Management of serious infections caused by metallo ß-lactamases with or without OXA-48-like expressing Enterobacterales with aztreonam and ceftazidime/avibactam combination: Dosing strategy for better clinical outcome.

Serious infections caused by MBLs with or without OXA-48-like expressing Enterobacterales remain challenging to treat. Since aztreonam is stable to MBLs, it can be combined with ceftazidime/avibactam to protect against concurrently expressed ESBLs and class C ß-lactamases in MBL pathogens. However, in the light of dose-limiting hepatotoxicity of aztreonam, short half life of avibactam, significant protein binding of aztreonam, appropriate dosing and method of administration to optimize PK/PD and toxicodynamics for this combination is being debated. Based on in-vitro PK/PD studies, simultaneous administration of 6/1.5 g of ceftazidime/avibactam and 8 g of aztreonam per day has been recently suggested.

Is it time to move away from polymyxins?: evidence and alternatives.

Increasing burden of carbapenem resistance and resultant difficult-to-treat infections are of particular concern due to the lack of effective and safe treatment options. More recently, several new agents with activity against certain multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative pathogens have been approved for clinical use. These include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, and cefiderocol. For the management of MBL infections, clinically used triple combination comprising ceftazidime-avibactam and aztreonam is hindered due to non-availability of antimicrobial susceptibility testing methods and lack of information on potential drug-drug interaction leading to PK changes impacting its safety and efficacy. Moreover, in several countries including Indian subcontinent and developing countries, these new agents are yet to be made available. Under these circumstances, polymyxins are the only last resort for the treatment of carbapenem-resistant infections. With the recent evidence of suboptimal PK/PD particularly in lung environment, limited efficacy and increased nephrotoxicity associated with polymyxin use, the Clinical and Laboratory Standards Institute (CLSI) has revised both colistin and polymyxin B breakpoints. Thus, polymyxins 'intermediate' breakpoint for Enterobacterales, P. aeruginosa, and Acinetobacter spp. are now set at ≤ 2 mg/L, implying limited clinical efficacy even for isolates with the MIC value 2 mg/L. This change has questioned the dependency on polymyxins in treating XDR infections. In this context, recently approved cefiderocol and phase 3 stage combination drug cefepime-zidebactam assume greater significance due to their potential to act as polymyxin-supplanting therapies.

Fosfomycin Susceptibility in Urinary Tract Enterobacteriaceae.

INTRODUCTION: Antibiotic treatment of Urinary Tract Infections (UTI) is becoming increasingly difficult due to emergence of multi-drug resistant (ESBLs, AmpC, CRE) uropathogens. Fosfomycin is an old antibiotic that has evoked renewed interest with unique properties of not sharing any structural similarity and lack of cross-resistance with other antimicrobial agents. Our aim is to evaluate in-vitro activity of Fosfomycin against urinary tract Enterobacteriaceae. MATERIAL & METHODS: The study period was March 2014 to September 2015. All 72 isolates were identified using conventional biochemical tests. Antimicrobial susceptibility testing was performed using the automated broth microdilution system Vitek 2 (bio- Mérieux, Inc., Durham, NC). Fosfomycin susceptibility was determined by the E-test (bioMérieux, Inc., Durham, NC) method. Interpretive criteria from the Clinical and Laboratory Standards Institute (CLSI) for fosfomycin susceptibility are not available for the Enterobacteriaceae other than Escherichia coli. Therefore, results were interpreted according to criteria for E. coli (i.e., susceptible at a MIC of ≤ 64 µg/ml), as has been reported previously. RESULTS: Overall, 79.16% (57/72) isolates were susceptible to fosfomycin w i t h 92.00% (23/25) susceptibility in ESBL producing enterobacteriaceae and 72.34% (34/47) in CRE. One CRE isolate has developed resistant while on treatment. There was not much difference in number of susceptible isolates CLSI:EUCAST = 57:53,but number of resistant isolates was more with EUCAST (CLSI:EUCAST = 10:19). CONCLUSION: Study demonstrate that, a considerable proportion (79.16%) of the multidrug-resistant Enterobacteriaceae with diverse resistance mechanisms, including ESBL and CRE, found susceptible to fosfomycin. Consequently, fosfomycin may currently be considered a useful antibiotic agent in the treatment armamentarium of UTIs.

Antibiotic Lock Therapy in the Era of Gram-Negative Resistance.

BACKGROUND: Central-line-associated blood-stream infection (CLABSI) is a highly consequential nosocomial infection. The most effective management includes the removal of the infected catheter. Retention of the catheter and antibiotic lock therapy (ALT) along with systemic antibiotics may be attempted only if there are unusual extenuating circumstances. CLABSIs due to Gram-negative bacteria (GNB) is more common in our setting and the organisms are often highly resistant. Hence, there is a need to explore the use of novel antimicrobials for catheter lock solutions along with antibiofilm agents. PATIENTS AND METHODS: We report the use of antibiotic lock therapy in the first 29 patients who had 37 episodes of bacteremia (CLABSI/symptomatic colonization) due to long-term catheters in our unit from February 2008 to September 2014. Patients received ALT if they had CLABSI or were symptomatic with a colonized catheter. Patients who needed removal of the catheter were ineligible for ALT. Patients received systemic antibiotic therapy and lock solutions were kept in the catheter for dwell times of 24 hours, and therapy was continued for 14 days. Successful treatment was defined as any of the following: 1) Clinical cure with disappearance of signs of sepsis 2) Microbiological cure with resolution of bacteremia (confirmed by a negative blood culture which was obtained through the catheter 2-5 days after stopping therapy. RESULTS: Among the 37 episodes treated with ALT, 30 episodes were caused by GNB and four episodes were caused by Gram-positive cocci (GPC); Enterococcus, methicillin-sensitive S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), and methicillin-sensitive coagulase-negative staphylococcus (CoNS). There were three episodes of CRBSI due to Candida and one episode each due to L. monocytogens and Bacillus spp. Of the other 30 episodes due to GNB, Acinetobacter baumannii were isolated in eight episodes, Stenotrophomonas (n=6), E. coli (n=5), Flavobacterium (n=2), and P. aeruginosa (n=4), and B. cepacia in three episodes. The other organisms isolated were K. pneumoniae, and non-typhoidal Salmonella (1 episode each). Successful treatment with ALT was observed in 30 (81.08%) of the 37 episodes. CONCLUSIONS: In patients with CLABSI due to Gram-negative pathogens, the use of ALT along with systemic antibiotics has an excellent catheter salvage rate. Newer antibiotics (tigecycline and colistin) may be useful options as antibiotic lock solutions along with antibiofilm agents especially in the setting of resistant Gram-negative bacilli producing CLABSI.

Successful management of highly drug resistant tuberculosis with individualised drug susceptibility testing.

INTRODUCTION: Many tuberculosis (TB) patients have resistance patterns intermediate between multidrug-resistant (MDR) and extensively drug-resistant (XDR). We defined MDR+ as resistance to rifampin (RMP), isoniazid (INH) and at least one more drug other than fluoroquinolone (FQ) and second-line injectable agent (IA); and Pre-XDR as MDR with additional resistance to either FQ or IA. Such patients too, have compromised treatment options that require various combinations of second line drugs (SLD). The aim of our study was to assess the clinical outcome of patients having such resistance patterns, managed on the basis of prior drug exposure and drug susceptibility testing (DST). METHODOLOGY: 52 consecutive patients were studied. Treatment regimen was devised as per DST and predominantly consisted of a second-line injectable agent (IA), para-aminosalicylic acid (PAS) and clofazimine. Additionally, cycloserine, linezolid, co-amoxiclav and clarithromycin were used to complete a regimen of four to five drugs. Clinical and radiological outcome was evaluated at follow-up and at the end of treatment. RESULTS: 49/52 (94%) patients had good outcome. However, 34 different regimens had to be used, as options for individual patients were limited. CONCLUSION: Management on the basis of prior drug exposure and individualised DST led to good clinical outcomes. No single regimen emerged as having a wide applicability. This study supports the clinical relevance of DST of oral second line drugs.

The outcome of treating ESBL infections with carbapenems vs. non carbapenem antimicrobials.

BACKGROUND: In India where the prevalence of extended spectrum beta lactamase (ESBL) producing organisms among gram negative organisms is 60-70% and Ertapenem was unavailable at the beginning of this study, exclusive use of Group 2 Carbapenems (Imipenem and Meropenem) for treatment raises issues of cost and development of resistance. Therefore the role of non-Carbapenem alternatives, chiefly Betalactam + Betalactamase inhibitors (BL-BLI) was explored in this prospective observational study at a private tertiary care teaching hospital. PATIENTS AND METHODS: 522 consecutive in door patients from the period between June 2006 to March 2007and June 2008 to December 2008, who had true infections with ESBL producing organisms were enrolled in the study. Antimicrobials were prescribed or changed by the treating physicians on the basis of the nature and severity of infection, the susceptibility of the organism and the affordability of the patient. Patients who received a Carbapenem at any time during treatment were considered in the Carbapenem group. Those who never received a Carbapenem at any time during treatment were considered in the non-Carbapenem group. RESULTS: Of the 522 infections, 287 were urinary tract infections, 60 were skin structure infections, 60 were bacteremias, 55 were hospital acquired pneumonias, 31 were intra-abdominal infections and 29 were other infections. There were 351 E. coli, 119 K. pneumoniae, 23 K. oxytoca, 16 Enterobacter aerogenes, 5 Kozoanae, 4 Enterobacter agglomerans, 3 Citrobacter freundi, 1 E. cloacae, 1 Enterobacterspp. and 1 Morgenella morganii isolates. Clinical outcomes were available for 486 patients. 339 patients who were in the non-Carbapenem group and who might have had less serious infections had a clinical success rate of 79.6%. 147 patients who were in the Carbapenem group and who might have had more serious infections had a clinical success rate of 85.71%. CONCLUSIONS: It is possible to successfully treat at least the less serious infections due to ESBL producing gram negative organisms with non-Carbapenem antimicrobials. This will not compromise outcomes but will likely result in restricting the use of Carbapenems which may help preserve their efficacy against increasingly resistant organisms.

The relevance of ESBL producing isolates in patients surgically treated for acute appendicitis.

BACKGROUND: In India, there is a high prevalence of ESBL producing organisms among intraabdominal isolates and in stool flora of 'normal' individuals. Hence, it may be presumed that unless antimicrobial therapy effective for ESBL flora is used perioperatively for abdominal surgery, the outcome will be adverse. We selected patients surgically treated for appendicitis as a model to explore the relevance of ESBL producing isolates in this retrospective observational study. AIMS AND OBJECTIVES: To assess the impact of ESBL producing isolates in patients surgically treated for acute appendicitis and to determine whether the perioperative antibiotic use needs to be changed in view of the high ESBL prevalence. METHOD: Chart review of 221 consecutive patients who had undergone appendicectomy between January 2004 and December 2009. RESULTS: 55 of 221 patients had cultures of relevant specimens done based on the discretion of the treating surgeon. 40 yielded 1 or more organisms. 19 showed ESBL producing Enterobacteriaceae (ESBL+) and 21 showed non ESBL producing Enterobacteriaceae (ESBL-). 118 of 221 patients had presented without any complications and had a good outcome after surgery. The other 33 of 221 patients had complications like perforation or an abscess at presentation. Out of these, 16 patients received inappropriate therapy and 17 received appropriate therapy. The patients with appropriate therapy had good outcome. Among the 16 patients with inappropriate therapy 15 were ESBL+and 1 was ESBL-. Out of the 15 ESBL+isolates, 9 developed an initial postoperative complication like postoperative fever or wound infection. The cultures of the relevant specimen were done in all these 9 patients, all of which were positive. Therapy was changed in 7 of these 9 patients to pathogen directed therapy like amikacin, chloramphenicol and levofloxacin. Meropenem was used in only one case. All these 7 patients as well as the 2 patients whose treatment was not changed made a complete recovery. CONCLUSION: For patients surgically treated for acute appendicitis, a change of perioperative antibiotics to those effective for ESBL+organisms is not needed at present only on the basis of ESBL prevalence rates. Routine cultures may not be necessary. Cultures are needed if there is a complication such as an abscess or perforation at presentation or an initial post operative complication. A change to pathogen directed therapy, including even to older or non beta-lactam antimicrobials may be needed in these cases. Our results support continuing the use of older antimicrobials rather than changing to carbapenems and beta-lactamase-beta-lactamase inhibitor combination in low risk surgically treated patients. This may prevent generation of further resistance without compromising outcomes.

New Delhi Metallo-beta lactamase (NDM-1) in Enterobacteriaceae: treatment options with carbapenems compromised.

BACKGROUND: Carbapenems are among the few useful antibiotics against multidrug resistant gram negative bacteria particularly those with extended spectrum beta lactamase. However resistance to carbapenems occurs and is mediated by mechanisms like loss of outer membrane proteins and production of beta lactamase that is capable of hydrolyzing carbapenems. An alert issued in the UK in 2009 warned of an increasing number of carbapenem resistant Enterobacteriaceae strains identified in UK hospital patients. Many of them were recently hospitalized in India and Pakistan and had new type of metallo beta lactamase designated as New Delhi Metallo-1 (NDM-1). OBJECTIVE: To assess the production of NDM-1 type Metallo beta lactamase enzyme in Enterobacteriaceae at a tertiary care centre in Mumbai. MATERIALS AND METHODS: Consecutive carbapenem resistant Enterobacteriaceae isolates were collected from August 2009 to November 2009. Susceptibility testing for carbapenems was performed by the disc diffusion method. Carbapenemase production was confirmed by Modified Hodge test. These strains were then subjected to single target PCR. A 475bp product was amplified by the NDM primers and visualized on 3% agarose gel. RESULTS AND CONCLUSIONS: Modified Hodge test was positive for all carbapenem resistant isolates. Of 24 carbapenem resistant Enterobacteriaceae 22 were NDM producers while 2 were NDM non producers. Amongst the 22 NDM producing organisms 10 were Klebsiella spp, 9 were Escherichia coli, 2 were Enterobacter spp and 1 was Morganella morganii. This high number in a relatively short span is a worrisome trend that compromises the treatment options with the carbapenems.