From penicillin to naphthalene
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From Penicillin to Naphthalene. End of antibiotic era?. Prof. Raul Raz Infectious Diseases Unit Ha’Emek Medical Center Afula. Resistance to antimicrobial drugs – A worldwide calamity. Kunin C, 1993.

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From penicillin to naphthalene

From Penicillin to Naphthalene

End of antibiotic era?

Prof. Raul Raz

Infectious Diseases Unit

Ha’Emek Medical Center


Resistance to antimicrobial drugs a worldwide calamity

Resistance to antimicrobial drugs – A worldwide calamity

Kunin C, 1993

From penicillin to naphthalene

  • Antibiotics are being recognized as agents that are truly societal drug, since their use in individual patients can also affect the family and the community.

  • As each patient is treated, there is an influence upon the entire normal bacterial flora shed in his/her surroundings.

From penicillin to naphthalene

  • No other group of drugs has such an effect on society by its misuse, not only by the costs involved, but also by the effects on bacterial resistance.

  • Therefore, the time has come for the medical profession (administrators, physicians, etc.) to moderate its insistence on clinical freedom to prescribe what it likes when it likes.

    J.M. Gould, 1985.

The use of antibiotics

The use of antibiotics


Community Veterinary medicine

Use of antibiotics

Use of antibiotics



Agricultural use


Growth promotion


Highly questionable




Human use






U s a


11.2 million Kg.-growth promotion

900 Kg.-animal therapy

1.3 million Kg.-humans

From penicillin to naphthalene

  • Salmonella multiresistant

  • E.coli

  • Campylobacter jejuni

  • Enterococcus faecium

    Over 80% of infections with salmonella and campylobacter in humans are acquired from animals’ food.

From penicillin to naphthalene

There are today:

50 penicillins

75 cephalosporins

12 tetracyclines

9 aminoglycocides

3 carbapenemes

1 monobactams

9 macrolides

20 quinolones

From penicillin to naphthalene

Given this huge array of antibiotics, it would seem that an individual could not possibly die of an infection in a hospital.

(H. Neu, 1993)

From penicillin to naphthalene

Antimicrobial resistance has emerged as a major public health issue in the last 10-15 years.

A steady increase in resistance continues despite the introduction of new antibiotics, and resistant bacteria have been associated with increased patients morbidity and mortality as well as with increased cost.

Emerging resistant pathogens






ESBL producing by Enterobacteraceae







Emerging resistant pathogens

From penicillin to naphthalene

More than half of hospitalized patients receive antibiotics and those drugs cost up to 50% of hospital budget!

In addition, 25-50% of all antibiotics prescription are inappropriate as a result of incorrect choice of drugs, dose and duration.

From penicillin to naphthalene

Influence of the appropriateness of antimicrobial treatment upon mortality rates in the management of nosocomial bacteraemia in different specialties (adapted from Jamuitrat et al)

Assessment of Mortality rate in specialty (%)

Antimicrobial therapySurgeryMedicinePaediatricsTotal

Appropriate21.932.7 7.727.3


From penicillin to naphthalene

The cost of caring for patients with infections caused by resistant bacteria is much higher than those with antibiotic – sensitive organisms. In the USA it is estimated between $100 million and $30 billion annually.

Factors contributing to increased antimicrobial resistance

Factors contributing to increased antimicrobial resistance

  • Sicker in-patients populations

  • Large immunocompromised pts.

  • New procedures and instrumentation.

  • Emerging pathogens.

  • Ineffective infection control.

  • Increased antibiotic use.

Mechanisms related to the appearance and spread of antimicrobial resistance

Mechanisms related to the appearance and spread of antimicrobial resistance

  • Introduction of a resistant organisms to previously susceptible population.

  • Acquisition of resistance by a susceptible strain (spontaneous mutation or genetic transfer).

  • Dissemination or spread of a resistant organism.

From penicillin to naphthalene

Overuse of antimicrobials and poor compliance with infection-control measures have been identified as the major reason for an increasing trend in antimicrobial resistance.

From penicillin to naphthalene

  • “Patients often pressure physicians for unneeded antibiotics”.

  • Physicians appear to be trying to maximize patient’s satisfaction by giving antibiotics when patients want.

  • And..”any intervention to reduce antibiotic prescribing must pay as much attention to the patient as to the physician”.

    (Journal of Family Practice, 10/2001).

From penicillin to naphthalene

  • Bacteria will develop resistant to virtually every antibiotic given enough time.

  • Resistance may eventually occur to any antibiotic. The time to resistance, however, can vary considerably.

From penicillin to naphthalene

  • For example: penicillin -resistant pneumococcus took 25 years to emerge as a clinical problem.

  • Quinolones- resistant Enterobacteracae became a problem after 10 years.

From penicillin to naphthalene

With some bacteria, resistance to new drugs has emerged much more rapidly.

From penicillin to naphthalene

  • Organisms resistant to one antimicrobial agent are likely to become resistant to others.

  • For example:

    • First gonococci resistant to tetracycline was also resistant to penicillin.

    • First pneumococci resistant to penicillin showed also resistance to macrolides.

Effect of antibiotic resistance on patient management

Effect of antibiotic resistance on patient management

Patient-relatedIncreased length of hospital stay

Increased risk of therapy with an inappropriate antimicrobial

Increased risk of treatment with more toxic antimicrobials

Increased risk of death

Hospital-relatedIncreased antimicrobial costs

Increased cost of length of patient stay

Increased costs during patient stay from additional supportive/supplementary therapies.

What can be done to reduce use of antibiotics

What can be done to reduce use of antibiotics?

Antibiotics Are Not Antipyretics Or…

… Doctor’s tranquilizers...

Is antibiotic resistance reversible

Is antibiotic resistance reversible?

Several studies show that antibiotic resistance can be reversed by stop using the drug.

From penicillin to naphthalene

The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance

in group A streptococci in Finland

The New England Journal of Medicine 1997; 337:441-6

From penicillin to naphthalene

The total amount of antibiotics sold for human use in Norway 1981 – 1997 by average DDD/1000 inhabitants/day (%)



Penicillins4.5 ( 39)5.0 ( 37)7.2 ( 44)7.4 ( 50)

Penicillin V3.1 ( 27)3.7 ( 28)5.3 ( 33)5.1 ( 34)

Amoxicillin0.3 ( 3)0.3 ( 2)0.6 ( 4)0.9 ( 6)

Ampicillin0.6 ( 5)0.6 ( 5)0.4 ( 3)0.3 ( 2)

Macrolides0.6 ( 5)1.3 ( 10)1.6 ( 10)1.6 ( 11)

Tetracyclines3.0 ( 26)4.0 ( 30)4.8 ( 29)3.5 ( 23)


co-trimoxazole3.2 ( 28)2.5 ( 19)2.0 ( 12)1.4 ( 9)

Other antibiotics0.3 ( 3)0.5 ( 4)0.6 ( 4)0.9 ( 6)

Sum 11.6 (100) 13.3 (100) 16.2 (100) 14.8 (100)

From penicillin to naphthalene

Sulfonamides and





Macrolides, Lincosam.,









Total outpatient antibiotic use in 26 European countries in 2002 + Israel 2002 European Surveillance of Antimicrobial Consumption (ESAC)



From penicillin to naphthalene

The ICU are the main source of the appearance of multidrug resistant bacteria

From penicillin to naphthalene

  • Antimicrobial resistance has emerged as an important determinant of outcome for patients in ICU.

  • ICU’s are facing increasingly rapid emergence and spread of antibiotic-resistant bacteria.

High antibiotic consumption in danish icu total supply to 30 major icus in denmark in 1995

High antibiotic consumption in Danish ICU?Total supply to 30 major ICUs in Denmark in 1995

AntimicrobialsSupply of antibiotics (DDD/100 patient days)



Penicillin G16.5 9.0-23.05.0-53.0

Second-generation cephalosporins 9.5 6.4-17.01.8-51.4

Macrolides11.2 7.6-16.50.0-40.8

Metronidazole12.6 7.1-15.20.0-23.4

Aminoglycosides 9.5 5.5-13.10.5-35.6

Penicillin-resistant penicillins 6.1 3.7- 9.21.0-19.9

Quinolones 3.7 2.0 -6.80.4-22.9

Penicillin V 2.2 0.8- 5.30.0-21.8

Third-generation cephalosporines 1.7 0.6- 5.00.0-14.1

Antifungal agents 1.3 0.7- 3.10.0-31.6

Vancomycin 0.6 0.2- 1.40.0-20.6

Carbapenems 0.5 0.0- 1.10.0-38.2

Rifampicins 0.3 0.0- 2.30.0- 6.7

Sulfonamides and trimethoprim 0.2 0.0- 1.00.0-11.7

Carboxy-and ureido-penicillins 0.5 0.1- 1.30.0- 2.7

Sulfonamides 0.7 0.0- 1.20.0- 6.7

Antimicrobial use in long term care facilities

Antimicrobial use in long-term-care facilities

  • 40% of all systemic drug prescribed are antibiotics

  • Point prevalence studies showed that more than 10% of LTCF residents received antibiotics.

  • A resident will receive al least one course of systemic antibiotics during a 1-year period.

  • 50-75% of systemic antibiotics are prescribed inappropriately.

From penicillin to naphthalene

Susceptibility of uropathogens


From penicillin to naphthalene

Susceptibility of uropathogens


From penicillin to naphthalene

Susceptibility of uropathogens


From penicillin to naphthalene

Susceptibility of uropathogens


From penicillin to naphthalene

Can an educational program improve the diagnosis and treatment of pharyngotonsillitis in the ambulatory care setting?Israel Journal of Medical Sciences 1995;31 (7)432-435.

From penicillin to naphthalene

  • Education programs can have some impact in the reduction of the use of antibiotics, at least as a temporary basis.

From penicillin to naphthalene

New Strategies

Structure of a hospital wide quality improvement program to address antimicrobial resistance

















Infection-Control Strategies

Antibiotic-Control Strategies

Structure of a hospital-wide quality-improvement program to address antimicrobial resistance

Antimicrobial Resistance Leadership Team

(Hospital Committees)


From penicillin to naphthalene

עשרת הדברות לשימוש מושכל באנטיביוטיקה

6. להשתמש באנטיביוטיקה מניעתית בצורה מבוקרת.

1. אין לוותר מול דרישות החולים במתן לא מוצדק של אנטיביוטיקה.

7. להזכיר לצוותים רפואיים לפעול בהתאם לנהלים כדי למנוע העברת חיידקים בין חולים (רחצת ידיים).

2. חינוך חולים וקרובי משפחה לשימוש מושכל.

3. ניסיון לזיהוי פתוגן.

8. לעודד חולים ועובדים להתחסן.

4. בחירת קורסים קצרים עם תכשירים בעלי ספקטרום צר.

9. תוכניות לניטור מתמשך של חיידקים ורגישויות.

10. שימוש מושכל באנטיביוטיקה בחקלאות.

5. לדאוג לסיום כל הקורס שניתן.

From penicillin to naphthalene

ת ו ד ה

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