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Beta lactam and beta lactamase inhibitor combinations
Antimicrobials in Clinical Practice Beta lactam and Beta lactamase Inhibitor combinations Dr.Vijay Yewale, Dr.Dhanya Dharmapalan Consultant Pediatricians, Dr.Yewale Hospital, Vashi, Navi Mumbai Introduction: Bacteria posses an almost unlimited capability to
through the presence of a core β -lactam ring.
survive under adverse conditions. .The ability to
pathogens developed early in the history of their
produce beta-lactamases, enzymes that destroy
use(3). Of the various mechanisms of resistance,
beta-lactam antibiotics, presented a distinct
the most widespread and most important is
survival advantage for the pathogenic bacteria. A beta-lactam ring (β-lactam) is a lactam with
thedestruction of the β -lactam ring, which is
a heteroatomic ring structure, consisting of three
Resistance to β -lactam antibiotics among target
mediated by β -lactamases.
carbon atoms and one nitrogen atom.(Fig 1)(1) Beta lactam antibiotics act by binding to the penicillin-binding proteins (PBPs), thus inhibiting bacterial cell wall synthesis. β lactamases are enzymes that split the amide bond of β-lactam ring. When the β-lactam ring of this antibiotic class is hydrolyzed, antimicrobial activity is destroyed.[
Fig. 2. Hydrolysis of the b-lactam ring by b-
Fig 2]
lactamases
(3)
β -lactamases are commonly produced by Staphylococcus species, the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter species, and some anaerobes. The beta lactamases may be coded on plasmid or chromosomal DNA, and more than one type may be produced by the same species at the same or different times. The fact that these resistance Fig 1 Penicillin nucleus. Beta lactam is the square at the center.
(2)
enzymes may be coded on plasmids means that they are mobile within a bacterial community and that they have spread widely.
Penicillin, the first of the β -lactam antibiotics, was Since then, a large number of different β-lactams,
Mechanism of action of beta lactam inhibitors β -lactamase inhibitors are structurally related to
including penicillins, cephalosporins,
penicillin, retaining the amide bond of the β -
monobactams, and carbapenems, have been
lactam group of the parent compound, but with a
developed, all of which are structurally related
modified side chain. These structural features
introduced into medical practice in the 1940s.
enable the inhibitors to bind irreversibly as suicide Correspondence : Dr. Vijay Yewale Consultant Pediatrician, Dr.Yewale Hospital, Vashi, Navi Mumbai
substrates to the β -lactamases, rendering them inactive. Currently available β lactamase inhibitors are clavulanic acid, sulbactam and
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
69
tazobactam. Some β lactam inhibitors like
by the SPICE group of organisms including
sulbactam also have an additional intrinsic
Serratia, Pseudomonas, Citrobacter and
antibacterial activity.
Enterobacter)
nor
against
the
metallobetalactamases produced by The beta lactam inhibitors are mainly effective against organisms producing the first generation beta lactamases (TEM-1, SHV-1) or the extended spectrum beta lactamases (ESBL). None of the beta lactamase inhibitors are effective against the the inducible Amp C beta lactamases (produced
Pseudomonas and Acinetobacter.(4,5) Additionally beta lactamase inhibitors mauy be ineffective if there is a high organism burden such that copious amounts of ESBL are produced a phenomenon called inoculum effect.
Table 1 Details of classification of the beta lactamases
Beta lactamase Source
Inactivates
First generation Staph, E col i, H flu, Amoxicillin, Moraxella penicillin
Drugs effective Cephalosporins Cloxacillin, Amox clav
Extended spectrum (ESBL)
Enterobacteriaceae, Cephalosporins Penicillins Salmonella, Aztreonam Pseudomonas
Cephamycins BL-BLI combinations Carbapenems
Amp C beta lactamases
Pseudomonas, Serratia, Proteus, Enterobacter, Citrobacter
BL-BLI combinations, cephamycins
Carbapenems
Metallo beta lactamases
Pseudomonas, Acinetobacter, Klebsiella, E coli
Carbapenems
Colistin, Tigecycline, aztreonam
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
70
Pharmacology Clavulanic acid is a natural product, whereas
are well absorbed from the gut, the prodrug
sulbactam and tazobactam are semisynthetic.
80%, which is comparable to the about 90%
Generally they have little intrinsic antimicrobial
availability for oral amoxicillin/clavulanate.(6) The β
impact, but together with penicillins or
-lactam-to-inhibitor ratio ranges from 1:1 to 30:1 in
cephalosporins they effect a wider spectrum of
terms of weight per dose. Intravenous
activity in association with lower minimum
amoxicillin/clavulanate contains a smaller
inhibitory concentrations (MICs)
proportion of clavulanate than do oral formulations
Dosing should be based on the parent betalactam and not the beta-lactam combination. Many factors influence the activity and pharmacodynamics of these combinations, including
potency
of
both
agents,
pharmacokinetics of the inhibitor, type and quantity of β -lactamase produced by the target bacterium, and potential for the inhibitor to induce expression of chromosomal cephalosporinases in
combination achieves a bioavailability of about
because parenteral clavulanate is not subject to first-pass metabolism. Each component of all current beta-lactam/beta-lactamase inhibitor combinations have elimination half lives of about 30 to 60 minutes. Tissue penetration is generally good but data for cerebrospinal fluid are lacking. They are principally excreted through the kidneys and require dosage adjustment in the face of significant renal insufficiency.
the target bacterium. Although neither ampicillin nor sulbactam alone
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
71
Microbiology Table 1: Antimicrobial spectrum of currently available Beta lactam and beta lactamase inhibitor (7)
combination with dosage.
Drug Dosage Combination Amoxicillin Oral 20-40 mg/kg/day of the Clavulanic acid amoxicillin component in 2(2:1 ) 3 divided doses. Intravenous 50-100 mg/kg of the amoxicillin component in divided doses 6-8 hrly.
Ticarcillin Intravenous 80 mg/kg of Clavulanic acid ticarcillin every 6-8 hours (every 12 hoursin neonates) (15:1)
Antibacterial spectrum Gram positive: Streptococci spp, beta lactamase producing strains of S.aureus and enterococci species. Gram negative: First generation beta lactamase producing strains of Escherichia coli, Klebsiella spp, Proteus spp.H.influenzae, Moraxella catrrhalis, Bacteroides fragilis and Neisseria gonorrhoeae Gram positive:S aureus (methicillin sensitive),S.epidermis and Streptococcus spp. Gram negative:beta lactamase producing H.influenzae, Moraxella catarrhalis,B.fragilis,Neisseria gonorrhoea and extended spectrum beta lactamase producing Escherichia coli, Klebsiella spp, Proteus spp.
Piperacillin Tazobactam (8:1)
150-400 mg/kg/day given 68 hourly as intravenous injection over 30 mins. Maximum dose is 4.5 gm every 6 hours
Gram positive Betalactamase producing S aureus, Staphylococcus epidermidis, Streptococcus spp and Enterococcus faecalis Gram negative Beta lactamase and extended spectrum betalactamase producing Pseudomonas aeruginosa, Enterobacteriaceae spp, Ecoli, Klebsiella pneumonia, Proteus spp, Salmonella spp, Shigella spp, Haemophillus influenzae, Neisseria gonorrhoea.
Ampicillinsulbactam (1.5/2:1)
100-200 mg/kg/day of ampicillin in 6 hourly doses, total dose of sulbactam should not exceed 4 gm/day
Cefaperazone Sulbactam
50-100 mg/kg/day of cefaperazone IV in 12 hourly
Gram positive bacteria except methicillin resistant staphylococcal aureus. Gram negative-ESBL producing enterobacteriaceae namely Ecoli,Klebsiella. No antipseudomonal activity.Also effective against multidrug resistant Acinobacter. Similar to piperacillin tazobactam
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
72
Although ticarcillin-clavulanate and piperacillin-
children below the age of 5 where H. influenzae is
tazobactam have similar spectra of activity, they
an important pathogen amoxicillin clavulanate
have many differences. Most notable are
may offer an advantage over amoxicillin for
increased potency of piperacillin against
pneumonia. However in children aged above 5
Enterobacteriaceae and P aeruginosa (Of all the
where the contribution of H influenzae is low and
antipseudomonal penicillins, Piperacillin is the
pneumococcus or atypical organisms such as
most potent compound), increased activity of
Mycoplasma are the main etiologic agents,
piperacillin-tazobactam against gram-negative
amoxicillin clavulanate offers no advantage over
pathogens producing penicillin-sensitive enzyme other plasmid-encoded beta-lactamases, and the
amoxicillin. Nosocomial pneumonia : In patients with nosocomial pneumonia, resistant
more favorable pharmacokinetics of tazobactam.
gram negative bacilli (including Pseudomonas
When treating pseudomonal infections, it must be
aeruginosa) are frequent pathogens.
remembered that clavulanate has the potential of
Piperacillin/tazobactam
inducing cephalosporinase that may hamper the
cefoperazone/sulbactam are useful in such a
antibacterial activity of the partner drug ticarcillin.
setting and sometimes obviate the need to use
These are not concerns with piperacillin-
carbapenems.
(PSE)-class beta-lactamase or hyperproducing
tazobactam.(8) Side effects The most common side effects of beta-
and
(6)
Skin and soft tissue infections. Most of the bacterial skin infections seen in clinic practice are caused by streptococcus pyogenus
lactam/beta-lactamase inhibitor combinations
or staphylococcal aureus. Though streptococcus
include diarrhea, elevated liver enzyme levels,
does not produce beta lactamase, 90% of
and rashes. These are usually mild and transient,
staphylococcal produce first generation
although they may be somewhat more frequent
betalactamases while 10% are methicillin
than with the corresponding beta lactam antibiotic
resistant. Amoxicillin/clavulanic may be used as
alone. Clavulanate has been associated with rare and usually reversible cholestatic hepatitis
(6)
an alternative to cephalexin or cefadroxil. However for methicillin resistant staphylococcus aureus, one must use either linezolid or
Uses
clindamycin or vancomycin.
Upper and Lower Respiratory Tract Infections. Upper Respiratory Tract Infections For streptococcal sore throat amoxicillin is
Intra-abdominal Infections. Intraabdominal infections are generally polymicrobial. While standard regimens using
standard therapy; amoxicillin clavulanate may be
various combinations of clindamycin,
used only in repeated infections. For severe otitis
metronidazole, aminoglycosides, and second- or
media and acute bacterial sinusitis where H
third generation cephalosporins are complicated
influenzae, M catarrhalis may be the etiologic
and require monitoring, monotherapy with β -
agents (both of which produce the first generation
lactam/ β-lactamase inhibitor combinations afford
beta lactamases) amoxicillin clavulanate is
simpler alternatives. The efficacy and cost-
indicated and as effective as cefpodoxime a 3rd
effectiveness of piperacillin/ tazobactam are
generation cephalosporin. Lower Respiratory Tract Infections Community acquired pneumonia(CAP) : In
comparable to those of standard combination
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
regimens or imipenem/cilastatin monotherapy,
73
and clinical response rates approach 90%.
generation cephalosporins like ceftriaxone and
Results with sulbactam combinations are similar
cefotaxime are recommended as the first line
In addition, amoxicillin/clavulanate,
empiric treatment due to their high cure rates
ampicillin/sulbactam, and piperacillin/tazobactam
against all the above mentioned pathogens. In
(but not ticarcillin/clavulanate) provide clinically
patients with pneumococcal meningitis caused by
significant activity against enterococci.
(6)
cephalosporin-resistant strains meropenem is an alternative to cephalosporins.
Urinary Tract Infections With the increasing incidence of ESBL production in community acquired urinary tract infections, the
Limitations of BL-BLI combination therapy 1) A fixed ratio of antibiotics is available, especially
role of BL-BLI in management of these infections
in oral formulations. This can lead to unequal
is increasing. Oral Bl_BLI combinations such as
tissue distribution, and different dosages might
cefixime clavulanate / cefpodoxime clavulanate
provide better coverage at multiple sites. 2) Also appropriate dose adjustments in special
though having demonstrable in vitro activity have not been evaluated clinically. However, their therapeutic role against these
situations becomes difficult. For instance, while
infections is being hampered by emergent
clavulanate undergoes
inhibitor resistant strains
(6)
tazobactam and sulbactam are excreted renally, extensive
hepatic
metabolism. Consequently, in patients with renal failure (for whom dosing intervals are usually
Febrile neutropenia,nosocomial infections There is evidence to suggest that they are
increased), a relative deficiency of clavulanate
efficacious in treating patients with neutropenic
may occur .(6) 3) As mentioned earlier BL-BLI combinations may
fever and nosocomial infections, especially in
not work if there is high bacterial load due to
combination with other agents. Their role in
inoculum effect. Also if there is co production of
treating various multi-resistant pathogens such as
Amp C betalactamases BL-BLI combinations will
Acinetobacter species and Stenotrophomonas
not work and carbapenems are the only
maltophilia are gaining importance (9)
therapeutic option. Finally there is emergence of
Bacterial meningitis In children older than 4 weeks, S. pneumonia, H.influenza B and N meningitidis are the most
inhibitor resistant TEM's (IRT) type of
ESBL's
which are not inhibited by any BLI.
common etiological agents. Because both
Choice of the beta lactamase inhibitor There is not much to choose between the various
sulbactam and ampicillin can penetrate the
inhibitors. Subtle differences however exist
cerebral spinal fluid, the combination has been
especially determined by the type of the ESBL and
used to successfully to treat bacterial
are highlighted in table 3.
meningitis.
(10)
However, at present ,there are
insufficient data to make a recommendation on the use of betalactam inhibitors in pediatric bacterial meningitis. Monotherapy with third
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
74
Table 3: Extended spectrum beta lactamases and choice of BL-BLI combination.
Type
Organisms
Characteristics
TEM
E coli
SHV
Klebsiella
Clavulinic acid better than sulbactam better than tazobactam.
CTX M
E coli Salmone Enterobacteriaceae (Community, India)
Cefotaxime affected Tazobactam better
OXA
Pseudomonas aeruginosa
Poorly inhibited by clavulanate
IRT
(Inhibitor resistant TEMs)
None works
Indigenous BL-BLI combinations(12) Examples of irrational combinations are
combination (e.g. 1 gm of ceftriaxone- tazobactam has only 500 mg of ceftriaxone).
ceftriaxone - tazobactam, cefotaxime – sulbactam, cefixime – clavulanic acid,
The potential role of the parenteral lactamase -
cefpodoxime – clavulanic acid. These
beta lactamase combinations is for treatment of
combinations have been launched without
nosocomial infections by ESBL producing
adequate research into pharmacokinetic
organisms. Here again the limitation is the poor
compatibility of the partner drugs and clinical
activity against nosocomial pathogens such as
efficacy.
Pseudomonas and Acinetobacter of ceftriaxone/ cefotaxime based combinations unlike the good
These are being promoted for management of
activity of piperacillin/ cefoperazone based
community acquired infections such as
combinations.
meningitis, enteric fever and respiratory tract infections. Most of the causative organisms for
Cefixime/ cefpodoxime are misused widely; the
these infections do not produce resistance by
addition of clavulanic acid to these drugs makes
production of beta lactamases (meningococcus,
the outlook even more bleak. The only potential
salmonella, pneumococcus) or even if they
role of these drugs is in the outpatient
produce betalactamase, the beta lactam
management of urinary tract infections due to
component is effective by itself (beta lactamase
ESBL producing organisms, an emerging
producing Hib is susceptible to all third generation
problem. More efficacy data is needed to support
cephalosporins). Hence addition of the beta
this indication.
lactamase inhibitor does not give any added advantage. Paradoxically it may cause accidental under dosing of the effective beta lactam component if the dose is calculated for the entire Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
Conclusions The development of drug combinations containing the beta-lactamase inhibitors has given clinicians
75
a novel approach to controlling resistant
5. Sanders CC and Sanders,Jr WE. Emergence of
organisms. They are particularly important in India
resistance during therapy with the newer beta lactam
when ESBL producing organisms are widespread and help take off the pressure from the carbapenems. Although betalactam and betalactamase inhibitor combinations have been
antibiotics: role of inducible beta-lactamases and implications for the future, Rev. Infect. Dis.1983;5: 639648. 6. Nelson LS, Yuen KY, Kumana CR. β -Lactam Antibiotic and β Lactamase Inhibitor Combinations. JAMA 2001
used successfully in a variety of clinical situations,
Jan;285(4):386-88. 7. Shah RC,Goyal R, Gadgil P.Penicillins and
combination therapy should not be used when a
Monobactams.Rational Antimicrobial Practice in
single agent would be effective. Acknowledgement - We are deeply grateful to
Pediatrics.(Under IAP Action Plan 2006). The Indian Academy of Pediatrics.2006:31-37 8) Lister PD Beta-lactamase inhibitor combinations with extended-spectrum penicillins: factors influencing
Dr. Tanu singhal for her expert review and
antibacterial activity against enterobacteriaceae and
invaluable contribution.
Pseudomonas aeruginosa Pharmacotherapy..2000 Sept;
References
20(9Pt2):213-18. 9) Nelson LS, Yuen KY, Kumana CR. Clinical role of βlactam/ β -lactamase inhibitor combinations.Drugs
1. Gilchrist T. Heterocyclic Chemistry. Harlow: Longman Scientific; 1987. 2. Beta-Lactam.Wikipedia.[cited 2010 Feb 23] .Available from: URL: http://en.wikipedia.org/wiki/Beta-lactam 3. Williams JD. Beta lactams and beta lactamase inhibitors.
2003;63(14):1511-24. 10) Rodriguez WJ, Khan WN, Puig J, Feris J, Harmon S, Gold BG,
et
al.
Sulbactam/ampicillin
vs
chloramphenicol/ampicillin for the treatment of meningitis
International Journal of Antimicrobial Agents. 1999;12(1) :
in infants and children. Rev.Infect. Dis.1986;8:620-29. 11) Bush K. -Lactamase Inhibitors from Laboratory to Clinic.
3-7 4. Piddock LJV and Wise R. Newer mechanism of
Clinical Microbiology Reviews.1988 Jan: 109-23. 12) Singhal T. Irrational antibiotic combinations .IAP
resistance to beta lactam antibiotics in Gram-negative
Infectious Disease Chapter.
bacteria.J. Antimicrob. Chemother.1985;15:279-84
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
76
through the presence of a core β -lactam ring.
survive under adverse conditions. .The ability to
pathogens developed early in the history of their
produce beta-lactamases, enzymes that destroy
use(3). Of the various mechanisms of resistance,
beta-lactam antibiotics, presented a distinct
the most widespread and most important is
survival advantage for the pathogenic bacteria. A beta-lactam ring (β-lactam) is a lactam with
thedestruction of the β -lactam ring, which is
a heteroatomic ring structure, consisting of three
Resistance to β -lactam antibiotics among target
mediated by β -lactamases.
carbon atoms and one nitrogen atom.(Fig 1)(1) Beta lactam antibiotics act by binding to the penicillin-binding proteins (PBPs), thus inhibiting bacterial cell wall synthesis. β lactamases are enzymes that split the amide bond of β-lactam ring. When the β-lactam ring of this antibiotic class is hydrolyzed, antimicrobial activity is destroyed.[
Fig. 2. Hydrolysis of the b-lactam ring by b-
Fig 2]
lactamases
(3)
β -lactamases are commonly produced by Staphylococcus species, the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter species, and some anaerobes. The beta lactamases may be coded on plasmid or chromosomal DNA, and more than one type may be produced by the same species at the same or different times. The fact that these resistance Fig 1 Penicillin nucleus. Beta lactam is the square at the center.
(2)
enzymes may be coded on plasmids means that they are mobile within a bacterial community and that they have spread widely.
Penicillin, the first of the β -lactam antibiotics, was Since then, a large number of different β-lactams,
Mechanism of action of beta lactam inhibitors β -lactamase inhibitors are structurally related to
including penicillins, cephalosporins,
penicillin, retaining the amide bond of the β -
monobactams, and carbapenems, have been
lactam group of the parent compound, but with a
developed, all of which are structurally related
modified side chain. These structural features
introduced into medical practice in the 1940s.
enable the inhibitors to bind irreversibly as suicide Correspondence : Dr. Vijay Yewale Consultant Pediatrician, Dr.Yewale Hospital, Vashi, Navi Mumbai
substrates to the β -lactamases, rendering them inactive. Currently available β lactamase inhibitors are clavulanic acid, sulbactam and
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
69
tazobactam. Some β lactam inhibitors like
by the SPICE group of organisms including
sulbactam also have an additional intrinsic
Serratia, Pseudomonas, Citrobacter and
antibacterial activity.
Enterobacter)
nor
against
the
metallobetalactamases produced by The beta lactam inhibitors are mainly effective against organisms producing the first generation beta lactamases (TEM-1, SHV-1) or the extended spectrum beta lactamases (ESBL). None of the beta lactamase inhibitors are effective against the the inducible Amp C beta lactamases (produced
Pseudomonas and Acinetobacter.(4,5) Additionally beta lactamase inhibitors mauy be ineffective if there is a high organism burden such that copious amounts of ESBL are produced a phenomenon called inoculum effect.
Table 1 Details of classification of the beta lactamases
Beta lactamase Source
Inactivates
First generation Staph, E col i, H flu, Amoxicillin, Moraxella penicillin
Drugs effective Cephalosporins Cloxacillin, Amox clav
Extended spectrum (ESBL)
Enterobacteriaceae, Cephalosporins Penicillins Salmonella, Aztreonam Pseudomonas
Cephamycins BL-BLI combinations Carbapenems
Amp C beta lactamases
Pseudomonas, Serratia, Proteus, Enterobacter, Citrobacter
BL-BLI combinations, cephamycins
Carbapenems
Metallo beta lactamases
Pseudomonas, Acinetobacter, Klebsiella, E coli
Carbapenems
Colistin, Tigecycline, aztreonam
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
70
Pharmacology Clavulanic acid is a natural product, whereas
are well absorbed from the gut, the prodrug
sulbactam and tazobactam are semisynthetic.
80%, which is comparable to the about 90%
Generally they have little intrinsic antimicrobial
availability for oral amoxicillin/clavulanate.(6) The β
impact, but together with penicillins or
-lactam-to-inhibitor ratio ranges from 1:1 to 30:1 in
cephalosporins they effect a wider spectrum of
terms of weight per dose. Intravenous
activity in association with lower minimum
amoxicillin/clavulanate contains a smaller
inhibitory concentrations (MICs)
proportion of clavulanate than do oral formulations
Dosing should be based on the parent betalactam and not the beta-lactam combination. Many factors influence the activity and pharmacodynamics of these combinations, including
potency
of
both
agents,
pharmacokinetics of the inhibitor, type and quantity of β -lactamase produced by the target bacterium, and potential for the inhibitor to induce expression of chromosomal cephalosporinases in
combination achieves a bioavailability of about
because parenteral clavulanate is not subject to first-pass metabolism. Each component of all current beta-lactam/beta-lactamase inhibitor combinations have elimination half lives of about 30 to 60 minutes. Tissue penetration is generally good but data for cerebrospinal fluid are lacking. They are principally excreted through the kidneys and require dosage adjustment in the face of significant renal insufficiency.
the target bacterium. Although neither ampicillin nor sulbactam alone
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
71
Microbiology Table 1: Antimicrobial spectrum of currently available Beta lactam and beta lactamase inhibitor (7)
combination with dosage.
Drug Dosage Combination Amoxicillin Oral 20-40 mg/kg/day of the Clavulanic acid amoxicillin component in 2(2:1 ) 3 divided doses. Intravenous 50-100 mg/kg of the amoxicillin component in divided doses 6-8 hrly.
Ticarcillin Intravenous 80 mg/kg of Clavulanic acid ticarcillin every 6-8 hours (every 12 hoursin neonates) (15:1)
Antibacterial spectrum Gram positive: Streptococci spp, beta lactamase producing strains of S.aureus and enterococci species. Gram negative: First generation beta lactamase producing strains of Escherichia coli, Klebsiella spp, Proteus spp.H.influenzae, Moraxella catrrhalis, Bacteroides fragilis and Neisseria gonorrhoeae Gram positive:S aureus (methicillin sensitive),S.epidermis and Streptococcus spp. Gram negative:beta lactamase producing H.influenzae, Moraxella catarrhalis,B.fragilis,Neisseria gonorrhoea and extended spectrum beta lactamase producing Escherichia coli, Klebsiella spp, Proteus spp.
Piperacillin Tazobactam (8:1)
150-400 mg/kg/day given 68 hourly as intravenous injection over 30 mins. Maximum dose is 4.5 gm every 6 hours
Gram positive Betalactamase producing S aureus, Staphylococcus epidermidis, Streptococcus spp and Enterococcus faecalis Gram negative Beta lactamase and extended spectrum betalactamase producing Pseudomonas aeruginosa, Enterobacteriaceae spp, Ecoli, Klebsiella pneumonia, Proteus spp, Salmonella spp, Shigella spp, Haemophillus influenzae, Neisseria gonorrhoea.
Ampicillinsulbactam (1.5/2:1)
100-200 mg/kg/day of ampicillin in 6 hourly doses, total dose of sulbactam should not exceed 4 gm/day
Cefaperazone Sulbactam
50-100 mg/kg/day of cefaperazone IV in 12 hourly
Gram positive bacteria except methicillin resistant staphylococcal aureus. Gram negative-ESBL producing enterobacteriaceae namely Ecoli,Klebsiella. No antipseudomonal activity.Also effective against multidrug resistant Acinobacter. Similar to piperacillin tazobactam
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
72
Although ticarcillin-clavulanate and piperacillin-
children below the age of 5 where H. influenzae is
tazobactam have similar spectra of activity, they
an important pathogen amoxicillin clavulanate
have many differences. Most notable are
may offer an advantage over amoxicillin for
increased potency of piperacillin against
pneumonia. However in children aged above 5
Enterobacteriaceae and P aeruginosa (Of all the
where the contribution of H influenzae is low and
antipseudomonal penicillins, Piperacillin is the
pneumococcus or atypical organisms such as
most potent compound), increased activity of
Mycoplasma are the main etiologic agents,
piperacillin-tazobactam against gram-negative
amoxicillin clavulanate offers no advantage over
pathogens producing penicillin-sensitive enzyme other plasmid-encoded beta-lactamases, and the
amoxicillin. Nosocomial pneumonia : In patients with nosocomial pneumonia, resistant
more favorable pharmacokinetics of tazobactam.
gram negative bacilli (including Pseudomonas
When treating pseudomonal infections, it must be
aeruginosa) are frequent pathogens.
remembered that clavulanate has the potential of
Piperacillin/tazobactam
inducing cephalosporinase that may hamper the
cefoperazone/sulbactam are useful in such a
antibacterial activity of the partner drug ticarcillin.
setting and sometimes obviate the need to use
These are not concerns with piperacillin-
carbapenems.
(PSE)-class beta-lactamase or hyperproducing
tazobactam.(8) Side effects The most common side effects of beta-
and
(6)
Skin and soft tissue infections. Most of the bacterial skin infections seen in clinic practice are caused by streptococcus pyogenus
lactam/beta-lactamase inhibitor combinations
or staphylococcal aureus. Though streptococcus
include diarrhea, elevated liver enzyme levels,
does not produce beta lactamase, 90% of
and rashes. These are usually mild and transient,
staphylococcal produce first generation
although they may be somewhat more frequent
betalactamases while 10% are methicillin
than with the corresponding beta lactam antibiotic
resistant. Amoxicillin/clavulanic may be used as
alone. Clavulanate has been associated with rare and usually reversible cholestatic hepatitis
(6)
an alternative to cephalexin or cefadroxil. However for methicillin resistant staphylococcus aureus, one must use either linezolid or
Uses
clindamycin or vancomycin.
Upper and Lower Respiratory Tract Infections. Upper Respiratory Tract Infections For streptococcal sore throat amoxicillin is
Intra-abdominal Infections. Intraabdominal infections are generally polymicrobial. While standard regimens using
standard therapy; amoxicillin clavulanate may be
various combinations of clindamycin,
used only in repeated infections. For severe otitis
metronidazole, aminoglycosides, and second- or
media and acute bacterial sinusitis where H
third generation cephalosporins are complicated
influenzae, M catarrhalis may be the etiologic
and require monitoring, monotherapy with β -
agents (both of which produce the first generation
lactam/ β-lactamase inhibitor combinations afford
beta lactamases) amoxicillin clavulanate is
simpler alternatives. The efficacy and cost-
indicated and as effective as cefpodoxime a 3rd
effectiveness of piperacillin/ tazobactam are
generation cephalosporin. Lower Respiratory Tract Infections Community acquired pneumonia(CAP) : In
comparable to those of standard combination
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
regimens or imipenem/cilastatin monotherapy,
73
and clinical response rates approach 90%.
generation cephalosporins like ceftriaxone and
Results with sulbactam combinations are similar
cefotaxime are recommended as the first line
In addition, amoxicillin/clavulanate,
empiric treatment due to their high cure rates
ampicillin/sulbactam, and piperacillin/tazobactam
against all the above mentioned pathogens. In
(but not ticarcillin/clavulanate) provide clinically
patients with pneumococcal meningitis caused by
significant activity against enterococci.
(6)
cephalosporin-resistant strains meropenem is an alternative to cephalosporins.
Urinary Tract Infections With the increasing incidence of ESBL production in community acquired urinary tract infections, the
Limitations of BL-BLI combination therapy 1) A fixed ratio of antibiotics is available, especially
role of BL-BLI in management of these infections
in oral formulations. This can lead to unequal
is increasing. Oral Bl_BLI combinations such as
tissue distribution, and different dosages might
cefixime clavulanate / cefpodoxime clavulanate
provide better coverage at multiple sites. 2) Also appropriate dose adjustments in special
though having demonstrable in vitro activity have not been evaluated clinically. However, their therapeutic role against these
situations becomes difficult. For instance, while
infections is being hampered by emergent
clavulanate undergoes
inhibitor resistant strains
(6)
tazobactam and sulbactam are excreted renally, extensive
hepatic
metabolism. Consequently, in patients with renal failure (for whom dosing intervals are usually
Febrile neutropenia,nosocomial infections There is evidence to suggest that they are
increased), a relative deficiency of clavulanate
efficacious in treating patients with neutropenic
may occur .(6) 3) As mentioned earlier BL-BLI combinations may
fever and nosocomial infections, especially in
not work if there is high bacterial load due to
combination with other agents. Their role in
inoculum effect. Also if there is co production of
treating various multi-resistant pathogens such as
Amp C betalactamases BL-BLI combinations will
Acinetobacter species and Stenotrophomonas
not work and carbapenems are the only
maltophilia are gaining importance (9)
therapeutic option. Finally there is emergence of
Bacterial meningitis In children older than 4 weeks, S. pneumonia, H.influenza B and N meningitidis are the most
inhibitor resistant TEM's (IRT) type of
ESBL's
which are not inhibited by any BLI.
common etiological agents. Because both
Choice of the beta lactamase inhibitor There is not much to choose between the various
sulbactam and ampicillin can penetrate the
inhibitors. Subtle differences however exist
cerebral spinal fluid, the combination has been
especially determined by the type of the ESBL and
used to successfully to treat bacterial
are highlighted in table 3.
meningitis.
(10)
However, at present ,there are
insufficient data to make a recommendation on the use of betalactam inhibitors in pediatric bacterial meningitis. Monotherapy with third
Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
74
Table 3: Extended spectrum beta lactamases and choice of BL-BLI combination.
Type
Organisms
Characteristics
TEM
E coli
SHV
Klebsiella
Clavulinic acid better than sulbactam better than tazobactam.
CTX M
E coli Salmone Enterobacteriaceae (Community, India)
Cefotaxime affected Tazobactam better
OXA
Pseudomonas aeruginosa
Poorly inhibited by clavulanate
IRT
(Inhibitor resistant TEMs)
None works
Indigenous BL-BLI combinations(12) Examples of irrational combinations are
combination (e.g. 1 gm of ceftriaxone- tazobactam has only 500 mg of ceftriaxone).
ceftriaxone - tazobactam, cefotaxime – sulbactam, cefixime – clavulanic acid,
The potential role of the parenteral lactamase -
cefpodoxime – clavulanic acid. These
beta lactamase combinations is for treatment of
combinations have been launched without
nosocomial infections by ESBL producing
adequate research into pharmacokinetic
organisms. Here again the limitation is the poor
compatibility of the partner drugs and clinical
activity against nosocomial pathogens such as
efficacy.
Pseudomonas and Acinetobacter of ceftriaxone/ cefotaxime based combinations unlike the good
These are being promoted for management of
activity of piperacillin/ cefoperazone based
community acquired infections such as
combinations.
meningitis, enteric fever and respiratory tract infections. Most of the causative organisms for
Cefixime/ cefpodoxime are misused widely; the
these infections do not produce resistance by
addition of clavulanic acid to these drugs makes
production of beta lactamases (meningococcus,
the outlook even more bleak. The only potential
salmonella, pneumococcus) or even if they
role of these drugs is in the outpatient
produce betalactamase, the beta lactam
management of urinary tract infections due to
component is effective by itself (beta lactamase
ESBL producing organisms, an emerging
producing Hib is susceptible to all third generation
problem. More efficacy data is needed to support
cephalosporins). Hence addition of the beta
this indication.
lactamase inhibitor does not give any added advantage. Paradoxically it may cause accidental under dosing of the effective beta lactam component if the dose is calculated for the entire Pediatric Infectious Disease, Vol.II- Apr - Sept 2010.
Conclusions The development of drug combinations containing the beta-lactamase inhibitors has given clinicians
75
a novel approach to controlling resistant
5. Sanders CC and Sanders,Jr WE. Emergence of
organisms. They are particularly important in India
resistance during therapy with the newer beta lactam
when ESBL producing organisms are widespread and help take off the pressure from the carbapenems. Although betalactam and betalactamase inhibitor combinations have been
antibiotics: role of inducible beta-lactamases and implications for the future, Rev. Infect. Dis.1983;5: 639648. 6. Nelson LS, Yuen KY, Kumana CR. β -Lactam Antibiotic and β Lactamase Inhibitor Combinations. JAMA 2001
used successfully in a variety of clinical situations,
Jan;285(4):386-88. 7. Shah RC,Goyal R, Gadgil P.Penicillins and
combination therapy should not be used when a
Monobactams.Rational Antimicrobial Practice in
single agent would be effective. Acknowledgement - We are deeply grateful to
Pediatrics.(Under IAP Action Plan 2006). The Indian Academy of Pediatrics.2006:31-37 8) Lister PD Beta-lactamase inhibitor combinations with extended-spectrum penicillins: factors influencing
Dr. Tanu singhal for her expert review and
antibacterial activity against enterobacteriaceae and
invaluable contribution.
Pseudomonas aeruginosa Pharmacotherapy..2000 Sept;
References
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