Synergistic activity and mechanism of action of ceftazidime and apigenin combination against ceftazidime-resistant Enterobacter cloacae
Graphical abstract
Introduction
Enterobacter cloacae are significant causes of nosocomial infections. It is emphasized that E. cloacae are mainly responsible for pneumonia, wound infection and urinary tract infection in the most hospital. The three specimen types of sputum, secretions and pus, urine in the past 8 years in the First Bethune Hospital investigation showed that the antimicrobial resistance of E cloacae had increased. E. cloacae are intrinsically resistant to aminopenicillins, cefazolin, and cefoxitin due to the production of ampC β-lactamases (Anggakusuma et al. 2009). Similarly, the resistance to antimicrobial agents in Enterobacteriaceae has become an increasingly relevant problem. International travel and tourism are important modes for the acquisition and spread of antimicrobial-resistant Enterobacteriaceae (Rukayadi et al. 2010). In addition, the E. cloacae from blood of inpatients at an urban public hospital in Berkeley was found that it carried globally-dispersed drug-resistance genes (Yanti et al. 2009b). Furthermore, the SHV-12 β-lactamase of clinical isolates of E. cloacae with reduced susceptibility to ceftazidime and cefepime recovered from 2009 to 2010 at the university hospital of Mahdia, Tunisia, was analyzed by PCR analysis (Yoon et al. 2005). Likewise, the prevalence of infection by plasmid mediated ampC (pampC), which can hydrolyze penicillins, oxyimino-, 7-α-methoxycephalosporins and monobactams, varies depending on the type of enzyme and geographical location and blaCMY-2 is the most frequently detected worldwide. Typically, pampC producing isolates are associated with resistance to multiple antibiotics making the selection of an effective antibiotic difficult (Rukayadi et al. 2009). For these reasons, antibiotics available for the treatment of multi-drugs resistant E. cloacae infection are fairly toxic and their use is frequently associated with unwanted side-effects. Imipenem/cilastatin, often reserved for more serious hospital-acquired infections, is thought to be associated with a higher risk of seizures than other penicillins and carbapenems (Yanti et al. 2009a). Therefore, novel flavonoids or new generation of phytopharmaceuticals approaches that show synergistic effect with antibacterial agents, which have lost their original effectiveness, or enable their use to treat diseases instead of synthetic drugs alone are research objectives of far reaching importance (Eumkeb et al., 2010, Wagner and Ulrich-Merzenich, 2009). In this study, we have investigated the in vitro activity of naturally occurring plant flavone (4′, 5, 7,-trihydroxyflavone), apigenin, which is abundantly present in common fruits such as grapefruit, plant-derived beverages and vegetables such as parsley, onions, oranges, tea, chamomile, wheat sprouts and in some seasonings, against ceftazidime-resistant E. cloacae (CREC) when used alone and in combination with ceftazidime. Chamomile is one of the most common sources of apigenin consumed as single ingredient herbal tea, prepared from the dried flowers from Matricaria chamomilla. Apigenin has been shown to possess remarkable anti-inflammatory, antioxidant and anti-carcinogenic properties (McKay and Blumberg, 2006, Patel et al., 2007, Shukla and Gupta, 2010). The activity of quercetin and naringenin when used alone and in combination with ceftazidime were also investigated (see also Fig. 1).
Section snippets
Materials and methods
Apigenin, β-lactam antibiotics, chemicals and bacterial strains sources (see also Fig. 1).
The tested flavonoids (apigenin, quercetin and naringenin) were obtained from Indofine Chemical Company (New Jersy, USA). Cefepime, ceftazidime, imipenem, clavulanic acid, polymyxin B sulphate (PMX) and o-nitrophenyl-β-d-galactoside (ONPG) were obtained from Sigma (Sigma–Aldrich UK). Flomoxef was obtained from Shionogi (Osaka, Japan). Nitrocefin (NCF) and Mueller–Hinton broth were obtained from Oxoid
Screening test of ESBL phenotype and ampC genes detection
Ceftazidime resistant E. cloacae DMST strains (21394, 21549 and 19719) were positive in the screening test for ESBL. Resistance genes were detected of these isolates: ampC gene of EBC type and ESBL gene of TEM type. The resistance mechanisms were caused by ESBL–ampC combinations of these strains. These findings are in substantial agreement with those of Kao et al. (2010) that the resistance genes, ampC gene of EBC type and ESBL gene of TEM type were found in multiple drug resistance E. cloacae
Acknowledgements
The authors are indebted grateful to the following persons and institutions for their invaluable assistance in carrying out this study: Miss Supatcharee Siriwong and Mr. Yothin Teethaisong for kind to assist me in laboratory. The Thailand Research Fund for grant support, and National Research Council of Thailand for research fund.
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