In general and for serious life threatening infections, the carbapenems are the drugs of choice for infections caused by these organisms [ 12 , 35 ]. However, the surge in using the carbapenems, resulted in the evolution of CRE/CRP, so there were multiple recent trials evaluating, carbapenem-sparing are regimens, mostly for less severe infections [ 12 , 45 , 46 , 47 , 48 ].
In general, there is no clear consensus on managing these organisms. The available data are drawn from expert opinion or from small trials. There are few controlled trials that determined the best therapeutic so far [49, 50].
In the following sections, we will review the available data on different classes of antibiotics that have been used in managing ESBL, and then if applicable, will discuss their roles in treating CRE/CRP.
They have a broad spectrum of antimicrobial activity more than any other classes of antimicrobials, and are potent bactericidal (ertapenem lakes anti-pseudomonas activities) [51, 52, 53, 54].
In multiple non-randomized studies that included large number of patients with bacteremia, sepsis, and other serious infections, they showed high cure-improvement rates with great safety profile [54, 55].
Studies of the pharmacokinetic/pharmacodynamics data also showed superiority of this class of antibiotic in achieving the proper concentration above the bacterial minimal inhibitory concentrations (MICs) .
In vitro activities against many ESBL isolates are well documented against large collections of ESBL producing Enterobacteriaceaeand P. aeruginosaisolates .
For treating CRE/CRP, limited data on combination regimens involving carbapenems (if MICs ≥ 8 mg/L) adding colistin or high-dose tigecycline or aminoglycoside or even triple combinations, seem to confer decent therapeutic advantage over monotherapy. For organisms with higher MIC, a combination of two or even three antibiotics may be needed.
In a recent meta-analysis of 22 studies of using, the most common regimen, carbapenems plus colistin or polymyxin had mortality advantages .
On the other hand, a retrospective study of 436 patients were recruited in the INCREMENT study-cohort (26 tertiary hospitals from 10 countries). The main outcome variable was 30 day all-cause mortality in patients with CRE/CRP bloodstream infection. Overall mortality was not different between those receiving combination therapy and monotherapy (35% vs. 41%) .
Synergy is another potential benefit arising from the use of antibiotic combinations.
Tigecycline with colistin, colistin with a carbapenem, fosfomycin with a carbapenem, fosfomycin with an aminoglycoside, and a carbapenem with an aminoglycoside have been reported as antibiotic combinations effectively administered to series of patients infected with carbapenemase-producing Enterobacteriaceae.
Efforts have been exerted to limit the usage of their precious agents by using alternative regimens whenever .
188.8.131.52. Piperacillin-tazobactam (PTZ)
PTZ is a broad-spectrum drug combination used in serious infections. However, the extensive usage of this agent accelerated the emergence of resistance [48, 59].
Some ESBL E. coliproducers’ isolates might have high in vitro susceptibility to PTZ; however, its clinical utility in serious UTIs, especially when associated with bacteremia, has been controversial. In a prospective, randomized, open-label comparison of the therapeutic efficacy of (PTZ), cefepime, and ertapenem in nosocomial UTIs with ESBL producers, 66 participants were evenly randomized to the PTZ and ertapenem treatment groups (cefepime arm was eliminated because of high treatment failure rate). The clinical and microbiological responses to both antibiotics were similar around 94% .
Similar non-inferiority of PTZ to carbapenems was shown in a retrospective analysis of bloodstream infection by an ESBL-producing organism, if susceptible in vitro .
In a post hoc analysis of patients with bloodstream infections due to ESBL producing isolates from 6 published prospective cohorts, the effect of amoxicillin-clavulanic acid, PTZ, and carbapenems were compared. The mortality rates at day 30 were much higher with the first 2 antibiotics than with carbapenems .
In a retrospective observational study, 331 patients with ESBL bacteremias were evaluated. Empiric therapy with PTZ was used in 48% while 52% received carbapenems. The adjusted risk of death (14-day mortality) was 1.92 times higher for patients receiving empiric PTZ compared with carbapenem therapy (95% confidence interval, 1.07–3.45) .
In an editorial that tried to explain these controversial results, the authors mentioned various variables including the inoculum of the bacteria in the bloodstream, the sources of bacteremia (less fatal if from UTIs than central line infections), selection bias inherent to observational studies, and the presence of different genetic and virulence of the included bacteria .
A large recent multicenter randomized controlled open-label non-inferiority trial, MERINO trial, comparing meropenem (standard arm) against PTZ in adult patients with bacteremia caused by E. colior Klebsiellaspp., is ongoing, and hopefully, it will provide better answer to these conflicting data .
Cephalosporins have been less effective than comparative regimens in treating severe/serious infections with ESBL-producing bacteria. They are rapidly hydrolyzed by many ESBLs stains .
In many clinical studies, it was associated with a trend toward clinical and microbiological failure, as well as a trend of increased mortality [64, 65].
Despite their in vitro activities, there are reports of mutations and/or acquiring plasmids encoding AmpC-resistant genes during therapy with these agents. Others concerns about this agent failure include the decreased activity with high bacterial load (inoculum effect) and the failure to meet necessary pharmacodynamics targets due to inadequate dosing and/or interval schedules .
The most studied agent in this class is the cefepime. In the above-mentioned recent prospective, randomized, open-label that compared (PTZ), cefepime, and ertapenem in nosocomial UTIs, the microbiological and therapeutic efficacies of cefepime in febrile nosocomial urinary tract infection with ESBL E. coliwere much less than the other competitors at 33% .
Data is more clear in patients with serious infections associated with ESBL-producing organisms’ bloodstream infections. In a recent study, the mortality risk was 2.87 times higher for patients receiving cefepime compared with carbapenems (95% confidence interval (0.88–9.41) .
Another retrospective study included adult patients with BSI due to ESBL-producing K. pneumoniaeor E. coli. In multivariate analysis, using cefepime as empirical therapy was associated with a trend toward an increased mortality risk, while empirical carbapenem therapy was associated with a trend toward decreased mortality .
There is few data from limited studies (with small number of participants) that showed cefepime is effective if used against in vitro susceptible ESBL-producing Enterobacteriaceaeand as a de-escalation therapy in patients with uncomplicated UTIs [53, 67].
There are less robust data for the efficacy of other cephalosporins, cefmetazole (a cephamycins), in treating patients with extended-spectrum β-lactamase producing .
Aminoglycosides are very potent antibiotics; however, their use is associated with significant renal and auditory toxicities. They have been successful in treating ESBL-UTIs as a monotherapy or in combinations with other agents. Combinations with other agents were effective in the treatment of CRE/CRP infections if the strain is susceptible to aminoglycosides .
Many of the plasmids that carry ESBL-producing genes also carry genes encodes resistant to aminoglycosides, mostly against tobramycin and gentamicin. In contrast, amikacin has retained high susceptibility rates, particularly against E. coli.
In a small study of UTI caused by highly resistant ESBL (also resistant to nitrofurantoin, fosfomycin, and quinolones and trimethoprim/sulfamethoxazole), amikacin intramuscular injections for 10 days achieved clinical success in 97.2%. Overall bacteriological success rate was 94.1% on the 7–10 days after treatment .
In a review of 20 studies evaluating CRE infections therapy, combination of aminoglycosides and carbapenems displayed the lowest mortality rate (11.1%) .
In many parts of the world, E. colifluoroquinolone resistance rates are >20% among patients with community-acquired uncomplicated UTI and 50% among patients with complicated infections. The rate of resistance is even higher against Klebsiellaspp. up to 70% in one recent international surveillance study [8, 72].
The co-existing of ESBL and fluoroquinolone resistant is extremely high in some areas of the world, in those who uses quinolones prophylaxis and in returned travelers to theses endemic areas . Therefore, they are in general not recommended in the setting of high ESBL isolates .
Sitafloxacin is the newest member (fourth generation) of the fluoroquinolone family of antibiotics which has a broad-spectrum activity including many anaerobes . In a recent prospective randomized controlled trial, comparing the clinical and bacteriological efficacy of sitafloxacin and ertapenem for non-bacteremic acute pyelonephritis caused by ESBL-EC was evaluated. Carbapenems were initially given to all patients, and then were randomized to one of the study drugs. The 2 arms were equal in the rates of clinical and microbiological cure .
These data suggest that fluoroquinolones may no longer be effective as first-line therapy for Gram-negative UTI in hospitalized patients and definitely in ESBL-producing organisms.
Although treatment with trimethoprim/sulfamethoxazole was traditionally effective in treating UTIS, the evolution of resistance is a current major concern. The Infectious Diseases Society of America guideline recommends against using it if local bacterial resistance rate is ≥20% . Genes that encode for ESBLs are usually found on large plasmids accompanied by genetic determinants of resistance against multiple classes of antibiotics, such as aminoglycosides, sulfonamides, and fluoroquinolones. TMP-SMX is not recommended as an empiric treatment option of UTIs caused by resistant strains of E. colior K. pneumoniaethat reaches 40–66% in some areas in the world .
Tigecycline has potent activity against a vast majority of organisms including Gram-negatives, Gram-positives, and anaerobes. It has almost susceptibility rates of 100% against ESBL-producing E. coli, however less potency against K. pneumoniaeisolates producing. However, its use has concerning safety issues [11, 79]. Insufficient urinary excretion of the unchanged drug (15–22% of the dose) has prompted recommendations to avoid tigecycline for UTIs therapy [80, 81].
In a systematic review of the literature, 14 patients received tigecycline for UTIs caused by MDR Gram-negative bacilli. In 12 patients, there were initial microbiological clearance. Eleven patients had evidence of clinical response. However, there were post-therapy growth of tigecycline-resistant organisms in 2 cases .
Few studies tried to overcome this obstacle by using higher than the recommended dose for highly resistant organisms (initial dose of 200 mg one time followed by 100 mg every 24 h) .
The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for bloodstream or urinary tract infections .
This agent has no activity against Pseudomonas, Proteus, Providencia, and Morganella.
184.108.40.206. The polymyxins
The polymyxins are antibacterial agents that are produced from different strains of Bacillus polymyxa. Colistin and polymyxin B are available commercially; both have similar chemical structures and antibacterial activity in vitro, however they differ in their pharmacokinetic profiles. They can cause significant nephrotoxicity (reported in 20–60%) and neurotoxicity . However, the spreading of extensively resistant Gram-negative bacteria as well as the paucity of newer effective antimicrobials let to the extensive usage of these agents as a last resort . The vast majority of ESBL-producing E. coliand K. pneumoniaeare susceptible to these drugs.
Currently, they are the backbone of most of the regimens used against the CRE/CRP organisms. Common combination regimens include tigecycline, carbapenem, minocycline, rifampicin, aminoglycosides, ampicillin/sulbactam, and piperacillin-tazobactam. Large clinical trials are underway to clarify the use of polymyxin different combinations .
Polymyxin B is administered directly as the active antibiotic, whereas colistin methanesulfonate is converted in vivo to colistin. The optimal dosing of these agents is still controversial.
Higher doses of colistin were proposed for managing serious CRE/CRP associated infections.
A recent systematic review that included 22 studies (observational studies as well as randomized controlled trials) of polymyxin-based combination therapy in adult patients with infections caused by CRE/CRP was published. The primary outcome was a 30-day mortality. Mortality was significantly higher with polymyxin monotherapy compared with combination therapy of polymyxin with tigecycline, aminoglycosides or fosfomycin, of 1.57 (95% CI = 1.06−2.32). However, the authors caution about the low quality of the evidence .
The mechanism of colistin resistance can be generally classified intrinsic or acquired by a recently recognized plasmid-mediated resistance gene .
In November 2015, plasmid-borne colistin resistance gene mcr-1 was initially identified in animal and clinical samples from China. As of September 2016, the mcr-1 gene was detected in 35 countries worldwide in human sources in 22 countries . This created a real lethal superbug.
220.127.116.11. Fosfomycin (Fosf)
This agent has gained attention, as it has activities against both Gram-positive and Gram-negative MDR and XDR bacteria [89, 90, 91, 92, 93, 94]. It exhibits bactericidal activity against many Gram-positive and Gram-negative pathogens including many of the ESBL-producing E. coliand K. pneumoniae. Fosf achieves very high concentrations within the urine and is therefore an excellent agent for cystitis, but it is not recommended for treating pyelonephritis or bacteremias due to inadequate concentrations in the blood. However, small studies have shown great results in using Fosf in complicated UTIs . It is currently approved by the American Food and Drug Administration for the treatment of uncomplicated cystitis as a one-time dose of 3 g. Several studies have shown clinical efficacy in the treatment of ESBL cystitis when the dosing is extended to 3 g every 48–72 h for 3 doses .
A meta-analysis that evaluated the antimicrobial activity, or the clinical effectiveness of Fosf, reviewed 17 studies. Out of a total of 5057 clinical isolates of Enterobacteriaceae, 4448 were ESBL producers. Almost 90% of the isolates were susceptible to Fosf. Eighty percent of 748 K. pneumoniaeisolates produced ESBL and were susceptible to Fosf .
In a prospective study of 47 patients with UTI caused by E. coli-ESBL-producing organisms, the outcome was evaluated. Fosfomycin was used in 27 patients and 20 patients received meropenem. The clinical and microbiological success was similar in 2 groups; however, the costs were significantly lower in the Fosf group (p < 0.001). Fosfomycin was used orally 3 g sachet every other night total of 3 doses, while meropenem was used as a dose for 14 days .
In a retrospective study, 60 patients were treated for MDR UTI. There were cases infected with Enterobacteriaceae, P. aeruginosa, and VRE. The clinical response rate was 55%. Chronic kidney disease was associated clinical failure (p = 0.04) .
For the carbapenem-producing organisms, a very few clinical data on using this agent are available.
In Europe, an intravenous Fosf formulation is available. In a small (in 11 ICU patients) European study, intravenous Fosf (2–4 g q6 h) in combination with other antibiotics was associated with good bacteriological and clinical outcomes in all patients with carbapenem-resistant K. pneumoniaeinfections .
In an in vitro study, 365 isolates out of 2229 urine samples were evaluated. ESBL producers were detected in 65% were, 16% were carbapenem-resistant Enterobacteriaceae, almost 95% of the total isolates were susceptible to Fosf .
A recent, albeit pessimistic, data came from China. A study collected 233 clinical isolates CRE/CRP Carbapenem ResistantEnterobacteriaceae/Carbapenem ResistantPseudomonasat four different hospitals. Forty-five percent of the strains (105/233) were resistant to Fosf. Plasmid-mediated fosfomycin-modifying enzymes fosA, fosA2, fosA3, and fosA5 genes were identified .
Another oral antimicrobial agent that can be considered for the treatment of ESB cystitis is nitrofurantoin. One study showed clinical cure rates of 69% in patients with ESBL cystitis in which all isolates were also resistant to SMX/TMP and ciprofloxacin .
Nitrofurantoin should only be used for lower UTI and should be avoided in patients with a creatinine clearance less than 60 (few studies accepted GFR more than 40) mL/min as reduced renal function results in decreased active drug within the urine . It is contraindicated in pregnancy.
In a larger in vitro study, against the GNBs, a total of 18,386 organisms including 13,224 Enterobacteriaceaeand 3536 Pseudomonaswere collected (2013–2014) as part of the SENTRY Antimicrobial Surveillance Program. Cefoperazone/sulbactam inhibited 94% of Enterobacteriaceae. There are limited clinical data on the usefulness of this agent against ESBL or CRE/CRP organisms in the urinary tract.
18.104.22.168. Ceftazidime-avibactam (Cef-Avb)
Ceftazidime, a third-generation cephalosporin, when combined with avibactam has potent activities against β-lactamase-producing Gram-negative pathogens including ESBL, AmpC β-lactamases, and CRE.Currently, Cef-Avb is approved for complicated UTIs (limited to patients without other treatment options in the empiric and documented treatment of MDROs).
In an in vitro study, it was tested against collection of international urinary isolates (1797 isolates were collected from 159 medical centers). All ESBL isolates as well as meropenem-non-susceptible E. coliand K. pneumoniaeisolates were susceptible to Cef-Avb .
In another study, 34,062 isolates of Enterobacteriaceaefrom patients (with mostly UTIs) were collected (International Network for Optimal Resistance Monitoring, surveillance from 39 countries). Overall, 99.5% of isolates were susceptible to Cef-Avb. It was also active (99.9%) against molecularly confirmed ESBL-producing, plasmid-mediated AmpC-producing (100%), and ESBL- and AmpC-producing (100%). It lacks activity against the metallo-β-lactamase producers (NDM-1 enzyme) .
The REPRISE, an international, randomized, open-label trial, recruited 333 patients from 16 countries worldwide. The study recruited patients mostly with complicated UTIs caused by ceftazidime-resistant Enterobacteriaceaeor P. aeruginosa. They were randomly assigned, 165 to Cef-Avb and 168 to best available therapy. The overall proportions of patients with a clinical cure were similar in the 2 arms .
In another clinical study, Cef-Avb was compared to imipenem-cilastatin in hospitalized adults with serious complicated UTI due to Gram-negative pathogens. Patients were allowed to switch to oral ciprofloxacin after at least 4 days on the study drug. Patients in the Cef-Avb group had a better microbiological response (70% vs. 71%) .
The RECAPTURE study recruited 033 patients, who were randomized in 2 arms, 393 received Cef-Avb and 417 received doripenem, with possible oral antibiotic switch (total duration was 10–14 days). Combined symptomatic resolution/microbiological were similar in the 2 arms (70.2% vs. 66.2%, respectively) .
In a recent study, the outcome of therapy with ceftazidime-avibactam (38 patients) was compared to the outcome of therapy with colistin (99 patients) with CRE infections. Most patients received additional anti-CRE agents as part of their treatment. All-cause hospital mortality at 30 days and after were 9% vs. 32%, respectively .
Salvage therapy: in a case series of 36 patients, mostly with life-threatening infections received Cef-Avb as a salvage therapy. The causative organisms were CRE (2 were CRP). In 65.8% of patients, other concurrent antibiotics were used. More than 70% of the patients experienced clinical and/or microbiological cure .
Resistance: in less than 2 years since its approval, resistant strains have been isolated. Cef-Avb-resistant K. pneumoniaeemerged in 3 patients after using Cef-Avb for 10–19 days .
22.214.171.124. Ceftolozane-tazobactam (Cef-Taz)
This agent was approved in 2015 for the treatment of complicated urinary tract infections (adults with limited or no other therapeutic options) . There are many in vitro studies that demonstrated activity against Gram-negative and Gram-positive microorganisms, including E. cloacae, E. coli, K. oxytoca, K. pneumoniae, Proteus mirabilis, P. aeruginosaas well as coverage of most ESBL-producing organisms and some anaerobes [110, 111].
Cef-Taz was tested in vitro against 3851 P. aeruginosaisolates collected from 32 U.S. hospitals. It was active against 97.0% of the isolates, which was better than 7 other broad spectra antibiotics. A total of 363 isolates were classified as extensively drug resistant; Cef-Taz was active against 76.9% of these isolates .
The ASPECT is a randomized, double-blind, double-dummy, non-inferiority trial over 25 countries. 1083 patients enrolled, of whom 82% had pyelonephritis. Patients were randomly assigned to receive Cef-Taz or intravenous high-dose levofloxacin for 7 days. Overall, the composite cure rates were higher in the Cef-Taz group than in the levofloxacin. In a subgroup analysis, clinical cure was seen in 90% compared with 73% in patients with ESBL-producing uropathogens .
Ceftaroline is a cephalosporin with broad-spectrum activity against Gram-positive and Gram-negative organisms. When Ceftaroline combined with avibactam, it gains activities against many ESBL-producing organisms in vitro. It was tested in one study against 272 ESBL Enterobacteriaceaestrains. All isolates were inhibited by ceftaroline-avibactam at ≤4 μg/mL; however, it exhibited limited activity against Acinetobacterspp. and P. aeruginosa.
There are no clinical studies that tested the activity of this agent on UTIs caused by any MDROs.
126.96.36.199. Ceftriaxone + sulbactam + disodium edetate (Elores)
It is a novel molecule, which combines β-lactam plus β-lactamase inhibitor. It has shown activities against many resistant Gram-negative bacterial infections. There is a limited data on its spectrum, usage (mostly in India), and its role in urinary tract infections in specific.
In one study, Elores activity was compared to other comparators (including carbapenems) in treating various infectious syndromes. There were 2500 patients enrolled in the study, in which 24% of the patients had UTIs (no specifics on severity or the causative organisms). The clinical cure/improvement was achieved in 98%. There was no clear description on the types or the incidence of resistant organisms in the study .