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Phenotype

modification

Microcolonies EPS production

Source: World Health Organization /CDS

CIM

Area under curve (AUC)

MIC

Pick MaxC

T

Pla

sma

con

cen

trat

ion

T1/2

1940

1950

1960

1970

1980

Staphylococcus aureus resistance

N.gonorrhoeae resistance

First Inhibitors

Semisinthetic penicillins

H.Influenzae resistance

Clavulanic acid

Sulbactam (6-desaminopenicillin sulfona

Tazobactam

RESISTANCE TO BETALACTAMIC ANTIBIOTICS DUE TO BETALACTAMASES : CRONOLOGIC EVOLUTION AND SINTHESIS OF

INHIBITORS

Ambler classification of ß-lactamases

ß-lactamases(based upon their amino acid sequences)

4 classes (A-B-C-D)

A- ß-lactamases IBL+ : penicillinases-BSBL-ESBL-KPC

B- metallo-ß-lactamases IBL- : carbapenemases (VIM-

IMP)

C- AmpC ß-lactamases (serine enzymes) IBL- : inductible

cephalosporinases, CMY

D- serine enzyme IBL+/-: oxacilinases (OXA)

Schematic diagram of Ambler classification system

(Serine)

B-lactamase

Class B

(metallo)

Class A Class C Class D unnamed subclass B3

subclass B1 subclass B2

Sequence homology

Structural homology,

no sequence homology

No homology, hydrolyse by

different machanisms

By the end of the 70´s, the first irreversible beta-lactamase

inhibitor (suicide) began to be clinically developed: the

clavulanic acid.

In parallel, there appeared the firsts reports on sulbactam,

another beta-lactamase suicidal inhibitor with pharmacodynamics

and clinical tolerance advantages over clavulanic acid.

β-Lactamase inhibitors are most active against plasmid-encoded b-lactamases

The most common is TEM-1, so called for the initials of the original patient from whom the E coli β -lactamase containing isolate was derived.

There are also TEM-2; oxacillin-hydrolyzing enzymes OXA-1, -2, and -3; sulfhydro-inhibited enzymes SHV-1 and HMS; and PSE-1, -2, -3, and -4, originally thought to be enzymes found only in Pseudomonas but now found occasionally in E. coli.

Sulbactam is a 6-desaminopenicillin sulfone

Sulbactam is a broader-spectrum b-lactamaseinhibitor than clavulanic acid

Sulbactam does not induce chromosomal β-lase, nor does it select for derepressed β-lase–producing bacteria

Sulbactam does not inhibit chromosomal β-lases

(Chromosomal β-lases of of Legionella and Bacteroides

are inhibited by β-lases inhibitors, as are some other

chromosomally mediated β-lases , such as the class IV

enzymes produced by Klebsiella)

Sulbactam has pharmacokinetics in humans similar to those of amoxicillin

Sulbactam is excreted by the kidney and has a urinary recovery rate of 70 to 80% of a dose

It can be removed by hemodialysis

Concentrations of sulbactam in interstitial fluid and peritoneal secretions are comparable to levels in serum.

Amoxicillin shows a better pharmacokinetics profile thanampicillin, allowing dosing at longer intervals and, inaddition, it has a high bactericidal activity againstS.pneumoniae

Irreversible inhibitor of the majority of the most frequent βL in the clinical setting

Its higher stability in an aqueous solution

Possibility to be given by oral or parenteral (I.M. – I.V.) route

Good tissue penetration

It does not induce generation of bacterial β-lactamases

It exerts an own bactericidal activity against some species (N. gonorrhoeae and Acinetobacter)

Mean plasma concentrations of amoxicillin and sulbactam

in 7 healthy volunteers, after the intake of one tablet

containing amoxicillin 250 mg and sulbactam 250 mg

Amoxicillin

Sulbactam

Hours

mcg/ml

Amoxicillin and sulbactam plasma levels in Children with a

Single Dose (Ax 17 mg + Sb 17 mg) /kg1

Amoxicillin

Sulbactam

Am

oxic

illi

n an

d su

lbac

tam

m

g/L

T (h)

Pharmacokinetics of Amoxicillin and Sulbactam in

pregnant and non pregnant women.

Amoxicillin Pregnancy

Amoxicillin non pregnancy

Sulbactam Pregnancy

Sulbactam non pregnancy

T (h)

Pla

smat

ic le

vels

mg/

L

Since 1984……..

• In 1984 – in Argentina – our working group provided the first report (the first one at international level) on the combination of Amoxicillin – sulbactam

II Pan-American Congress of Infectology held in Buenos Aires

Since 1984……..

TRIFAMOX IBL associates sulbactam withamoxicillin, thus recovering the originalactivity of amoxicillin and its greaterantimicrobial activity is evidenced againstmultiple microorganisms

Since 1984……..

• Its most important medical use is for:

• URTI and LRTI: otitis, sinusitis, bronchitis, CAP

• Urinary tract and OBS-GYN infections

• Intra-abdominal infections

• In patients undergoing gyn surgery (prophylactic antibiotic)

• Skin and soft tissue infections.

Bacterial Causes of Community Acquired

RTIs

Typical Atypical

• Streptococcus

pneumoniae

• Haemophilus influenzae

• Moraxella catarrhalis

• Staphlococcus aureus

(post influenza)

•Group A streptococcus

(Upper RTI)

Mycoplasma pneumoniae

• Chlamydophila

pneumoniae

• Chlamydophila psittaci

• Legionella pneumophila

• (Mycobacterium

tuberculosis)

Causes of primary community acquired

pneumonia

Typical pathogens Atypical bacteria Viruses

Streptococcus pneumoniae

Haemophilus influenzae

Moraxella catarrhalis

Staphylococcus aureus

(Gran negative bacilli : e.g

Klebsiella pneumoniae)

Mycoplasma pneumoniae

Chlamydophila

pneumoniae

Legionella pneumophila

Coxiella sp

(M.tuberculosis)

Influenza A and

B

Parainfluenzae

Adenoviruses

RSV

Comparative activity of AMX/SULB against other common antibiotics (RTIs)

ANTIMICROBIAL AGENTS

RESISTANT STRAINS %

n=55 n=44 n=19 n=52

S.pneumoniae H.influenzae S.pyogenes S.aureus

Amoxicillin (AMX) 9,1 12,3 0 96,9

AMX/sulbactam 7,3 0 0 46,9

Cefuroxime 7,3 0 0 56,3

Azithromycin 0 0 0 59,3

Clarithromycin 0 9,1 0 59,3

First Argentinian clinical experiences

ACUTE OTITIS MEDIA, EFFICACY AND TOLERABILITY OF AMOXICILLIN-SULBACTAM COMBINATIONCLAVERO, Carlos A.Chief of OtorhinolaryngologyNational University of CórdobaLa Prensa Médica Argentina, 1990; (Ed. Esp.) 77: 20-23

Age (years)

Nº patients

0-56-910-1920-2930-3940-4950-58Total

3345942

30

TreatmentAdults:500/500<13 y:24mg/kg/day3/day; 5-12 d

Sulbactam administration (20 mg/kg) allowed to reach middle ear concentrations between 0.3 and 2.7 g/ml (serum concentrations 1.3 - 9 g/ml). (Reilly et al.)

Cure criterion in the study was exclusively clinical. Not any patient was submitted to tympanocentesis.

Adverse effectsDiarrhea was constated on 7 patients, being mild in 3, moderate in 3 and severe in 1 case

THERAPEUTIC VALUE OF THE ASSOCIATION AMOXICILLIN-SULBACTAM ADMINISTERED EVERY 12 HOURS IN CHILDREN WITH ACUTE OTITIS MEDIA

MULTICENTRIC TRIAL

Aim : to assess the effectiveness and tolerability of amoxicillin + sulbactam (50/50 mg/kg/d total dose) administered orally twice daily, for the treatment of AOM in infants and children.

Coordinator: Prof. Enrique Mansilla. Head. Pediatric ORL Outpatient Service. Hospital de Clínicas. UBA. Buenos Aires.

Coordinator: Dr Andres Sibbald. Head. Department of Pediatrics. Hospital Británico. Buenos Aires

Rev Enf Infecciosas Ped 2000; 53:16-22

Treatment: amoxicillin + sulbactam 50/50 mg/kg/d, administering the total dose twice daily for 10 days

Results: 7 centers enrolled 231 patients; data from 222 of them were evaluated. In 41 cases miringocentesis was performed. The microorganisms more frequently isolated were: S. pneumoniae, H. influenzae, and M. catarrhalis.Otodynia decreased from 6.8 ± 0.11 to 2.3 ± 0.09 (p< 0.001) (days 1 and 10). There was also a dramatic improvement of clinical symptoms and otomicroscopic signs throughout the study.After a 10-day treatment period 100% of the patients had cure or improved.

Common Causes of Pneumonia Listed

by Patient Age

Age Most Likely Organisms

Neonatal (0–1 month) Escherichia coli, Streptococcus

agalactiae (group B)

Infants (1–6 months) Chlamydia trachomatis, respiratory

syncytial virus

Children (6 months–5

years)

Respiratory syncytial virus,

parainfluenza viruses

Children (5–15 years) Mycoplasma pneumoniae, influenza

virus type A

Young adults (16–30

years)

Streptococcus pneumoniae ,M.

pneumoniae,

Older adults Streptococcus pneumoniae,

Haemophilus influenzae

Treatment of LRTIsGuidelines????

0

2

4

6

8

1 0

1 2

1 4

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2007

Actualización de las recomendaciones ALAT sobre la neumonía adquirida en la comunidad. Grupo de trabajo de la Asociación Latinoamericana del Tórax (ALAT). Arch Bronconeumol 2004;40(8):364-74

In vitro ATB activity against 7365 strains of S.pneumoniae-SENTRY*programm

USA Latinamérica Europa Asia Pacífico

n=4193 n=948 n=1478 n=746

ATB MIC 90 %R MIC 90 %R MIC 90 %R MIC 90 %R

Amoxicillin

Amoxi-sulb

Cafaclor

Cefuroxime

Cefotaxime

Clarithromycin

Azithromicin

2

2

>32

4

1

2

2

3.2

2.8

26.2

21.8

3.7

16.0

13.6

1

2

>32

4

1

0.5

0.5

0.51

0.4

21.7

15.8

1.8

9.8

8.6

1.7

2

>32

4

1

>32

>16

2

1.7

21.1

16.6

2.6

18.2

17.8

2

>32

8

1

>32

>16

0

0

35.7

29.1

3.7

38.7

36.7

H.influenzae

in vitro ATB activity against 7365 strains of

H.influenzae- SENTRY-programm

USA Latinamérica Europa Asia

Pacífico

n=4193 n=948 n=1478 n=746

ATB MIC 90 %R MIC 90 %R MIC 90 %R MIC 90 %R

Amoxicillin

Amoxi-sulb

Cefuroxime

Cefotaxime

Azithromycin

>8

2

2

0.03

2

31.5

0.3

0.6

0

0.5

>8

1

2

0.03

2

12.5

0

0

0

0.4

8

1

2

0.03

2

11.8

0.2

0

0

0.2

>8

1

4

0.03

1

16.2

0

0.4

0.03

0.2

AMOXICILLIN-SULBACTAM COMBINATION IN THE TREATMENT OF

GYNECOLOGICAL BACTERIAL INFECTIONS (Prensa Med Arg; 1992; 79: 3-6.).

AMOXICILLIN + SULBACTAM: EFFICACY AND TOLERABILITY STUDY IN THE TREATMENT

OF BACTERIAL VAGINOSIS (VII PANAMERICAN CONGRESS OF

INFECTOLOGY. VI LATINAMERICAN CONGRESS OF PEDIATRIC INFECTOLOGY.

VI COLOMBIAN CONGRESS OF INFECTOLOGY. CARTAGENA DE LAS INDIAS –

COLOMBIA. 1995)

TREATMENT OF GONOCOCCAL URETHRITIS AND CERVICITIS WITH AMOXICILLIN-

SULBACTAM. (Prensa Med Arg, 1992; 79: 24-27)

OBS/GYN Infections

Diagnosis Microorganisms

Susceptibility

Amoxicillin Amoxicillin /Sulbactam

Bartholin’s gland abscess Staphylococcus aureus S S

Bartholin’s gland abscess Staphylococcus aureus S S

Bartholin’s gland abscess Staphylococcus epidermidis S S

Ovarian tube abscess Peptostreptococcus sp -- --

Abdominal wall abscess Streptococcus viridans

Bacteroides spp

----

----

---

---

Abdominal wall abscess Escherichia coli R S

Mammary abscess Staphylococcus aureus R S

Necrotic infected myoma Staphylococcus aureus R S

AMOXICILLIN PLUS SULBACTAM IN THE ENDOMETRITIS TREATMENT VI WORLD

CONFERENCE ON CLINICAL PHARMACOLOGY AND THERAPEUTICS. (A. Farinati, C. Ortega

Soler; P. Pucheta; M. Jugo; R. Guntin; G. Peñalba Buenos Aires, Argentina , 1996.)

“IN VIVO” EFFICACY OF AMOXICILLIN – SULBACTAM ASSOCIATION IN URINARY

TRACT INFECTIONS (Prensa Med Arg, 1990; 77: 49-50 )

MANAGEMENT OF URINARY TRACT INFECTIONS WITH AMOXICILLIN SULBACTAM

(Prensa Med Arg, 1992; 79: 21-23)

EFFECTIVENESS OF AMOXICILLIN-SULBACTAM IN THE TREATMENT OF URINARY TRACT

INFECTIONS (XXVIII ARGENTINE CONGRESS OF PEDIATRICS( Buenos Aires , Argentina, 1988.)

Amoxicillin sulbactam (Trifamox IBL) in UTI

In vivo studies

Infection types N Efficacy (range)

Urinary Tract InfectionsObs/GynPediatric Upper Respiratory Tract InfectionsPediatric Lower Respiratory Tract InfectionsSTI (Non Disseminated N.gonorrhoeae)

19164 15397233

91 (83-99)94 (90-98)97 (94-100)100 (97-100)93,5 (90-97)

OthersCholecistytisSurgical p, CAP, PPB

364 90 (87-94)

H.L MuguerciaACTA MÉDICA 2000;9(1-2):96-100Cuba

Clinical studies of the combination of sulbactam plus amoxicillin have revealed

no major renal, hematologic, hepatic, or central nervous system reactions

Sulbactam- amoxicillin has been used in the treatment of mixed bacterial infections such

as intra-abdominal infections, obstetric and gynecologic infections, and soft tissue and

bone infections.

It has been used to treat meningitis in infants and children and to treat epiglottitis and

selected other pediatric infections but third-generation cephalosporins would be preferred

in such infections.

Clinical experiences support the use in empirical treatment of upper and lower

respiratory tract infections