Carbapenems can usually be used to treat infections due to AmpC-producing bacteria, but carbapenem resistance can arise in some organisms by mutations that reduce influx (outer membrane porin loss) or enhance efflux (efflux pump activation). see http://www.ncbi.nlm.nih.gov/pubmed/19136439

Some literature also saying that Biapenem and Doripenem are good against Pseudomonas. U can search for it.

Pseudomonas has many other mechanisms as well which make this bacterium not very good for carbapenems and these u can check in the reference below.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738602/

And this also interesting;

The vast majority of Enterobacteriaceae, including ESBL producers, remain susceptible to carbapenems, and these agents are considered preferred empiric therapy for serious Enterobacteriaceae infections. Carbapenem resistance, although rare, appears to be increasing.

 http://www.ncbi.nlm.nih.gov/pubmed/16735147

also we know that AmpC expression is inducible mainly..and probably more pronounced in Enterobacters.

Agree... but the main resistance stem mainly from selection of derepressed mutants of Amp C rather than induction and given the fact that (correct me if I am wrong)

1) Pseudomonas (PA) compared to even Enterobacter may have a higher baseline mutants

2) Pseudomonas have a higher baseline MIC in wild types due to presence of multiple AmpD genes leading to higher degree of induction

3) ceftazidime is such a good inducer compared to penems and still use for susceptible PA

Why then the same is not applicable and we still continue using carbapenem for other intrinsic AmpC producers compared to PA regardless of the MIC

- and with the CRE and colistin resistance in the plasmids now shouldn't we review our stand on this...

i.e. use non carbapenem beta lactams for non PA ampC producers only when the infection is not severe?

Here is an excellent paper which you may find useful which goes into some of the enzyme kinetics and regulation of AmpC in pseudomonas compared to Enterobacteraciae: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2620637/pdf/0036-08.pdf

However, in short, I think one easy answer is provided in this sentence I lifted right from the paper:

"Because P. aeruginosa has at least three ampD genes, enhanced AmpC production occurs in a stepwise fashion, producing resistance to antipseudomonas penicillins, oxyiminocephalosporins, and, with full derepression, cefepime."

In general, given this slow evolution in pseudomonas compared to monogenetic mediated bacteria, the MIC's have a chance to catch up and are more reliable when picking an antibiotic in the case of pseudomonas.

Thanks for the answer, although I must admit that I honestly I do not really understand the above as it is beyond me.. I am not too good with molecular stuffs...

Correct me if I am wrong, but with AmpD genes, that would represent  induction rather than derepressed mutants pathway... And as derepressed mutants are the main concern, does the above theory apply too to PA?

Hi Helmi - the reasons you seek are somewhat historical.  When 3rd generation cephalosporins were introduced and became widely used, a fairly high failure rate was noticed in Enterobacter species that initially tested susceptible, especially for bacteraemia or meningitis - in one classic study this occurred in 6 of 31 (19%) patients (see Chow et al, 1991 Annals Intern Med, 155(8)) and this occurred via selection for so-called AmpC 'de-repressed mutants'. Furthermore, prior use of 3GCs has been a strong risk factor being infected with AmpC-hyperproducing strains.  This findings have ben replicated in  a few later and larger studies, with variable risk.  It is worth noting that this significant risk of clinical failure has only really been consistently seen with Enterobacter (esp. E. cloacae and aerogenes), and much less with other AmpC-producers, although it can occur.  It is also true that the MIC breakpoints used then were much higher and we would have called many of those strains resistant by today's standards I suspect.

However, because of this phenomenon, all other non-carbapenem beta-lactams have been coloured with the same brush (e.g. piperacillin-tazobactam), and the 'rule' (of avoiding 3GCs for Enterobacter) has been rather overstretched to include all AmpC-producing Enterobacteriaceae - leaving options such as carbapenems or quinolones as preference... which has significant consequences in terms of selection pressure for resistance, C diff etc and makes antimicrobial stewardship problematic.   It is worth noting also that resistance to carbapenems has been frequently described emerging in Enterobacter via AmpC plus porin mutations or efflux, so no drug is a magic bullet.  Just because resistance 'can' occur, does not mean it should never be used as this would invalidate almost everything we ever use.  It is a question of risk / benefit and this is poorly quantified at the moment. 

My impression is that the risk may be over-played for many infections, and agents such as piperacillin-tazobactam and especially cefepime (which is stable to AmpC) are entirely appropriate in many situations.  The caveat to this may still be relevant in complex circumstances (e.g. no source control, deep tissue infections, endovascular focus etc.).  So we probably need a more nuanced discussion - assuming that generally we can treat organisms as tested using current breakpoints, but be mindful that resistance can develop, watch for this and reach for carbapenems only when critically required.  The honest truth is we lack well designed studies to address this question directly and the literature is sparse.  We recently undertook a meta-analysis on this subject (attached for interest), and found no clear evidence that carbapenems were superior for bloodstream infections caused by AmpC producers, but this has to be treated with some caution given the paucity of evidence.  We are in the process of running an RCT in this area so watch this space! I have also attached an interesting letter from a few years back questioning the whole thinking behind our clinical approach to AmpC which is worth a read.  

I would caution getting too bogged down in the molecular explanations - important and interesting though they are - as this has rather led us down this pathway of over-reliance on carbapenems.  What we need now are clinically focussed studies, looking at true patient outcomes to determine which options are optimal.    

Hope that helps (a bit...) - sorry for the long answer but I think it is an interesting question

Best wishes

Patrick Harris

UQCCR

Helmi,

AmpD is an enzyme which alters the substance which induces ampC. Therefore, normally ampD activity decreases expression of AmpC. However, when ampD acquires mutations, it no longer represses AmpC. This, in fact, is the most common cause of AmpC over expression or hyperinducibility. (Again, link from my last post includes further info about this if desired). Hope that helps

Elise

Thanks Patrick for your answer...

Issue is in Malaysia, I believe the physicians will use carbapenem almost all the time for any ESCPM organisms which is very worrying

I do agree the MERINO trials (1 and 2) would help us answer whether non carbapenem agents esp. Pip taz can be used for both ESBL and AmpC organisms especially with low inoculum/infection burden

Besides AmpC detection is rarely done except in large reference/ research centres.

Thanks Elise too for the answer