In vitro Time-Kill Curves of Cefepime and Cef pirome Combined with Amikacin, Gentamicin or Ciprofloxacin against <i>Klebsiella pneumoniae</i> Producing Extended-Spectrum Beta-Lactamase

Abstract

Extended-spectrum β-lactamases (ESBLs) are found in numerous Enterobacteriaceae, mainly in Klebsiella pneumoniae. We investigated the pharmacodynamics of two new extended-spectrum cephalosporins, cefepime and cefpirome, alone and combined with either amikacin or gentamicin or ciprofloxacin by means of time-kill curves against ESBL-producing, amino-glycoside-resistant K. pneumoniae. When used alone, cefepime (8 and 16 mg/l) resulted in a 2 and 3 log decrease at 6 h, respectively, but at 24 h regrowth occurred. The combination of cefepime (8 mg/l) with amikacin (4 mg/l) resulted in a 4 log decrease at 6 h, but there were no surviving bacteria at 6 h when combined with amikacin (8 mg/l). The combination of cefepime (16 mg/l) with gentamicin (4 mg/l) resulted in a 4 log decrease in 24 h. The antimicrobial combiantion of cefepime (32 mg/l) with ciprofloxacin (2 mg/l) resulted in a 4 log decrease in 24 h. Cefpirome (8 mg/l) induced a 2 log decrease at 4 h; 32 mg/l cefpirome resulted in a 3 log decrease followed by regrowth at 24 h. The regrowth observed in the late phase with cefpirome alone disappeared when combined with aminoglycoside. When cefpirome (32 mg/l) was used in combination with ciprofloxacin (1 mg/l), it resulted in a 4 log decrease in 24 h.

Pharmacodynamics of Intermittent- and Continuous-Infusion Cefepime Alone and in Combination with Once-Daily Tobramycin against <i>Pseudomonas aeruginosa</i> in an in vitro Infection Model

“…This observation has previously been reported with P. aeruginosa under similar experimental conditions using cefepime, other ß-lactams and aminoglycosides [37][38][39][40]. For ß-lactam antibiotic therapy, this in vitro regrowth phenomenon has also been observed with other organisms [41] and has been attrib- Tessier/Nicolau/Onyeji/Nightingale uted to suboptimal treatment or release of adherent bacteria from the walls of the in vitro model chambers [42]. The same explanation can equally apply to the bacterial regrowth in the presence of aminoglycosides, but more specific underlying mechanisms have been postulated.…”

Low cefpirome levels during twice daily dosing in critically ill septic patients: pharmacokinetic modelling calls for more frequent dosing

“…It should be noted that there is experimental work suggesting that combination therapy (such as a b-lactam plus an aminoglycoside) provides better kill-characteristics than a single agent [37,38]. Although this is difficult to clinically validate a case could be made to use such combination therapy for difficult-to-treat infections caused by Pseudomonas sp.…”

Extended-Spectrum β-Lactamases: a Clinical Update

“…Cefepime should not be used as first-line therapy against ESBL-producing organisms; if it is used (for example, against organisms with a cefepime MIC of Ͻ2 g/ ml), it should be used in high dosage (at least 2 g twice a day). In vitro synergy may be achievable between cefepime and amikacin (123,287).…”

“…Addition of ciprofloxacin to imipenem and to the combination of cefotaxime and sulbactam has been found to be synergistic (14). The antimicrobial combinations of ciprofloxacin plus either cefpirome or cefepime resulted in a 4 log decrease in ESBL-producing Klebsiella pneumoniae (123). There are no publications on the clinical use of these combinations.…”