity when the activity of the combination is less than of the combination is less than could be achieved by using the could be achieved by using the agents separately. agents separately.

The combination of an inhibitThe combination of an inhibitor of cell-wall synthesis with or of cell-wall synthesis with an aminoglycoside antibiotic an aminoglycoside antibiotic

The combination of agents The combination of agents acting on sequential steps acting on sequential steps in a metabolic pathwayin a metabolic pathway

The combination of agents iThe combination of agents in which one (such as an inn which one (such as an inhibitor of β-lactamases) inhihibitor of β-lactamases) inhibits an enzyme that inactivbits an enzyme that inactivates the other compound, sates the other compound, such as clavulanate with amuch as clavulanate with amoxicillinoxicillin

Antibiotic decision Antibiotic decision making after therapy making after therapy has startedhas 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 Duration (days)

Pneumococcal pneumonia

3-5 days after fever resolves

Other pneumonia variable, often 14

Bacteremia variable, often 10-14 days without endocarditis

Endocarditis 28-42

Meningitis 7-14

Osteomyelitis 42

Septic arthritis 21

12.12. Antibiotic Antibiotic resistance concernsresistance 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)

杨晓霞事件杨晓霞事件

19941994 年右手拇指局部感染抗生素治疗无效。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，病情逐渐恶化直反复转院多次抗生素治疗，病情逐渐恶化直至右手坏死至右手坏死 33 个月后截肢。创面继续感染。个月后截肢。创面继续感染。此后，经首都此后，经首都 1313 家医院的家医院的 50 50 名中西医专家名中西医专家先后两次会诊。几十次的细菌培养试验，伤先后两次会诊。几十次的细菌培养试验，伤口上分离出口上分离出 1212 种细菌并且这些细菌已经对大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。其中有一种细多数的抗生素产生了耐药性。其中有一种细菌对菌对 5959 种药物和种药物和 2121 种抗生素具有耐药性。种抗生素具有耐药性。泰能泰能

泰能含有两种成分：亚胺培南是新泰能含有两种成分：亚胺培南是新型的型的 β-β- 内酰胺抗菌素内酰胺抗菌素 -- 硫霉素，其硫霉素，其特性是杀菌谱较其它抗菌素广泛；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，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，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司他丁钠盐的重量比率为 11 ：： 11 。。

Antibiotic resistance can be Antibiotic resistance can be intrintrinsicinsic or or acquired.acquired. PseudomonPseudomonas aeruginosaas aeruginosa outer membrane outer membrane

Acquired resistance can be due Acquired resistance can be due to mutation of existing genetic ito mutation of existing genetic information or acquisition of new nformation or acquisition of new genes.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-specificviruses (bacteriophages) transfer DNA between two closely related bacteria

Mechanisms of bacterial resistance to antibiotics

reduced uptake into cell

1. Reduced uptake into cell2. 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 molecule5. 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 genecould eliminate uptake.

Decreased uptake has been desDecreased uptake has been described for aminoglycosides, somcribed for aminoglycosides, some β-lactams, tetracyclines, and oe β-lactams, tetracyclines, and others. thers.

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 mecEfflux pumps are the main mechanism of resistance for tetracyhanism of resistance for tetracyclines and have also been descclines and have also been described for quinolones.ribed for quinolones.

Eliminate or reduce binding of antibiotic to cell target• Antibiotic must be bound to cell surface before transport. Mutation in thebinding protein gene reduces ability of antibioticto 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 hydrolβ-lactamases catalyze the hydrolysis of penicillins, cephalosporins,ysis of penicillins, cephalosporins, and other β-lactams. When hydr and other β-lactams. When hydrolyzed, the β-lactam is unable to olyzed, the β-lactam is unable to bind to bacterial transpeptidases bind to bacterial transpeptidases and other enzymes needed for cand other enzymes needed for cell wall synthesis and repair. ell wall synthesis and repair.

Many enzymes have been deMany enzymes have been described that inactivate aminoscribed that inactivate aminoglycosides. glycosides.

Metabolic bypass of inhibited pathway

• Bacterium develops a new pathway which bypasses the inhibited reaction(s)

Some thymidine-requiring streptocoSome thymidine-requiring streptococci are not inhibited by trimethoprim cci are not inhibited by trimethoprim and sulfonamides. because the resiand sulfonamides. because the resistant bacteria produce adequate costant bacteria produce adequate concentrations of thymidine nucleotidncentrations of thymidine nucleotides by an alternative pathway and aes by an alternative pathway and as a result survive exposure to these s a result survive exposure to these drugs. exposed to these agents. 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 situationse.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 non-medical purposes

Antimicrobial prophylaxis in surgery. Antimicrobial prophylaxis in surgery. Medical Medical LettLett 2001; 43:92. 2001; 43:92.

Gold HS, Moellering RC Jr. Antimicrobial-druGold HS, Moellering RC Jr. Antimicrobial-drug resistance. g resistance. N Engl J MedN Engl J Med 1996; 335:1445-1 1996; 335:1445-1453. 453.

Steinberg JP, Blass MA. Non-surgical antibioSteinberg JP, Blass MA. Non-surgical antibiotic prophylaxis. In Schlossberg D: tic prophylaxis. In Schlossberg D: Current theCurrent therapy of infectious diseases,rapy of infectious diseases, Philadelphia, Mo Philadelphia, Mo

sby-Harcourt Health Sciences, 2000.sby-Harcourt Health Sciences, 2000.