Pseudomonas aeruginosa and some of the species of Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae are the leading causes of hospital-acquired infections that are mostly difficult to treat, because these species acquired different ways to resist to antibacterial agents [1,2]. The Centers for Disease Control and Prevention defines multidrug-resistant (MDR) Gram-negative bacilli as those organisms that are resistant to three or more classes of antimicrobials. The classes of antimicrobials are β-lactams, carbapenems, aminoglycosides, and fluoroquinolones . Carbapenem antibiotics such as imipenem and meropenem are intensive drugs for the treatment of infections caused by MDR Enterobacteriaceae, Acinetobacter baumannii, and P. aeruginosa [4,5]. Resistance to carbapenem drugs can depend on the continued expression of chromosomal AmpC β-lactamase enzymes or the expression of efflux pumps . Low-level carbapenem resistance can also depend on the overexpression of efflux pumps such as the OprD porin . Also, high-level resistance can arise via the production of metallo-β-lactamase enzymes such as IMP (Imipenem-type carbapenemases), VIM (Verona integron-encoded metallo-β-lactamase), and SPM (Sao Paulo metallo-β-lactamases). This review will describe MDR and carbapenemase-producing Enterobacteriaceae and P. aeruginosa and suggest some available antibiotics to be administered in the treatment of infections by these organisms.
Carbapenem drugs are a group of parenteral bactericidal β-lactam antibiotics. These antibiotics have an extremely broad spectrum. Carbapenem antibiotics were originally derived from thienamycin, a potent antibiotic that was discovered in Streptomyces cattleya in 1976 . These drugs are active against Haemophilus influenzae , most Enterobacteriaceae families that produce AmpC β-lactamase, and extended-spectrum β-lactamase (ESBL) enzymes [7,8], anaerobes [8,9], methicillin-sensitive staphylococci [8,10], and streptococci . Members of this group of drugs are imipenem, meropenem, doripenem, ertapenem, panipenem, biapenem, and lenapenem. Older carbapenems such as imipenem were often susceptible to degradation by the enzyme dehydropeptidase-1 (DHP-1), located in the renal tubules, and required co-administration with a DHP-1 inhibitor such as cilastatin [11,12]. Later additions to the class such as meropenem, ertapenem, and doripenem demonstrated increased stability to DHP-1 and are administered without a DHP-1 inhibitor [7,12]. The major character of novel carbapenems is erthapenem (MK-826), which has a prolonged half-life of 4.5 h and is developed as a single-daily-dose carbapenem . Some carbapenem drugs such as L-084  and CS-834  that can be taken orally have been developed [11,12]. Some of the carbapenems have to be administered as co-drugs such as a combination of imipenem and panipenem or imipenem and cilastatin to prevent degradation by renal dehydropeptidase and reduce nephrotoxicity .
Mechanisms of carbapenem resistance
Carbapenem resistance mechanisms are divided into four groups: the modification of penicillin-binding proteins (PBPs) , porins and efflux systems, carbapenem-hydrolyzing oxacillinase enzymes [16,17], and metallo-β-lactamase enzymes [16,17]. The OprD porin confers resistance to meropenem and imipenem . Overexpression of the MexAB-OprM efflux pump or expression of MexEF-OprN induces carbapenem resistance by pumping carbapenem out and repressing the transcription of OprD, respectively. NfxB gene mutants expressed MexCE-OprJ porin, which became mildly resistant to some β-lactams, imipenem, and biapenem . Chromosomal AmpC β-lactamase enzymes play a role in carbapenem resistance in P. aeruginosa and some members of the Enterobacteriaceae family [3,18,19]. The classification of carbapenemase enzymes is shown in Table 1 .
Studies showed that carbapenem drugs can be used for the treatment of a variety of infections including skin and skin structure infections, complicated intra-abdominal infections, community-acquired pneumonia, nosocomial pneumonia, meningitis, complicated urinary tract infections, and febrile neutropenia [3,8,16,21]. Carbapenem-resistant Enterobacteriaceae (CRE) infections have been associated with the use of medical devices such as urinary catheters, ventilators, and intravenous catheters, and through wounds caused by injury or surgery. CRE infections are very difficult to treat, because these bacteria have become resistant to antibiotics [3,21].
Carbapenem-resistant Gram-negative bacteria have been divided into two groups: Enterobacteriaceae family such as Citrobacter freundii, E. coli, Enterobacter aerogenes, Enterobacter cloacae, Entrobacer gergoviae, K. pneumoniae, Klebsiella oxytoca, Proteus mirabils, Salmonella enterica, and Serratia marcescens; and Pseudomonadaceae family such as P. aeruginosa, Pseudomonas putida, and Acinetobacter spp.
Carbapenem-resistance detection methods
The modified Hodge test (MHT) is widely used in clinical laboratories currently. MHT has a lower sensitivity to other carbapenemases such as New Delhi metallo-β-lactamase, but it has demonstrated a good sensitivity for KPC. In addition, MHT is not specific for carbapenemase production among some genera of Enterobacteriaceae (e.g., Enterobacter) . Several other methods have been developed for detecting carbapenemase enzymes, including the Carba NP test and PCR, but these are not widely used in clinical laboratories now . Thus, a definition that differentiates carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) from non-CP-CRE based on the pattern of susceptibility of the organism to antimicrobial drugs (phenotypic definition) would have utility for surveillance and prevention [3,21].
Carbapenem-resistant Pseudomonas spp. isolated treatment
Based on carbapenem susceptibility patterns in studies, the clinical isolates of carbapenem-resistant P. aeruginosa were classified into three groups of imipenem-sensitive and meropenem-resistant, imipenem-resistant and meropenem-sensitive, and imipenem-resistant and meropenem-resistant . Doripenem is a promising new carbapenem with similar properties to those of meropenem, although it appears to have a more potent in-vitro activity against P. aeruginosa than meropenem . Compared with imipenem, meropenem, and doripenem, the spectrum of activity of ertapenem is more limited, primarily because it lacks activity against P. aeruginosa and Enterococcus spp. . In recent years, the treatment of infections caused by P. aeruginosa has become a challenging task for clinicians. Delayed therapy in MDR P. aeruginosa infections correlates with increased mortality, even when a patient is considered clinically stable at the time of initial evaluation . Because the treatment of serious MDR P. aeruginosa infections is frequently empirical until the P. aeruginosa is isolated and susceptibility testing is performed, high resistance rates raise the probability of offering an inappropriate initial therapy. The patient's condition should be re-evaluated on a regular basis with appropriate measurements  to decide whether antibiotics should be continued. Antibiotics which are recommended in these conditions include antipseudomonal piperacillin (piperacillin should be dosed at 4 g IV every 4 h and Ticarcillin at 3 g IV every 4 h; piperacillin–tazobactam should be dosed at 4 g of piperacillin and 0.5 g of tazobactam IV every 6 h, or 3 g of piperacillin and 0.375 g of tazobactam IV every 4 h; ticarcillin-clavulanate should be dosed at 3 g of ticarcillin and 0.1 g of clavulanic acid IV every 4 h; cefepime should be dosed at 2 g IV every 8 h and ceftazidime at 2 g IV every 8 h; and finally, aztreonam should be dosed at 2 g IV every 8 h. P. aeruginosa isolates that produce metallo-β-lactamases may be susceptible to aztreonam, demonstrating resistance to hydrolysis by class B β-lactamases. Imipenem should be dosed at 500 mg IV every 6 h up to 1 g every 8 h for serious infections; meropenem should be dosed at 1 g IV every 8 h; and doripenem should be dosed at 500 mg IV every 8 h. Various carbapenems have different levels of activity against P. aeruginosa isolates: ciprofloxacin should be dosed at 400 mg IV every 8 h or 750 mg orally every 12 h; levofloxacin should be dosed at 750 mg orally or IV daily; and colistin base should be dosed daily at 2.5 to 5.0 mg/kg intramuscularly or IV in two to four divided doses . They are mostly used in combination with other antipseudomonal agents such as aminoglycosides (amikacin at 5.0–7.5 mg/kg of ideal body weight IV every 8 h; and gentamicin and tobramycin at 1.0–2.5 mg/kg of ideal body weight IV every 8–12 h) and rifampin (at 600 mg orally or IV once daily, particularly in cases of P. aeruginosa bacteremia refractory to standard treatment). Carbapenem-resistant P. aeruginosa isolates are more likely to be resistant to other common antipseudomonal agents than carbapenem-susceptible isolates . It is concluded that treatment with carbapenem antibiotics, but not with other β-lactam antibiotics, is a major risk factor for the detection of carbapenem-resistant P. aeruginosa in hospitalized patients, and that P. aeruginosa may often be resistant to other antipseudomonal agents (Fig. 1). Mesaros et al.  suggested that the antibiotics which can be administered for the treatment of metalo-β-lactamase-producing P. aeruginosa are gentamicin, tobramycin, amikacin, ciprofloxacin, and colistin, and for treatment of oxacillinase-producing isolates are imipenem, meropenem, gentamicin, tobramycin, amikacin, ciprofloxacin, colistin, and cefepime. Lister and Wolter  suggested that imipenem and levofloxacin might hamper the emergence of resistance. Troillet et al. claimed that an aminoglycoside and various β-lactams did not alter the risk of selection for resistant P. aeruginosa isolates.  Another study recommended various combination therapies of antipseudomonal agents such as tobramycin–piperacillin–tazobactam, ceftazidime–tobramycine, and ciprofloxacin–tobramycin for carbapenemase-producing and MDR-P. aeruginosa; and imipenem–tobramycin, imipenem–ciprofloxacin, and imipenem–isepamycin only for MDR-P. aeruginosa . Other studies found combinations to provide enhanced activity against highly resistant P. aeruginosa. For instance, Bialvaei et al. suggested the use of either ceftazidime or cefepime with a flouroquinolone , Zuravleff et al.  suggested ticarcillin with tobramycin and rifampin, Perez Urena et al.  suggested rifampin with polymixin B, Saiman et al.  recommended tobramycin and clarithromycin, Gunderson et al.  recommended colistin and ceftazidime, and Timurkaynak et al.  suggested rifampin with colistin. There are also some antibiotics in phase 2 trials, such as sitofloxacin , KB001 , FR264205 , and ceftazidime/NXL104 . Sitofloxacin is a quinolone with a better activity than ciprofloxacin . These antibiotics are activated against gyrA or parC mutants . Feldman et al.  mentioned that sitofloxacin was considered as safe and tolerable as imipenem for the treatment of pneumonia. KB001 is a high-efficiency Fab fragment human antibody against PcrV antigen of P. aeruginosa that can bring about the effective clearance of pulmonary P. aeruginosa infection by reducing toxicity and pathogenicity . FR264205 is a novel 3′-aminopyrazolium cephalosporin . FR264205 is active against ceftazidime-resistant, imipenem-resistant, and ciprofloxacin-resistant P. aeruginosa. Based on Takeda et al. , FR264205 is considered an antibacterial agent for P. aeruginosa and the reduction in the susceptibility of these agents is lower by AmpC B-lactamases than ceftazidime . NXL104 is a β-lactamase inhibitor combined with ceftazidime . Mushtaq et al.  indicated that this combination restores the in-vitro activity of ceftazidime against B-lactamase-producing P. aeruginosa and A. baumannii strains such as Class A, C, and some Class D β-lactamase enzymes. In addition, there are some drugs in phase 1 trials such as BLI-489/piperacillin  and CB-182,804 . BLI-489 is a lipopeptide broad-spectrum B-lactamase inhibitor combined with piperacillin. It is a novel imidazole-substituted 6-methylidene-penem and is a novel polymyxin analog active against P. aeruginosa, A. baumannii, E. coli, and K. pneumoniae , developed by Cubist Pharmaceuticals (Massachusetts, USA).
Carbapenem-resistant Enterobacteriaceae isolated treatment
CRE can be intermediate or fully resistant to carbapenems [3,21]. However, as already described, carbapenem resistance among Enterobacteriaceae can be acquired through multiple mechanisms such as the production of carbapenemase enzymes, which is currently the most concerning resistance mechanism [3,21].
Resistance to broad-spectrum antimicrobials such as extended-spectrum cephalosporins, especially the third generation, is a well recognized problem among Enterobacteriaceae , leading to problems in treatment. Carbapenems are β-lactam antimicrobial agents with an exceptionally broad spectrum of activity . They have served as an important antimicrobial class for the treatment of these organisms . Nevertheless, the emergence of novel β-lactamases with a direct carbapenem-hydrolyzing activity has contributed to an increased prevalence of CRE. CREs are particularly problematic given the frequency with which Enterobacteriaceae cause infections , the high mortality associated with infections caused by CRE , and the potential for widespread transmission of carbapenem resistance via mobile genetic elements . Enterobacteriaceae are common causes of both healthcare and community infections, raising the possibility of the spread of CRE into the community. CRE bacteria have emerged because of the increased use of carbapenems and broader-spectrum antibiotics, which contributed to resistance due to the selection of increasingly resistant organisms. Organisms capable of producing carbapenemase and β-lactamase enzymes include K. pneumoniae, other Klebsiella species, Enterobacter species, E. coli, and Serratia species [3,21].
To treat infections caused by ESBL-producing Gram-negative organisms, it is suggested the use of meropenem at 1 g intravenously (IV) every 8 h or imipenem at 500 mg IV every 6 h and up to 1 g IV every 8 h in serious infections . For ESBL-producing K. pneumoniae bacteremia, carbapenem use is an independent predictor of a lower mortality rate compared with the use of other antibiotics that exhibit in-vitro activity . Ertapenem at 1 g/day may be used successfully for ESBL enzyme-associated bacteremia . When dosed at 500 mg IV every 8 h, doripenem, the newest addition to the carbapenem class, exhibits an activity against ESBL-producing pathogens that is similar to that of imipenem and meropenem . Moreover, β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam, with other β-lactam antibiotics such as amoxicillin and piperacillin, can be used against ESBL-producing organisms . Amoxicillin–clavulanate can be administered in the treatment of simple cystitis and Urinary tract infection (UTI) . Furthermore, piperacillin–tazobactam can be administered in the treatment of UTI  and other infections by ESBL-producing E. coli and K. pneumoniae. Nevertheless, Rodríguez-Baño et al.  concluded that piperacillin–tazobactam should be avoided in serious infections such as bacteremia. Studies by Zanetti et al.  indicated that the use of cephalosporins such as cephamycin and cefepime is associated with a worse result compared with the use of cabapenems.
Indimiani et al.  observed a suboptimal response to quinolones versus carbapenems in ESBL-producing bacteremia isolates with retained susceptibility to quinolones. Aminoglycosides, trimethoprim–sulfamethoxazole, and fluoroquinolones should be administered with caution in serious infections, even after the documentation of in-vitro activity . Clinical response should be closely monitored, and switching to carbapenems should be considered in patients who do not improve . Fosfomycin and colistin may be useful in treating ESBL-producing E. coli and K. pneumoniae isolated from UTI . In addition to this, fosfomycin can be administered to treat systematic infection in patients who have been admitted in general tertiary care hospitals . Fosfomycin may be administered in the treatment of uncomplicated urinary tract infections at a single oral dose of 3 g . As with ESBL-producing K. pneumoniae, carbapenemase-producing isolates are likely to exhibit simultaneous resistance to fluoroquinolones and aminoglycosides . Antibiotics which are recommended for the treatment of carbapenemase-resistant Enterobacteriaceae include tigecycline, colistin , fosfomycin , and rifampin  (Fig. 1). Other agents include new β-lactamase inhibitors with an activity against carbapenemases such as oxyimino-cephalosporin, NXL104 , MK-7655 , 6-alkylidenepenam sulfones , and several bisindole compounds , which are currently under development and whose mode of actions are currently unidentified.
Treatment options for infections caused by MDR and carbapenemase-producing pathogens are limited and complicated. Nevertheless, antipseudomonal drugs, colistin, or combined therapy have been suggested to be administered in the treatment of carbanemase-producing P. aeruginosa. Tigecycline, colistin, and fosfomycin have been recommended for administration in the treatment of CRE.
This review was supported by Drug Applied Research Center, Tabriz University of Medical Sciences.
Conflicts of interest
The authors declare no conflicts of interest.
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