Multiple drug resistance

Abdullah Memon and Divyesh ZalaS.Y.B.Sc Semester III

contentWhat is drug resistance?Multiple drug resistanceHistory of antimicrobial agents and resistant

bacteriaMechanism in attaining multi drug resistanceCommon multiple drug resistant organismsMDR-TB

What is Drug resistance?It is tolerance of microorganisms to inhibitory

action of antimicrobials. Natural Resistance:Some microbes have always been resistant to certain AMAs(anti microbial antibodies .

They lack metabolic process or target site that is affected by specific drug.

Eg: gram-ve bacilli are not affected by penicillin G.

Acquired resistant:• It is development of resistant by an organism due to use

of an AMA over a period of time • This can happen with any microbes & is major clinical

problem However ;development of resistant depend on microorganism as well as drug .

• Resistance may be developed by mutation or gene transfer.

Resistant organisms can be:

Drug tolerant:-loss of affinity of the target biomolecule of the organism for a particular AMA(anti microbial antibodies) ,

Eg; resistant Staph.Aurus & E-Coli develop a RNA polymerase that does not bind to Rifampicn.

Drug destroying:- The resistant microbe elaborates an enzyme which inactivates the drug

Eg B- lactamases are produced by staphylococcus Hymophylus ,which inactivates Penicillin G.

Drug impermeable:- Many hydrophobic antibiotics gain access in to the bacterial cell through specific channels formed by proteins called porins or need specific transport mechanism .

Active efflux based resistant has been detected by the bacteria may also acquire plasmid directed inducible energy dependent efflux protein in their cell membrane which pump out tetracycline.

Cross-resistance: Acquisition of resistance to AMA confirming resistant to another AMA ,to which the organism is not to been exposed is called cross resistant. some times unrelated drugs show partial cross-resistant

Eg between tetracycline & chloramphenicol.

Hey kid wana be a MDR…? Stick some of this into your genome…

Even Penicillin won’t be able to harm you….

MULTIDRUG RESISTANCE

Multiple drug resistance or Multidrug resistance is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism.

Organisms that display multidrug resistance can be pathologic cells, including bacterial and neoplastic cells.

Multidrug-Resistant Organisms (MDROs) are defined as microorganisms that are resistant to one or more classes of antimicrobial agents.

Mechanisms in attaining multidrug resistance:

No longer relying on a glycoprotein cell wall

Enzymatic deactivation of antibiotics

Decreased cell wall permeability to antibiotics

Altered target sites of antibiotic

Efflux mechanisms to remove antibiotics

Increased mutation rate as a stress response

Common multi-drug-resistant organisms (MDROs)

MDROs are microorganisms, predominantly bacteria, that are resistant to one or more classes of antimicrobial agents

Methicillin-resistant Staphylococcus aureus (MRSA)Vancomycin-resistant enterococcus (VRE)MDR-TB (ESBLs) producing Gram-negative bacteria

MRSA

VRE

Gram negative bacilli

Every year, over 2 million people in the United States become infected with bacteria that are resistant to antibiotics, and around 23,000 people die as a result of these infections (CDC, 2013a). Multidrug-resistant organisms, are bacteria that are resistant to current antibiotic therapy and, therefore, difficult to treat. MDROs can cause serious local and systemic infections that can be severely debilitating and even life-threatening.In the past, these infections were usually controlled by penicillin.

The most serious concern with antibiotic resistance is that some bacteria have become resistant to almost all of the easily available antibiotics. For example, Staphylococcus aureus (‘golden staph’) and Neisseria gonorrhoeae (the cause of gonorrhoea) are now almost always resistant to benzyl penicillin. These bacteria are able to cause serious disease and this is a major public health problem.

Methicillin-Resistant Staphylococcus aureus

MRSA now accounts for more than 50% of hospital-acquired staph infections.

According to the CDC, almost 1,00,000 cases of invasive MRSA occurred in 2005, with 18% of these individuals dying during their hospitalization.

These infections account for more than 5,000 deaths each year which are directly attributable to MRSA.

Specifically, MRSA has an attributable mortality rate of 6.9% at 30 days and 16.7% at 1 year.

The additional cost of MRSA alone is 39,000$ per case in patients with a MRSA surgical-site infection

Mortality rates were 13% higher in patients with MRSA infection, regardless of mechanism of death.

Vancomycin Resistant Enterococci(VRE)

This are bacterial strains of genus vancomycin that are resistant to antibiotic vancomycin

Vancomycin-sensitive enterococci typically obtain new DNA in the form of plasmid or transposons which encode genes that confer vamcomycin resistance.

Six different types of vancomycin resistance are shown by enterococcus : Van-A, Van-B, Van-C, Van-D, Van-E and Van-G.

A swab from samples of the blood, spinal fluid, sputum or infectious tissue is taken and cultured in a petridish using the right medium.

Diagnosis requires culturing the organism. VRE can be easily cultured in a laboratory.

• Lactobacillus rhamnosus GG (LGG), a strain of L. rhamnosus, was used successfully for the first time to treat gastrointestinal carriage of VRE.

• Some of the current drugs include combinations of teicoplanin (Teichomycin) and amoxicillin or a combination of ampicillin imipenem, and vancomycin (Vancocin).

Extended spectrum beta-lactamaseproducers (ESBLs)

Gram negative organisms - Enterobacteriaceae

Excrete the enzyme beta-lactamase

Inactivates β-lactam (penicillin) type antibiotics

Resistance to β-lactams emerged several years ago and has continued to rise ESBLs

Klebsiella

E. coli

Serratia

others

Beta-lactam resistance

Drug resistance facts Drug resistance occurs when microbes survive and

grow in the presence of a drug that normally kills or inhibits the microbe's growth.

The history of drug resistance began with the development of antimicrobial drugs, and the subsequent ability of microbes to adapt and develop ways to survive in the presence of antimicrobials.

Diagnosis of antimicrobial drug resistance is performed by lab tests that challenge the isolated microbes to grow and survive in the presence of the drug.

Treatment of antimicrobial drug resistance depends on the type of infection and what the patient and their doctor decide.

Prevention of antimicrobial drug resistance is aided by preventing the overuse and misuse of antimicrobials; infections can be reduced by a healthy lifestyle, hand washing, and other good hygiene methods

Antimicrobial resistance is a growing health issue because more resistant microbes are being detected and societal pressures often result in overuse.

Multiple drug resistant Tuberclousis

What are the main types of drug resistant TB?There are two main types of drug resistant TB, MDR TB and XDR TB. Another type of drug resistant TB, variously referred to as totally drug resistant TB, XXDR TB or TDR TB has also now been detected.

What is the difference between the types MDR TB and XDR TB?

MDR (multi drug resistant) TB is the name given to TB when the bacteria that are causing it are resistant to at least isoniazid and rifampicin, two of the most effective TB drugs.

MDR & XDR TB WHO describing strains of TB, referred to as XDR TB,

that were resistant not only to isoniazid and rifampicin (that is they were MRD TB) but they were also resistant to at least three of the six classes of second line anti TB drugs.

In 1980 50% of TB bacilli were resistant to 1 drug.

Multi-drug resistant TB (MDR-TB) began to emerge. There are now an estimated 1.5million MDR cases worldwide.

Extreme drug resistance (XDR-TB) was reported in 2006.

The first completely drug resistant (CDR-TB) case was reported in Italy in 2007.

MDR-TB has emerged and spread due to the inadequacy of treatment. Today, treatment for drug-resistant TB can take up to two years, and is so complex, expensive, and toxic that a third of all MDR-TB patients die.

WHO treatment standards require that at least four drugs be used to treat TB in order to avoid the development of further resistance.

According to the WHO, Eastern Europe's rates of MDR-TB are the highest, where MDR-TB makes up 20% of all new TB cases.

In some parts of the former Soviet Union, up to 28% of new TB cases are multidrug-resistant.

Among previously treated cases in the same region, reported rates of drug resistance are commonly above 50% and as high as 61%.

During the late 1980s and early 1990s, outbreaks of MDR-TB in North America and Europe killed more than 80% of those who contracted the disease.

During a major TB outbreak in New York City in the early 1990s, one in 10 cases proved to be drug-resistant.

Today, drug-resistant TB is also quite common in India and China the two countries with the highest MDR-�TB burdens.

Treatment for MDR-TB consists of what are called second-line drugs. These drugs are administered when first-line drugs fail.

Treatment for MDR-TB is commonly administered for 2 years or longer and involves daily injections for six months. Many second-line drugs are toxic and have severe side effects.

The World Health Organization has issued a target of treating 80% of MDR-TB cases by 2015.

The cost of curing MDR-TB can be literally thousands of times as expensive as that of regular treatment in some regions.

Top MDR-TB High-Burden Countries

1. China2. India3. Russian Federation4. Pakistan5. South Africa6. Philippines7. Nigeria8. Bangladesh9. Indonesia10.Myanmar11.Ukraine12.Uzbekistan13.Kazakhstan14.Viet Nam

15. Democratic Republic of Congo16. Ethiopia17. Azerbaijan18. Tajikistan19. Republic of Moldova20. Kyrgistan21. Belarus22. Georgia23. Armenia24. Bulgari25. Lithuania26. Latvia27. Estonia

MDR & XDR TB is not spread by

Shaking someone’s hand

Sharing food or drink

Touching bed linens or toilet seats

Sharing toothbrushes

Kissing

Smoking or sharing cigarettes

Building a Treatment Regimen for MDR-TB

Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians. Chang KC, et al. Respirology. 2013;18:8-21.

Step 1: Include any first-line drugs to which the isolate is susceptible

InjectablesKanamycin Amikacin Capreomycin Streptomycin

Step 2: Add a fluoroquinolone

FluoroquinoloneLevofloxacinMoxifloxacin Gatifloxacin

First-line DrugsEthambutol Pyrazinamide

Step 3: Include an injectable agent

Oral Second-line DrugsEthionamide Prothionamide Cycloserine/terizidone Para-aminosalicylic acid

Third-line DrugsClofazimine Clarithromycin Amoxicillin-clavulanate Linezolid Thiacetazone Meropenem-clavulanateThioridazineOther new drugs

Step 4: Include second-line drugs until you have 4-6 drugs to which the isolate is susceptibleConsider third-line drugs if there are not 4-6 drugs to which the isolate is susceptible

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Step 3

Third line drugsImipenem Linezolid Macrolides Amoxicillin/Clavulanate

Consider use of theseIf there are not 4-6 drugs available consider 3rd line in consult with MDRTB experts

Step 1Use any available

Begin with anyFirst line agents toWhich the isolate is Susceptible

Add aFluoroquinoloneAnd an injectableDrug based onsusceptibilities

Fluoroquinolones

Levofloxacin Moxifloxacin

Injectable agentsAmikacin

Capreomycin Streptomycin Kanamycin

PLUSOne of these

One of these

First-line drugsPyrazinamideEthambutol

PLUS

Step 2 Pick one or more of these

Oral second line drugsCycloserine Ethionamide PAS

Add 2nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously)

BS

Prevent of MDR & XDR? Hand Hygiene – The Most Important Way to Prevent

Transmission of Microorganisms and Infection Use the appropriate

antimicrobial for an infection; e.g. no antibiotics for viral infections

Identify the causative organism whenever possible

Select an antimicrobial which targets the specific organism, rather than relying on a broad-spectrum antimicrobial

Complete an appropriate duration of antimicrobial treatment (not too short and not too long)

Use the correct dose for eradication; subtherapeutic dosing is associated with resistance, as demonstrated in food animals.

Minimize unnecessary prescribing and overprescribing of antibiotics.

TREATMENTInitial treatment with standardized regimens

(HRZE)Directly observed therapy (DOT)Drug susceptibility testing for all retreatment

casesInfection control precautionsMonitor drug resistance through surveysEffective contact management

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