In our retrospective study, we evaluated the efficacy and relevance of the chosen empirical antibiotic therapy especially non-antipseudomonal 3GCs in the light of the microbiologically identified pathogens and their susceptibility result. To assess whether 3GCs were really justified, we focused on CAP with microbiological documentation, which required definitive beta-lactam therapy. These infections were separated into three groups according to whether 3GCs appeared unjustified (pathogen susceptible either to amoxicillin or amoxicillin/clavulanate), appropriate (pathogen cefotaxime susceptible and resistant to amoxicillin/clavulanate) or insufficient (pathogen resistant to both amoxicillin/clavulanate and non-antipseudomonal 3GCs and requiring a broader-spectrum beta-lactam).
In the present study, 3GCs were the second most frequent empirical antibiotic used for severe CAP after macrolides (53 and 70%, respectively). This is in agreement with French guidelines [5]. Streptococcus pneumoniae and Haemophilus influenzae remain, as previously observed [18–22], the most frequent bacterial species causing CAP. These two pathogens accounted for 60% cases of documented pneumonias. These pathogens are most often highly susceptible to narrow-spectrum β-lactams such as amoxicillin or amoxicillin/clavulanate [20], except for some H. influenzae isolates. In the present studies, 10 H influenzae strains (21%) were amoxicillin/clavulanate resistant, but all were susceptible to both cefotaxime and spiramycin.
The group of unjustified third-generation cephalosporin prescription is the most important with 66% (159) of patients with documented infection; in this group, treatment with amoxicillin or amoxicillin/clavulanate would have been sufficient. Appropriate 3GC’s prescription was observed in only 18% (43 patients) of our cohort. Finally, the group in which third-generation cephalosporin use appeared insufficient represents 16% (39) of patients, meaning that in these patients a beta-lactam with a broader spectrum than 3GCs would have been required.
These results suggest that the use of third-generation cephalosporins as an empiric beta-lactam for treatment of severe community-acquired pneumonia admitted to the ICU is a perfectly tailored antibiotic therapy in only one out of five patients. Most of the time, a narrower-spectrum beta-lactam might be preferred. The amoxicillin/clavulanate combination would be a satisfactory alternative to 3GCs against two-thirds of overall recovered pathogens. Moreover, non-antipseudomonal 3GC spectrum appears insufficient in one out of six patients with CAP requiring beta-lactam.
In a second part of the study, we sought to delineate patients for whom amoxicillin/beta-lactamase inhibitor would be insufficient and who would require a broader-spectrum beta-lactam. For that, we assessed the presence or absence of risk factors associated with colonization/infection with resistant strains previously reported [21]. We found that chronic lung disease, ongoing cancer, non-ambulatory status and previous antibiotic therapy were significantly associated with amoxicillin/clavulanate-resistant strains.
These amoxicillin/clavulanate-resistant isolates (mainly Pseudomonas aeruginosa, non-fermenting Gram-negative bacilli and several Enterobacteriaceae) were most of the time sensitive to amikacin (94%), suggesting that this antibiotic could be considered in patients with risk factors for infection with an amoxicillin/clavulanate non-susceptible pathogen.
Prior use of 3CGs has been identified as a risk factor for infections caused by ESBL-producing Enterobacteriaceae [8, 23, 24]. Recent experiments report a decrease in ESBLEs emergence following decrease in cephalosporins use [10]. These data support, when possible, a decrease in the use of 3CGs to control ESBL-producing Enterobacteriaceae spreading. According to our results, amoxicillin/clavulanate could be proposed as an alternative beta-lactam for severe CAP in patients without risk factors for amoxicillin/clavulanate resistance. This situation (absence of A/C resistance risk factor) is observed in 55% of patients.
Such a strategy could contribute to limit the 3GCs use and then probably the emergence of extended-spectrum beta-lactamases (ESBLs). It is important to note that conversely to French recommendations, amoxicillin/beta-lactamase inhibitor is proposed as a possible first-line empirical beta-lactam for ICU patients with CAP in North American [11] and British [25] guidelines. Reducing the use of third-generation cephalosporins for CAP is already suggested in the emergency department [26].
Among patients with risk factors for amoxicillin/clavulanate resistance, strains encountered are very similar to those observed in patients with healthcare-associated pneumonia, and even this is still debated, to strains identified in patients with ventilator-associated pneumonia and/or hospital-acquired pneumonia [16–27]. The latter patients should receive at least 3GCs for empirical treatment and antipseudomonal beta-lactam (piperacillin/tazobactam, cefepime, ceftazidime) or carbapenem associated with an aminoglycoside for the most severe patients. Amikacin appears in the present study more frequently efficient than gentamicin.
The present study has, however, several limitations. First, whereas some of the observed data are similar to previously published results, the present study is a single-centre retrospective study with a moderate size population. Thus, these results should be interpreted cautiously and confirmed in a larger population. Second, our approach relies on an extensive infectious workup including invasive procedures, which is a strategy not supported by current guidelines in non-immunocompromised patients. Nevertheless, owing to significant increase in antibiotic resistance and to the necessity of a relevant antimicrobial stewardship, an aggressive diagnostic approach dedicated to increase the rate of microbiological identification in order to use the antibiotic therapy with the narrowest spectrum seems mandatory.