|Year : 2015 | Volume
| Issue : 3 | Page : 105-114
Antibiotic regimens for treatment of infections due to multidrug-resistant Gram-negative pathogens: An evidence-based literature review
Mandana Izadpanah, Hossein Khalili
Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
|Date of Web Publication||6-Aug-2015|
Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran
Source of Support: Nil., Conflict of Interest: There are no conflicts of interest.
Evidences regarding the efficacy of different antibiotic regimens proposed for treatment of multidrug-resistant (MDR) Gram-negative pathogens have been reviewed. Available data in Scopus, Medline, EMBASE, the Cochrane central register of controlled trials, and Cochrane database of systematic reviews have been collected. Several antibiotic regimens are proposed for treatment of MDR Gram-negative infections (defined as nonsusceptibility to at least one agent in three or more antimicrobial categories). The most challenging issue is the treatment of carbapenem-resistant (CR) Gram-negative pathogens. A carbapenem plus either colistin or tigecycline was the most effective regimen for treatment of CR Gram-negative pathogens with low-level resistance (minimal inhibitory concentration [MIC] ≤ 8 mg/L). However, in high-level resistance (MIC > 8 mg/L), combination of colistin and tigecycline showed promising effect.
Keywords: Antibiotic; Gram-negative bacteria; infection; resistant
|How to cite this article:|
Izadpanah M, Khalili H. Antibiotic regimens for treatment of infections due to multidrug-resistant Gram-negative pathogens: An evidence-based literature review. J Res Pharm Pract 2015;4:105-14
|How to cite this URL:|
Izadpanah M, Khalili H. Antibiotic regimens for treatment of infections due to multidrug-resistant Gram-negative pathogens: An evidence-based literature review. J Res Pharm Pract [serial online] 2015 [cited 2021 Dec 7];4:105-14. Available from: https://www.jrpp.net/text.asp?2015/4/3/105/162360
| Introduction|| |
In the recent years, increasing infections and mortality due to antibiotic-resistant pathogens is a challenging topic. Although this concern exists for both Gram-positive and negative bacteria, because of emergence of the strains resistant to the common antibiotics and absence of new effective antibiotics makes Gram-negative (g−) bacteria on the top of this attention. Available antibiotics have lost their effectiveness in managing these infections. Invasive pathogens may acquire resistance genes which enable bacteria to produce enzymes like beta-lactamase and carbapenemase, express efflux systems, and modify the drug's target site and an alternative metabolic pathway.,
Multidrug-resistant (MDR) organisms including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci and certain Gram-negative bacilli like Pseudomonas aeruginosa (Pa), Acinetobacter baumannii (Ab) and Enterobacteriaceae (Eb) cause severe and lethal human infections especially in critically ill patients. The term, “ESKAPE,” has been proposed to express the majority of nosocomial infections due to resistant pathogens, including Enterococcus faecium, S. aureus, Klebsiella pneumonia (Kp), Ab, Pa, and Enterobacter species.
Up to the year 2000, most g-microorganisms were susceptible to carbapenems. Carbapenem-resistant (CR) pathogens became a major clinical challenge within 15–20 years after approval of the first carbapenem.,,,
Carbapenamases enzymes, which belong to Ambler class A, B or D beta-lactamases. Class A and D enzymes have a serine-based hydrolytic mechanism, including members of the SME, IMI, NMC, GES, and Klebsiella pneumonia carbapenemase (KPC) families, of these, the KPC carbapenemases, which found commonly on plasmids in Kp are the most prevalent, while class B enzymes are metallo-beta-lactamases that contain zinc in the active site. The class D carbapenemases consist of OXA-type beta-lactamases frequently detected in Ab. The metallo-beta-lactamases belong to the IMP, VIM, SPM, GIM, and SIM families and have been detected primarily in Pa; however, there are increasing numbers of reports worldwide of this group of beta-lactamases in the Eb.
Choosing the best agent for the treatment of infections caused by these pathogens is one of the most important challenges facing practitioners. Here, evidences regarding the efficacy of different antibiotics and combinations that proposed for treatment of the MDR g-organisms have been reviewed.
| Methods|| |
In this narrative review, available English language data in the following databases have been evaluated: Scopus, Medline, EMBASE, the Cochrane central register of controlled trials, and Cochrane database systematic reviews. The time frame of the review was 1990–2014.
The key words used as search terms were “Acinetobacter,” “Klebsiella,” “Pseudomonas,” “Enterobacter,” “Eb,” “Gram-negative infection,” “resistant”, “prevention,” “MDR,” “extended drug-resistant (XDR),” “pan drug-resistant (PDR),” “treatment,” and “antibiotic regimen.” Randomized clinical trials, prospective or retrospective human studies, case series, and case reports were considered. Non-English language articles (5), as well as in vitro and experimental studies (12) were excluded. Finally, 80 articles were recruited in this review.
| Results|| |
Multidrug resistant pathogens
Pseudomonas aeruginosa has likely been the first pathogen to exhibit MDR and XDR phenotypes. XDR is defined as nonsusceptibility to at least one agent in all but two or fewer antimicrobial categories. Ab has become one of the major players in the ongoing antibiotic resistance crisis. The challenge, in this case, is due to CR-Ab strains, which are usually resistant to all the available anti-Ab agents except polymyxins. Carbapenem-resistant Enterobacteriaceae (CRE, mostly contributed by Kp) represents the most recent and worrisome evolution of the antibiotic resistance crisis. Currently, there are at least four types of carbapenemases that are spreading among Eb worldwide, including the KPC and OXA-48 serine carbapenemases (of molecular class A and D, respectively) and the MBLs of the VIM and NDM types.,
Extended-spectrum beta-lactamase (ESBL), CR, MDR, XDR, and PDR pathogens are included in this category. The emergence of metallo-beta-lactamases VIM, IMP and NDM (molecular class B), OXA-48 and its derivatives (molecular class D), and KPCs molecular class A is rapidly causing several paradigm shifts in antibiotic therapy against the g-bacteria. ESBL-producing Eb has been increasingly implicated in healthcare-associated infections.
Klebsiella pneumonia carbapenemases are at first detected in the Kp, but later has also been detected in other Eb, including Escherichia More Details coli, Enterobacter species, Salmonella More Details enterica, Proteus mirabilis, and Citrobacter freundii. Intensive Care Unit (ICU) admission, prolonged broad-spectrum antibiotic therapy, surgery or invasive procedures and immunosuppression are the major risk factors for colonization and subsequent infection with CR-Kp. The fatality rate is highest among patients with blood stream infection (BSI). Inappropriate empirical therapy increased the probability of poor outcome, whereas combination therapy and control of the infection source are associated with improved patient survival.
Limited clinical trials evaluated the role of combination therapy for treatment of MDR Ab. Different combinations of rifampin (RIF), sulbactam, aminoglycosides, colistin methate sulfate (CMS), carbapenems, and other agents have been evaluated against MDR-Ab infections. However, a carbapenem (imipenem, meropenem, or doripenem) is the drug of choice for treating carbapenem-susceptible MDR-Ab infections.,
In the following sections, case series included the treatment of nosocomial infections caused by resistant pathogens, have been reviewed at first. After that, treatment options for treatment of MDR infections of specific organs including blood stream, respiratory tract, central nervous system (CNS), and urinary tract infections (UTIs) have been separately reviewed.
Case series of nosocomial infections
Sobieszczyk et al. reviewed CMS efficacy and safety in the treatment of MDR g-respiratory tract infections. 29 courses of CMS in combination with other antimicrobial agent in 25 critically ill patients were included. Concomitant antibiotics were imipenem or meropenem, amikacin, tobramycin, cefepime, a quinolone, sulbactam, and aztreonam. In this study, colistin in combination with another antimicrobial agent showed considerable efficacy and safety.
Kasiakou et al. assessed the safety and efficacy of CMS in the treatment of nosocomial infections. The most common infections were Pneumonia (33.3%), bacteremia (27.8%), UTIs (11.1%) and intra-abdominal infections (11.1%). Ab (51.9%), Pa (42.6%), and Kp (3.7%) strains were isolated pathogens. In-hospital mortality was 24% in this survey. The response was observed in 66.7% (36/54) of the episodes. The results showed that CMS was a relatively safe and effective intervention in for severe hospital-acquired infections due to MDR g-bacteria.
In Saballs et al. study, RIF plus imipenem was considered for patients with serious infections due to CR-Ab that were only susceptible to colistin. RIF/imipenem was not an appropriate combination for CR-Ab infections. However, the evaluating efficacy of RIF in combination with other antibiotics should be considered in future studies.
Epidemiology and outcome of XDR-Ab bacteremia have been evaluated by Tseng et al. Antibiotic therapy was evaluated in three different regimens; sulbactam, a carbapenem (imipenem or meropenem) and a carbapenem (imipenem or meropenem) plus an aminoglycoside. Clinical outcomes of the patients were not different between the antibiotics' regimens. However, the severity of the illness at the onset of bacteria and the presence of immunosuppression were the only two significant predictors of 30-day mortality.
Oliveira et al. evaluated the efficacy and safety of CMS and ampicillin-sulbactam in treating infections caused by CR-Ab. During the study period, 283 infectious episodes caused by CR-Ab were included. 82 and 85 patients received polymyxins and ampicillin-sulbactam, respectively. Remaining episodes were treated with other antibiotic regimens. Treatment with CMS, higher Acute Physiological and Chronic Health Evaluation II (APACHE II) score, septic shock, delay in starting treatment, and renal failure were defined predictors of mortality. On multivariate analysis, prognostic factors for in-hospital mortality were older age, septic shock, and higher APACHE II score. In this study, sulbactam was more effective than CMS.
Efficacy and safety of fosfomycin have been evaluated in critically ill patients with CR-Kp infections. Fosfomycin plus either CMS (n = 6), gentamicin (n = 3) and piperacillin-tazobactam (n = 1) were the combinations used. All-cause ICU mortality was 18.2%. Fosfomycin in combination with other antibiotics showed promising effect in treating infections caused by CR-Kp in the adult critically ill patients.
Efficacy of CMS (3 million IU 3 times a day) and tobramycin (5–6 mg/kg daily) in managing of Ab-induced nosocomial infections in critically ill patients have been compared in a retrospective cohort study by Gounden et al. No significant differences in the ICU survival, time to the microbiological response and kidney injury have been detected in the tobramycin and CMS groups.
During a 2-year observational case series of 21 patients infected by PDR g-bacteria, the clinical outcome of CMS containing regimen (47.6%) was compared with the tigecycline-based regimen (33.3%). Treatment response was higher, and duration of hospitalization was shorter in the patients treated with tigecycline compared to the CMS group.
In BSI and Ventilator-associated Pneumonia (VAP) due to Ab, Pa, and Kp which were only susceptible to CMS, a 9 MIU loading dose and 9 MIU as a daily dose (in two divided doses) showed acceptable efficacy and relatively low kidney injury. Also in a brief report of an observational study in 22 poly-trauma critically ill patients, tigecycline combined with CMS or gentamicin was effective for the treatment of CR-Kp infections.
Kontopidou et al. included 107 patients with 127 infectious episodes, including central venous catheter bacteremia and VAP in a multicenter study. A high failure rate was detected among patients received tigecycline, especially as monotherapy. However, tigecycline is an option for treating severe infections due to CP-Kp.,
Blood stream infection
Kuo et al. reported the efficacy of different antimicrobial regimens for BSIs due to Ab. The results showed a combination of a carbapenem and ampicillin-sulbactam showed better outcome compared with a carbapenem plus amikacin, or a carbapenem alone.,
Treatment regimens in 47 patients with Ab-BSIs have been retrospectively reviewed by Choi et al. Cefoperazone-sulbactam and imipenem-cilastatin were used regimens in 25 and 12 patients respectively. The rates of acceptable response were not statistically different between the groups.
In a prospective observational study, Daikos et al. evaluated the role of VIM production on Kp-BSI outcome. A total of 162 patients; 67 (41.4%) and 95 (58.6%) with and without VIM-Kp infections, respectively, were included. The all-cause 14-day mortality rates were 15.8%, 18.9%, and 42.9% of patients infected with VIM-negative organisms, VIM-positive carbapenem-susceptible organisms, and VIM-positive CR organisms, respectively. The mortality rate was lower in combination therapy with two active drugs; a carbapenem plus either CMS or an aminoglycoside compared to monotherapy. The severity of underlying diseases and CR were independent predictors of death.
Lim et al. evaluated the outcomes of patients with MDR-Ab BSIs, who were treated with or without CMS-based regimen. In this study, colistin did not improve the overall hospital mortality in patients who had an MDR-Ab BSIs. A high APACHE II score at ICU admission was the only significant risk factor that predicted mortality.
Tumbarello et al. conducted a multicenter retrospective cohort study to evaluate the clinical outcome in 125 patients with BSIs caused by CR-Kp. Inadequate empirical antibiotic therapy was reported as one of the three predicting factors of mortality in BSIs caused by CR-Kp and it is the only one that is potentially modifiable. The other predictors were at admission septic shock and high APACHE III score. Combination therapy with tigecycline, CMS, and meropenem improved survival., Zarkotou et al. investigated outcomes, risk factors for mortality and impact of appropriate antimicrobial treatment in patients with BSIs caused by KPC producing Kp. Based on the results of the multivariate analysis, the major predictors of infection, mortality were the severity of the baseline condition, older age, and inappropriate treatment. Among them, the only modifiable variable that could be used to improve outcomes is the administration of appropriate treatment. The most common treatment regimen was the combination of colistin with tigecycline, received by nine patients. Colistin was used as monotherapy in seven patients with infection, mortality 66.7% while the tigecycline monotherapy was administered to five patients with infection mortality 40%.
Daikos et al. conducted a study to evaluate the clinical outcome of patients with CR-Kp BSIs received different antibiotic regimens. In this study, 103, 72, and 12 patients received combination therapy, monotherapy, and therapy with no active drug, respectively. Severe underlying diseases, septic shock, and treatment with a single active agent were independent predictors of death. Combination therapy provides significant survival benefit, especially when a carbapenem was considered. Another treatment-related factor that can affect the clinical outcome is the time of initiation of effective antibiotic regimen. Prompt initiation of effective antibiotic regimen for severe infections showed an important impact on patients'' survival.,
The clinical characteristics and treatment outcomes of 36 patients with BSIs due to CRE were investigated in a cohort study by Balkan et al. The microbiological and clinical responses within the first 7 days of the treatment were the major determinant of 28-day mortality. Colistin-based dual combinations and preferably triple combinations were associated with significantly better outcomes when compared to noncolistin based regimens.
Ventilator-associated Pneumonia and tracheobronchitis followed by bacteremia are the most frequent common infectious complications in critically ill patients. Late-onset VAP, which occurs after 4 days of intubation, mainly is induced by MDR bacteria such as MRSA, Ab, Pa, Kp and ESBL g-bacteria. In the empirical treatment of VAP due to the MDR pathogens, local resistance patterns are determining factor. In most cases, CMS and tigecycline are the unique treatment options for VAP caused by MDR pathogens.,,,,
Garnacho-Montero et al. prospectively evaluated efficacy and safety of intravenous (IV) colistin in 35 episodes of VAP due to MDR-Ab. CMS monotherapy was applied to 21 patients (in whom VAP caused by the susceptible pathogen to CMS) and the other patients were treated with imipenem (susceptible to imipenem). In this study, CMS was an effective alternative for imipenem in the management of the CR-Ab.
Experimental studies have shown that that CMS monotherapy was not an ideal option for treatment of CR-Ab associated Pneumonia. In one study, 7 critically ill patients with VAP caused by Ab-isolates were treated with either doxycycline or minocycline. The results showed that minocycline or doxycycline may be an option for treating imipenem and ampicillin-sulbactam resistant Ab-Pneumonia.
Lee et al. compared the efficacy of different antibiotic combinations in 89 patients with PDR-Ab nosocomial infections. A total of 59 patients were treated with a carbapenem plus sulbactam, and 30 patients were treated with a second or third generation cephalosporin, antipseudomonal penicillins, or a fluoroquinolone plus an aminoglycoside. In this study, carbapenem-sulbactam combination significantly decreased minimal inhibitory concentrations (MICs) for PDR-Ab. The clinical outcomes of both groups had not significant differences, either in terms of resolution of infection (25/59, 42% in first group vs. 12/30, 40% in second group) or survival (35/59, 59% vs. 17/30, 57%). Based on MICs, imipenem-sulbactam reversed resistance in 30% (14/46) of Ab isolates initially intermediate or resistant to imipenem alone. Meropenem-sulbactam had a similar effect in 11% (5/45) of isolates that were intermediate or resistant to meropenem.
Petrosillo et al. evaluated efficacy of CMS plus RIF in 14 critically ill patients who were diagnosed with CR-Ab VAP only or VAP plus BSI or surgical site infection (SSI). Five of the patients who had BSI or SSI, also received IV ampicillin–sulbactam. This combination resulted in the microbiological response in 9 (64%) patients with limited adverse effects. Overall, 7 (50%) of 14 patients died, three patients experienced a relapse of their Acinetobacter infection and received a second course of colistin–rifampicin; two of these patients died. Thus, therapy with colistin–rifampicin, and with ampicillin–sulbactam in case of susceptibility to this combination, resulted in microbiological clearance of CR-Ab infection with limited side effects.
In another study, efficacy of CMS-RIF combination in the treatment of nosocomial Pneumonia or bacteremia due to MDR-Ab been assessed in 29 critically ill patients. This combination showed acceptable efficacy.
High-dose of ampicillin-sulbactam has been proposed for treatment of VAP due to MDR-Ab. CMS (3 MIU every 8 h) and high-dose ampicillin-sulbactam (9 g every 8 h) were comparably safe and effective treatments in the treatment of MDR-Ab VAP.
Tasbakan et al. evaluated tigecycline efficacy in treating patients with MDR-Ab Pneumonia. Tigecycline was used as monotherapy in 23 cases. It was combined with cefoperazone-sulbactam, netilmicin, and amikacin in 26, 13, and three cases, respectively. Mortality and microbiological eradication rates were not different in the monotherapy group compared with the combination therapy group. Colistin-carbapenem combination improved the clinical response and survival compared to other regimens in solid organ transplant patients with XDR-Ab Pneumonia.
Efficacy of CMS alone or in combination with RIF has been evaluated in 210 critically ill patients with XDR-Ab infections by Durante-Mangoni et al. The length of hospitalization and mortality was similar in both groups, but the microbiological response was higher in the combination treatment group. In a retrospective analysis, the clinical and microbiological responses to IV colistin or colistin-sulbactam for the treatment of MDR-Ab VAP were assessed in 89 critically ill adult patients. In this study, although it was not statistically significant, the clinical cure rates (40.0% vs. 29.8%) and bacteriological clearance rates (85.7% vs. 72.3%) were better in the combination therapy group than colistin monotherapy.
In McLaughlin et al. study, 15 patients with CR-Kp infections were evaluated. Two patients who had received carbapenem monotherapy died. One patient on no-directed therapy was died. Directed therapy was defined as any antibiotic given to a patient in a directed manner after culture results were available. Time to directed therapy was defined as the time in hours from the culture draw to the receipt of antibiotic therapy. However, one patient on cefepime was discharged. Other patients received combination therapy and survived. Combination therapies were included carbapenems, tigecycline, colistin, aminoglycosides, cefepime, piperacillin/tazobactam, and fosfomycin. In a recently matched cohort analysis, it was proposed that colistin-based empiric therapy is superior to the tigecycline-based regimen for treating MDR-Ab Pneumonia.
Nosocomial g-bacillary meningitis due to Ab or Pa occurs occasionally in neurosurgical critically ill patients.,,
To treat CNS infections, bactericidal antibiotics should rapidly attain adequate concentrations within the CNS. Hydrophilic drugs, namely beta-lactams and glycopeptides, have low BBB permeability for which the presence of inflamed meninges is associated with an increase in CNS penetration. The new cephalosporins represent the backbone of several antimicrobial regimens for the treatment of bacterial meningitis. Among carbapenems, meropenem represents a drug for which the recommended dosage is 2 g every 8 h, as an IV 3-h infusion, with MIC values 0.25 mg/L. Its disposition into the cerebrospinal fluid (CSF) may increase in the presence of inflamed meninges. Data regarding tigecycline efficacy in meningitis are limited. In the case reports, tigecycline showed good CSF penetration. CSF linezolid concentrations have been found similar to those of the free fraction in plasma. Fosfomycin, rapidly distributes into the CSF and is a potential option in the treatment of multi-resistant Gram-positive and g-infections as well as “difficult-to-treat” bacterial infections. The disposition of trimethoprim and sulfamethoxazole into CSF is higher than beta-lactams, also in the presence of uninflamed meninges because of their lipophilic nature. Fluoroquinolones are able to achieve bactericidal concentrations in CSF. However, for microorganisms with high MIC values, these drugs should be used in combination therapy with other antibiotics. Due to their limited penetration and risk of toxicities, aminoglycosides are not good choices for treating meningitis.
Colistin and colistimethate sodium represent drugs of choice when the causative microorganisms are MDR strains. However, these drugs should be used in combination with other antibacterial agents, and in selected cases, intraventricular (IVT) administration should be adopted to augment the probability of cure because of modest and variable drug penetration into the CSF.
In a study, 51 cases with nosocomial meningitis due to Ab were followed. A carbapenem (21 cases), ampicillin-sulbactam (4 cases), and other antibiotics (2 cases) were used IV antibiotics. Four patients were treated with IV combination therapy. 19 patients were treated with IV and intrathecal (IT) regimens, CMS (8 cases), carbapenem (4 cases) or only IT aminoglycoside (5 cases), and other regimens (2 cases). 18 patients died. IT amikacin (20 mg/day) was associated with a cure rate of 80%. Although no patient in CMS group (10 mg every 12 h) died, no statistically significant difference in the mortality among the groups was detected.
IT or IVT CMS can be an effective and safe treatment for the management of MDR-Ab meningitis. IVT CMS is the last option for the treatment of CNS infections caused by PDR g-bacteria. The dosages of IVT/IT CMS ranged between 1.6 and 40 mg/day.,,
Falagas et al. collected 31 case reports/series, and reviewed 64 episodes of Gram-negative meningitis (34 of them in adults). Monotherapy with CMS via the IT or IVT and combination of systemic and local CMS was used for 11 and 25 episodes, respectively. In other episodes, different combinations were considered. In this report, IT/IVT CMS alone or in combination with systemic antibiotics was effective without considerable adverse effects. Markantonis et al. examined the penetration of CMS into the CSF. Only 5% of CMS were detected in the CSF that seems inadequate for treatment of bacterial meningitis.
Khawcharoenporn et al. evaluated the efficacy of IT/IVT colistin in CNS infections. The commonly administered dose was 40,000–500,000 IU/day for 2–3 weeks. Sterilization of the CSF was expected within 72 h. Systemic antibiotics were aminoglycosides (amikacin and tobramycin), colistin, imipenem, cefoperazone-sulbactam, ciprofloxacin, and ampicillin-sulbactam. There was no significant difference in the response rate between the IT/IVT CMS monotherapy and combination of IT/IVT colistin and other IV antibiotics. However, as most of the concurrent IV antibiotics (85%) had failed in monotherapy, role of IT/IVT colistin was dominant.
Imberti et al. evaluated the pharmacokinetic (PK) parameters of CMS in 9 adult patients developed CNS infections caused by a PDR-Kp (6 patients), PDR-Ab (2 patients) or PDR-Pa (1 patient). In this study, IVT administration of CMS produced concentration by CMS in CSF that never obtained with systemic administration. IVT CMS at doses of ≥5.22 mg/day was defined as appropriate.
Efficacy of IT or IVT of CMS in the management of MDR-Ab and XDR-Ab ventriculitis or meningitis was reviewed in 36 related articles. CMS was administered via the IVT and IT route in 52 and 22 cases, respectively. The exact route was not reported in 7 cases. The median duration of treatment and sterilization of CSF was 18.5 and 4 days, respectively. The response rate was 89%, and reversible local chemical reactions were reported in 9 patients.
Several antibiotic regimens were reviewed for the empiric treatment of Gram-negative meningitis. Meropenem 2 g every 8 h plus IT or IVT of an aminoglycoside (4 mg gentamicin or 30 mg amikacin as daily interval), IV CMS (2.5–5 mg/kg colistin base activity per day [equal to 6.67–13.3 mg/kg CMS]) in two to four divided doses, polymyxin B IV (1.5–2.5 mg polymyxin B base per kg per day in two divided doses) plus IT or IVT aminoglycoside (doses as above) with or without IV or PO rifampicin (600 mg/day) were studied regimens for treatment of CR-Ab meningitis. Removal of shunts and devices is one of the important concerns regarding treatment of meningitis, due to the probability of biofilm formation. Removal of shunt plus use of IV antibiotics caused the cured rate of 75%., The recommended duration of antibiotic therapy for acute g-bacterial meningitis is 21 days. However, the administration of antibiotics should continue until CSF becomes culture negative. In patients in whom external ventricular drains or other ready CSF access is not present, repeat lumbar puncture to sample CSF should be done after 4 days of IV therapy, since the median duration of therapy needed to clear the CSF is roughly 3 days.
Urinary tract infections
Many of the resistant g-bacillary infections caused complicated UTIs are acquired in the health-care-related facilities.
Although oral fluoroquinolones are the drug of choice for cystitis and outpatient pyelonephritis, but in inpatient pyelonephritis treatment with a parenteral third generation cephalosporin, cefepime, piperacillin-tazobactam or carbapenem should be considered.
Takeyama et al. reported the clinical conditions of three patients with acute pyelonephritis caused by MDR Pa. One of them treated with aspoxicillin and arbekacin, the other with piperacillin and the third case was treated with ceftazidime and arbekacin. Although none of the causative microorganisms were susceptible to the used antimicrobial agents, the clinical outcomes were all favorable. In a retrospective case series, 21 adult in-patients with bacteriuria caused by KPC-positive organisms were assessed. Aminoglycosides showed promising results in the treatment of CRE UTI. Volkow-Fernández et al. proposed that continuous intravesical administration of CMS is another useful way to eradicate an MDR-Ab urinary infection. They administrated colistimethate sodium, 3.5 mg/kg was dissolved in a 500 cm3 saline solution for 12 h and administered through a triple intravesical catheter with continuous irrigation over 7 days for a patient with a UTI caused by MDR-Ab.
| Conclusion|| |
Klebsiella pneumonia, Ab, Pa, and Enterobacter species are the most common resistant nosocomial g-infections around the word. BSI, Pneumonia, especially VAP, CNS infections, and complicated UTI due to these pathogens have been detected as main causes of morbidity and mortality in the hospitalized patients. These bacteria almost always are resistant to the conventional antibiotics. The resistant patterns of these organisms are changing from MDR to PDR pathogens.
Unfortunately, limited options are available for treatment of these infectious. Several variables including a history of antibiotic use, duration of hospitalization, major surgery, immunosuppression, parenteral nutrition, and diabetes are identified as predisposing factors for these infections. Infection control policies and antibiotic stewardships are two major well-evidenced strategies for prevention of antibiotic resistance in hospitals.
Differentiation between causative pathogen from colonization is another important issue in the clinical settings. Unfortunately, appropriate sampling and using rapid detection techniques for identification of pathogenic microorganisms are not available in many hospitals especially in the developing countries. Conventional disk diffusion methods usually are used as antimicrobial susceptibility tests. However, due to changing in the susceptibility pattern of bacteria, especially among MDR g-pathogens, identification of MIC for these microorganisms to selecting appropriate antibiotic regimen is essential.
Several antibiotic regimens are proposed for treatment of MDR g-infections. Most of the regimens are empirical, and some of them are based on the susceptibility patterns. Carbapenems are the treatment of choice for empirical treatment of infections due to ESBL-producing bacteria. The most challenging issue is the treatment of infections due to CR g-pathogens. Several evidences support the use of combination therapy regimens versus monotherapy for treatment of these infections. Tigecycline, polymyxins (polymyxin B, polymyxin E, CMS, carbapenems (imipenem, meropenem, doripenem), aminoglycosides (amikacin, gentamicin, tobramycin), quinolones (ciprofloxacin, levofloxacin), fosfomycin, RIF, ampicillin-sulbactam, piperacillin-tazobactam, and tetracyclines (minocycline and doxycycline) are common antibiotics that were used in the combinations. In these combinations, a carbapenem (always meropenem) plus either CMS or tigecycline was the most effective regimen for treatment of low-level resistant CR-Ab, CR-Kp infections. However, in high-level resistance (MIC > 8 mg/L) combination of CMS and tigecycline showed a better response. For PDR-Ab and PDR-Kp infections combination regimens including two or three effective antibiotics are recommended.
Besides selection of appropriate agent, considering site and type of infection and PK parameters of antibiotics, especially dosing strategies are essentials for designing an effective antibiotic regimen. To treat CNS infections, bactericidal antibiotics should rapidly attain adequate concentrations within the CNS. Aminoglycosides and CMS as backbone of antimicrobial regimens for treatment of g-bacterial meningitis have not good CNS penetration. IT/IVT administration of these antibiotics should be considered. However, carbapenems, tigecycline, fosfomycin, trimethoprim and sulfamethoxazole, RIF, and fluoroquinolones have good CSF penetration. Furthermore, aerosolized CMS and aminoglycosides as adjunct therapy may be helpful in the treatment of severe VAP due to MDR g-bacteria.,
Following decreasing antibiotic susceptibility of MDR g-microorganisms, high-dose CMS (9 MIU loading followed by 9 MIU/day in two divided doses) were recommended for treatment of severe nosocomial infections, especially VAP.
Increased mortality risk in patients treated with tigecycline was observed in the clinical trials. This may be due to the large volume of distribution and low blood concentration of tigecycline that is not adequate for bacteremia clearance. Optimizing antibiotic dosing with considering PK-pharmacodynamic parameters is one of the strategies to manage resistant pathogens. The available evidences suggest that extended or continuous infusion of carbapenems or piperacillin-tazobactam is associated with lower mortality.
| Authors Contribution|| |
Izadpanah M, was responsible for literature review, data collection and preparing the manuscript draft. Khalili H, was responsible for data analysis and editing the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Cloete TE. Resistance mechanisms of bacteria to antimicrobial compounds. Int Biodeterior Biodegradation 2003;51:277-82.
Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Med 2006;119:S3-10.
Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: No ESKAPE. J Infect Dis 2008;197:1079-81.
Zavascki AP, Bulitta JB, Landersdorfer CB. Combination therapy for carbapenem-resistant Gram-negative bacteria. Expert Rev Anti Infect Ther 2013;11:1333-53.
Zavascki AP, Carvalhaes CG, Picão RC, Gales AC. Multidrug-resistant Pseudomonas aeruginosa
and Acinetobacter baumannii
: Resistance mechanisms and implications for therapy. Expert Rev Anti Infect Ther 2010;8:71-93.
Livermore DM, Woodford N. Carbapenemases: A problem in waiting? Curr Opin Microbiol 2000;3:489-95.
Clatworthy AE, Pierson E, Hung DT. Targeting virulence: A new paradigm for antimicrobial therapy. Nat Chem Biol 2007;3:541-8.
Queenan AM, Bush K. Carbapenemases: The versatile beta-lactamases. Clin Microbiol Rev 2007;20:440-58.
Rossolini GM, Arena F, Pecile P, Pollini S. Update on the antibiotic resistance crisis. Curr Opin Pharmacol 2014;18:56-60.
Paterson DL. Resistance in gram-negative bacteria: Enterobacteriaceae
. Am J Infect Control 2006;34:S20-8.
Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al
. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18:268-81.
Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae
producing extended-spectrum ß-lactamases: A systematic review and meta-analysis. J Antimicrob Chemother 2012;67:2793-803.
Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. Deaths attributable to carbapenem-resistant Enterobacteriaceae
infections. Emerg Infect Dis 2014;20:1170-5.
Maragakis LL, Perl TM. Acinetobacter baumannii
: Epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis 2008;46:1254-63.
Levin AS, Barone AA, Penço J, Santos MV, Marinho IS, Arruda EA, et al
. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa
and Acinetobacter baumannii
. Clin Infect Dis 1999;28:1008-11.
Sobieszczyk ME, Furuya EY, Hay CM, Pancholi P, Della-Latta P, Hammer SM, et al
. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. J Antimicrob Chemother 2004;54:566-9.
Kasiakou SK, Michalopoulos A, Soteriades ES, Samonis G, Sermaides GJ, Falagas ME. Combination therapy with intravenous colistin for management of infections due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Antimicrob Agents Chemother 2005;49:3136-46.
Saballs M, Pujol M, Tubau F, Peña C, Montero A, Domínguez MA, et al
. Rifampicin/imipenem combination in the treatment of carbapenem-resistant Acinetobacter baumannii
infections. J Antimicrob Chemother 2006;58:697-700.
Tseng YC, Wang JT, Wu FL, Chen YC, Chie WC, Chang SC. Prognosis of adult patients with bacteremia caused by extensively resistant Acinetobacter baumannii
. Diagn Microbiol Infect Dis 2007;59:181-90.
Oliveira MS, Prado GV, Costa SF, Grinbaum RS, Levin AS. Ampicillin/sulbactam compared with polymyxins for the treatment of infections caused by carbapenem-resistant Acinetobacter
spp. J Antimicrob Chemother 2008;61:1369-75.
Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M, Falagas ME. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: A prospective evaluation. Clin Microbiol Infect 2010;16:184-6.
Gounden R, Bamford C, van Zyl-Smit R, Cohen K, Maartens G. Safety and effectiveness of colistin compared with tobramycin for multi-drug resistant Acinetobacter baumannii
infections. BMC Infect Dis 2009;9:26.
Tsioutis C, Kritsotakis EI, Maraki S, Gikas A. Infections by pandrug-resistant gram-negative bacteria: Clinical profile, therapeutic management, and outcome in a series of 21 patients. Eur J Clin Microbiol Infect Dis 2010;29:301-5.
Dalfino L, Puntillo F, Mosca A, Monno R, Spada ML, Coppolecchia S, et al
. High-dose, extended-interval colistin administration in critically ill patients: Is this the right dosing strategy? A preliminary study. Clin Infect Dis 2012;54:1720-6.
Sbrana F, Malacarne P, Viaggi B, Costanzo S, Leonetti P, Leonildi A, et al
. Carbapenem-sparing antibiotic regimens for infections caused by Klebsiella pneumoniae
carbapenemase-producing K. pneumoniae
in intensive care unit. Clin Infect Dis 2013;56:697-700.
Kontopidou F, Giamarellou H, Katerelos P, Maragos A, Kioumis I, Trikka-Graphakos E, et al
. Infections caused by carbapenem-resistant Klebsiella pneumoniae
among patients in intensive care units in Greece: A multi-centre study on clinical outcome and therapeutic options. Clin Microbiol Infect 2014;20:O117-23.
Balandin Moreno B, Fernández Simón I, Pintado García V, Sánchez Romero I, Isidoro Fernández B, Romera Ortega MA, et al
. Tigecycline therapy for infections due to carbapenemase-producing Klebsiella pneumoniae
in critically ill patients. Scand J Infect Dis 2014;46:175-80.
Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, et al
. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents 2014;43:52-9.
Smolyakov R, Borer A, Riesenberg K, Schlaeffer F, Alkan M, Porath A, et al
. Nosocomial multi-drug resistant Acinetobacter baumannii
blood stream infection: Risk factors and outcome with ampicillin-sulbactam treatment. J Hosp Infect 2003;54:32-8.
Kuo LC, Lai CC, Liao CH, Hsu CK, Chang YL, Chang CY, et al
. Multidrug-resistant Acinetobacter baumannii
bacteraemia: Clinical features, antimicrobial therapy and outcome. Clin Microbiol Infect 2007;13:196-8.
Choi JY, Kim CO, Park YS, Yoon HJ, Shin SY, Kim YK, et al
. Comparison of efficacy of cefoperazone/sulbactam and imipenem/cilastatin for treatment of Acinetobacter
bacteremia. Yonsei Med J 2006;47:63-9.
Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, Skoutelis A, et al
. Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae
blood stream infections. Antimicrob Agents Chemother 2009;53:1868-73.
Lim SK, Lee SO, Choi SH, Choi JP, Kim SH, Jeong JY, et al
. The outcomes of using colistin for treating multidrug resistant Acinetobacter
species blood stream infections. J Korean Med Sci 2011;26:325-31.
Neuner EA, Yeh JY, Hall GS, Sekeres J, Endimiani A, Bonomo RA, et al
. Treatment and outcomes in carbapenem-resistant Klebsiella pneumoniae
blood stream infections. Diagn Microbiol Infect Dis 2011;69:357-62.
Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al
. Predictors of mortality in blood stream infections caused by Klebsiella pneumoniae
carbapenemase-producing K. pneumoniae
: Importance of combination therapy. Clin Infect Dis 2012;55:943-50.
Zarkotou O, Pournaras S, Tselioti P, Dragoumanos V, Pitiriga V, Ranellou K, et al
. Predictors of mortality in patients with blood stream infections caused by KPC-producing Klebsiella pneumoniae
and impact of appropriate antimicrobial treatment. Clin Microbiol Infect 2011;17:1798-803.
Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, et al
. Carbapenemase-producing Klebsiella pneumoniae
blood stream infections: Lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014;58:2322-8.
Schwaber MJ, Carmeli Y. Mortality and delay in effective therapy associated with extended-spectrum beta-lactamase production in Enterobacteriaceae
bacteraemia: A systematic review and meta-analysis. J Antimicrob Chemother 2007;60:913-20.
Balkan II, Aygün G, Aydin S, Mutcali SI, Kara Z, Kuskucu M, et al
. Blood stream infections due to OXA-48-like carbapenemase-producing Enterobacteriaceae
: Treatment and survival. Int J Infect Dis 2014;26:51-6.
Kalanuria AA, Zai W, Mirski M. Ventilator-associated pneumonia in the ICU. Crit Care 2014;18:208.
Garnacho-Montero J, Corcia-Palomo Y, Amaya-Villar R, Martin-Villen L. How to treat VAP due to MDR pathogens in ICU patients. BMC Infect Dis 2014;14:135.
Naesens R, Vlieghe E, Verbrugghe W, Jorens P, Ieven M. A retrospective observational study on the efficacy of colistin by inhalation as compared to parenteral administration for the treatment of nosocomial pneumonia associated with multidrug-resistant Pseudomonas aeruginosa
. BMC Infect Dis 2011;11:317.
Gu WJ, Wang F, Tang L, Bakker J, Liu JC. Colistin for the treatment of ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: A systematic review and meta-analysis. Int J Antimicrob Agents 2014;44:477-85.
Ye JJ, Lin HS, Kuo AJ, Leu HS, Chiang PC, Huang CT, et al
. The clinical implication and prognostic predictors of tigecycline treatment for pneumonia involving multidrug-resistant Acinetobacter baumannii
. J Infect 2011;63:351-61.
Urban C, Go E, Mariano N, Berger BJ, Avraham I, Rubin D, et al
. Effect of sulbactam on infections caused by imipenem-resistant Acinetobacter
calcoaceticus biotype anitratus. J Infect Dis 1993;167:448-51.
Garnacho-Montero J, Ortiz-Leyba C, Jiménez-Jiménez FJ, Barrero-Almodóvar AE, García-Garmendia JL, Bernabeu-WittelI M, et al
. Treatment of multidrug-resistant Acinetobacter baumannii
ventilator-associated pneumonia (VAP) with intravenous colistin: A comparison with imipenem-susceptible VAP. Clin Infect Dis 2003;36:1111-8.
Wood GC, Hanes SD, Boucher BA, Croce MA, Fabian TC. Tetracyclines for treating multidrug-resistant Acinetobacter baumannii
ventilator-associated pneumonia. Intensive Care Med 2003;29:2072-6.
Lee CM, Lim HK, Liu CP, Tseng HK. Treatment of pan-drug resistant Acinetobacter baumannii
. Scand J Infect Dis 2005;37:195-9.
Petrosillo N, Chinello P, Proietti MF, Cecchini L, Masala M, Franchi C, et al
. Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii
infections: Clinical outcome and adverse events. Clin Microbiol Infect 2005;11:682-3.
Bassetti M, Repetto E, Righi E, Boni S, Diverio M, Molinari MP, et al
. Colistin and rifampicin in the treatment of multidrug-resistant Acinetobacter baumannii
infections. J Antimicrob Chemother 2008;61:417-20.
Betrosian AP, Frantzeskaki F, Xanthaki A, Georgiadis G. High-dose ampicillin-sulbactam as an alternative treatment of late-onset VAP from multidrug-resistant Acinetobacter baumannii
. Scand J Infect Dis 2007;39:38-43.
Tasbakan MS, Pullukcu H, Sipahi OR, Tasbakan MI, Aydemir S, Bacakoglu F. Is tigecyclin a good choice in the treatment of multidrug-resistant Acinetobacter baumannii
pneumonia? J Chemother 2011;23:345-9.
Shields RK, Clancy CJ, Gillis LM, Kwak EJ, Silveira FP, Massih RC, et al
. Epidemiology, clinical characteristics and outcomes of extensively drug-resistant Acinetobacter baumannii
infections among solid organ transplant recipients. PLoS One 2012;7:e52349.
Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, et al
. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii
: A multicenter, randomized clinical trial. Clin Infect Dis 2013;57:349-58.
Kalin G, Alp E, Coskun R, Demiraslan H, Gündogan K, Doganay M. Use of high-dose IV and aerosolized colistin for the treatment of multidrug-resistant Acinetobacter baumannii
ventilator-associated pneumonia: Do we really need this treatment? J Infect Chemother 2012;18:872-7.
McLaughlin MM, Advincula MR, Malczynski M, Barajas G, Qi C, Scheetz MH. Quantifying the clinical virulence of Klebsiella pneumoniae
producing carbapenemase Klebsiella pneumoniae
with a Galleria mellonella
model and a pilot study to translate to patient outcomes. BMC Infect Dis 2014;14:31.
Chuang YC, Cheng CY, Sheng WH, Sun HY, Wang JT, Chen YC, et al
. Effectiveness of tigecycline-based versus colistin-based therapy for treatment of pneumonia caused by multidrug-resistant Acinetobacter baumannii
in a critical setting: A matched cohort analysis. BMC Infect Dis 2014;14:102.
Krol V, Hamid NS, Cunha BA. Neurosurgically related nosocomial Acinetobacter baumannii
meningitis: Report of two cases and literature review. J Hosp Infect 2009;71:176-80.
Wroblewska MM, Dijkshoorn L, Marchel H, van den Barselaar M, Swoboda-Kopec E, van den Broek PJ, et al
. Outbreak of nosocomial meningitis caused by Acinetobacter baumannii
in neurosurgical patients. J Hosp Infect 2004;57:300-7.
Nagaveni S, Rajeshwari H, Oli AK, Patil SA, Chandrakanth RK. Widespread emergence of multidrug resistant Pseudomonas aeruginosa
isolated from CSF samples. Indian J Microbiol 2011;51:2-7.
van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012;380:1693-702.
Tsuji Y, Hiraki Y, Matsumoto K, Mizoguchi A, Sadoh S, Kobayashi T, et al
. Pharmacokinetics and protein binding of linezolid in cerebrospinal fluid and serum in a case of post-neurosurgical bacterial meningitis. Scand J Infect Dis 2011;43:982-5.
Di Paolo A, Gori G, Tascini C, Danesi R, Del Tacca M. Clinical pharmacokinetics of antibacterials in cerebrospinal fluid. Clin Pharmacokinet 2013;52:511-42.
Rodríguez Guardado A, Blanco A, Asensi V, Pérez F, Rial JC, Pintado V, et al
. Multidrug-resistant Acinetobacter
meningitis in neurosurgical patients with intraventricular catheters: Assessment of different treatments. J Antimicrob Chemother 2008;61:908-13.
Cascio A, Conti A, Sinardi L, Iaria C, Angileri FF, Stassi G, et al
. Post-neurosurgical multidrug-resistant Acinetobacter baumannii
meningitis successfully treated with intrathecal colistin. A new case and a systematic review of the literature. Int J Infect Dis 2010;14:e572-9.
Imberti R, Cusato M, Accetta G, Marinò V, Procaccio F, Del Gaudio A, et al
. Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate. Antimicrob Agents Chemother 2012;56:4416-21.
Falagas ME, Bliziotis IA, Tam VH. Intraventricular or intrathecal use of polymyxins in patients with Gram-negative meningitis: A systematic review of the available evidence. Int J Antimicrob Agents 2007;29:9-25.
Khawcharoenporn T, Apisarnthanarak A, Mundy LM. Intrathecal colistin for drug-resistant Acinetobacter baumannii
central nervous system infection: A case series and systematic review. Clin Microbiol Infect 2010;16:888-94.
Markantonis SL, Markou N, Fousteri M, Sakellaridis N, Karatzas S, Alamanos I, et al
. Penetration of colistin into cerebrospinal fluid. Antimicrob Agents Chemother 2009;53:4907-10.
Karaiskos I, Galani L, Baziaka F, Giamarellou H. Intraventricular and intrathecal colistin as the last therapeutic resort for the treatment of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii
ventriculitis and meningitis: A literature review. Int J Antimicrob Agents 2013;41:499-508.
Georges H, Chiche A, Alfandari S, Devos P, Boussekey N, Leroy O. Adult community-acquired bacterial meningitis requiring ICU admission: Epidemiological data, prognosis factors and adherence to IDSA guidelines. Eur J Clin Microbiol Infect Dis 2009;28:1317-25.
Rodríguez-Baño J, Martí S, Soto S, Fernández-Cuenca F, Cisneros JM, Pachón J, et al
. Biofilm formation in Acinetobacter baumannii
: Associated features and clinical implications. Clin Microbiol Infect 2008;14:276-8.
Kim BN, Peleg AY, Lodise TP, Lipman J, Li J, Nation R, et al
. Management of meningitis due to antibiotic-resistant Acinetobacter
species. Lancet Infect Dis 2009;9:245-55.
Levison ME, Kaye D. Treatment of complicated urinary tract infections with an emphasis on drug-resistant gram-negative uropathogens. Curr Infect Dis Rep 2013;15:109-15.
Takeyama K, Kunishima Y, Matsukawa M, Takahashi S, Hirose T, Kobayashi N, et al
. Multidrug-resistant Pseudomonas aeruginosa
isolated from the urine of patients with urinary tract infection. J Infect Chemother 2002;8:59-63.
Alexander BT, Marschall J, Tibbetts RJ, Neuner EA, Dunne WM Jr, Ritchie DJ. Treatment and clinical outcomes of urinary tract infections caused by KPC-producing Enterobacteriaceae
in a retrospective cohort. Clin Ther 2012;34:1314-23.
Volkow-Fernández P, Rodríguez CF, Cornejo-Juárez P. Intravesical colistin irrigation to treat multidrug-resistant Acinetobacter baumannii
urinary tract infection: A case report. J Med Case Rep 2012;6:426.
Rafailidis PI, Falagas ME. Options for treating carbapenem-resistant Enterobacteriaceae
. Curr Opin Infect Dis 2014;27:479-83.
Michalopoulos A, Kasiakou SK, Mastora Z, Rellos K, Kapaskelis AM, Falagas ME. Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Crit Care 2005;9:R53-9.
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