Does a reduction in antibiotic consumption always represent a favorable outcome from an intervention program on prescribing practice?

OBJECTIVES: In our hospital, a continuous intervention program aimed at optimizing the quality of antibiotic use was introduced by late 1999 and antibiotic consumption was a major outcome for assessment. However, healthcare conditions have been subject to change over the last five years, and a pronounced economic crisis in 2002 affected the availability of antibiotics. Therefore, we hypothesized that the consumption of these drugs could be a suitable indirect marker of the crisis. DESIGN: We performed segmented regression analysis between different periods. Variations in antibiotic consumption during periods corresponding to the four-phase intervention program (from 1999 to the first six months of 2001) were assumed to be 'intervention-induced', while those observed during the crisis period were considered as 'situation-enforced'. RESULTS: Whereas the intervention-induced (desirable) decrease of total antibiotic and carbapenem consumption proved to correlate with a decreased crude mortality rate during the control period prior to the crisis (R2, 0.82 and 0.91, respectively), the crisis-induced (undesirable) decrease in total antibiotic and carbapenem consumption correlated with an increased mortality during this phase (R2, 0.80 and 0.75, respectively). CONCLUSIONS: Our results illustrate that a reduction in antibiotic consumption does not always represent a favorable outcome from an intervention program on prescribing practice. Moreover, it may be a sensitive indirect marker of a deficient healthcare condition leading to an increase in in-hospital mortality.

A hospitalwide intervention program to optimize the quality of antibiotic use: impact on prescribing practice, antibiotic consumption, cost savings, and bacterial resistance.

Several findings from Argentina provide compelling evidence of the need for more rational use of antimicrobial agents. Thus, a multidisciplinary antimicrobial treatment committee for the development of a hospital-wide intervention program was formed to optimize the quality of antibiotic use in hospitals. Four successive steps were developed during 6-month periods: baseline data collection, introduction of a prescription form, education, and prescribing control. Sustained reduction of drug consumption was shown during the study (R2=0.6885; P=.01). Total cost savings was 913,236 US dollars. To estimate the consumption of cefepime and aminopenicillin-sulbactam in relation to that of the third-generation cephalosporins, 2 indices were calculated: Icfp and Iams, respectively. Decreasing resistance to ceftriaxone by Proteus mirabilis and Enterobacter cloacae proved to be associated with increasing Icfp. Decreasing rates of methicillin-resistant Staphylococcus aureus were related to increasing Iams. The present study indicates that a systematic program performed by a multidisciplinary team is a cost-effective strategy for optimizing antibiotic prescribing.

Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4.

Histone deacetylase 4 (HDAC4) regulates numerous gene expression programs through its signal-dependent repression of myocyte enhancer factor 2 (MEF2) and serum response factor (SRF) transcription factors. In cardiomyocytes, calcium/calmodulin-dependent protein kinase II (CaMKII) signaling promotes hypertrophy and pathological remodeling, at least in part by phosphorylating HDAC4, with consequent stimulation of MEF2 activity. In this paper, we describe a novel mechanism whereby protein kinase A (PKA) overcomes CaMKII-mediated activation of MEF2 by regulated proteolysis of HDAC4. PKA induces the generation of an N-terminal HDAC4 cleavage product (HDAC4-NT). HDAC4-NT selectively inhibits activity of MEF2 but not SRF, thereby antagonizing the prohypertrophic actions of CaMKII signaling without affecting cardiomyocyte survival. Thus, HDAC4 functions as a molecular nexus for the antagonistic actions of the CaMKII and PKA pathways. These findings have implications for understanding the molecular basis of cardioprotection and other cellular processes in which CaMKII and PKA exert opposing effects.

Replacement of broad-spectrum cephalosporins by piperacillin-tazobactam: impact on sustained high rates of bacterial resistance.

We have previously observed a significant reduction of ceftriaxone resistance in Proteus mirabilis associated with an increase in the use of cefepime, along with a decrease in the consumption of broad-spectrum cephalosporins (CEP). However, we did not observe such a reduction with Klebsiella pneumoniae. Therefore, we sought to determine whether replacement of CEP by piperacillin-tazobactam might be useful in reducing sustained high rates of CEP resistance by this organism. We used a 6-month "before and after model"; during the second (intervention) period, most prescriptions of CEP were changed to piperacillin-tazobactam at the pharmacy. No additional barrier precautions were undertaken. During intervention, consumption of ceftazidime decreased from 17.73 to 1.14 defined daily doses (DDD) per 1,000 patient-days (P < 0.0001), whereas that of piperacillin-tazobactam increased from 0 to 30.57 DDD per 1,000 patient-days (P < 0.0001). The levels of resistance to CEP by K. pneumoniae and P. mirabilis decreased from 68.4 and 57.9% to 37.5 and 29.4%, respectively (P < 0.05). We conclude that replacement of ceftazidime by piperacillin-tazobactam might be a suitable strategy to decrease endemic CEP resistance by K. pneumoniae and P. mirabilis, even where there are high bacterial resistance rates and irrespective of any additional precautions for controlling nosocomial infection.