gram - negative bacteria have developed resistance to many antibiotics including the last line -lactams , carbapenems . there are various mechanisms leading to an increase in multi - drug resistance in bacteria . among all these factors , broadly carbapenemases are categorized into three groups : class a ( penicillinases ) , class b ( metallo--lactamases [ mbl ] ) , and class d ( oxacillinases ) . they are present largely in enterobacteriaceae , but also in nonfermenters ( acinetobacter spp . ) and vibrionaceae ( vibrio cholerae ) . till now , both hospital- and community - acquired infections , such as wound , respiratory , bloodstream , and urinary tract infections ( utis ) , caused by blandm harboring bacteria , have been reported . studies have proved the inactivation of these carbapenems ( meropenem , imipenem [ ipm ] , doripenem , ertapenem ) by a number of mbl which pose extended spectrum activity against all -lactam antibiotics . the epidemiology of ndm is compounded by interspecies dispersion and recognized implications for patient care , public health , antimicrobial surveillance programs , and drug development . as the antibiotic pipeline offers little in the short - term , our most important tools against the spread of antibiotic resistant organisms a clinical isolate klebsiella pneumoniae was derived from a urinary culture of a 59-year - old male patient , who was hospitalized in ludhiana and new dehli . testing of this isolate suggested that the carbapenem resistance was due to the production of a novel mbl , designated ndm-1 , as the authors of the report believed the resistance originated from india . the same year , blandm was identified in 143 patients from multiple sites in the indian subcontinent . the infection caused by ndm - producing bacteria is now recognized as endemic throughout india and pakistan . it has spread worldwide due to travel ,  medical tourism  and the ability of the genetic element to transfer between bacteria . antimicrobial use while traveling was an independent risk for acquisition and prolonged carriage of such organisms . the ndm-1 was found in many species of bacteria , predominantly k. pneumoniae and escherichia coli , collected in an extended survey in the uk , india , pakistan and bangladesh in 20082009 . recent reports have indicated the spread of ndm-1 and its variants in many different countries [ table 1 ] including the united states , austria , australia , norway , belgium , canada , denmark , france , germany , kenya , the netherlands , the sultanate of oman , china , hong kong , taiwan , singapore , sweden , egypt , japan , switzerland , morocco , kuwait , italy , south korea , ireland , czech republic , guatemala , new zealand , israel , iran , russia , colombia , malaysia , sri lanka , algeria , mexico , tunisia , reunion island , nepal , mauritius and honduras . in addition , the balkans region such as montenegro , serbia , bosnia  herzegovina and kosovo , and the middle east ( oman and iraq ) , may constitute an additional reservoir for ndm-1 producers , which may or may not initially have reached these countries from the indian subcontinent . in view of this situation , we believe that an immediate response to the emergence of ndm - producing bacteria should be an urgent priority worldwide . at a local level , patients with a history of travel to or originating from high - risk countries or areas should be screened for ndm - producing bacteria . initial reports of the ndm-1 and its variants * ndm-11 is assigned without any information in genbank ; the articles about ndm-10 , ndm-11 , ndm-12 and ndm-13 remain unpublished . e. coli : escherichia coli ; k. pneumonia : klebsiella pneumonia ; a. baumannii : acinetobacter baumannii ; a. lwoff ii : acinetobacter lwoffii . the problem of ndm-1 was not confined to hospital strains of bacteria but was widespread in the community environment in india . given that ndm - positive bacteria are common in the environment that many infections in india are community acquired , and that these bacteria can colonize the gastrointestinal tract , it is likely that fecal - oral transmission plays a major role in transmission occurring through contaminated food , water , and hands . besides , wang et al . detected ndm-1 carbapenemase - producing acinetobacter calcoaceticus and acinetobacter junii in environmental samples from livestock farms in china . these findings highlighted the need for improvements in sanitary conditions as a key public health intervention . recently , a novel bleomycin resistance protein has been characterized , which was associated with the blandm-1 gene as part of the same operon . walsh and colleagues hypothesized that bleomycin or bleomycin - like molecules exert a selective pressure on the large spread of the blandm-1 gene in the environment . it is possible that bleomycin - like molecules contribute to selective pressure , leading to the further spread of ndm producers in the environment . rapid detection of mbl - producing strains , including ndm producers , is necessary to prevent their dissemination and associated nosocomial infections . identification of the microorganism bacteria isolated from patients were identified via the phoenix automated phenotypic identification criteria ( becton dickinson , oxford , uk ) or with api 20e strips ( biomerieux , basingstoke , uk ) . detection of carbapenemase minimum inhibitory concentrations the first cause for suspicion that a carbapenemase is involved in a clinical infection is an elevated carbapenem minimum inhibitory concentration ( mic ) . however , elevated carbapenem mics are generally predictive of carbapenemase production in the enterobacteriaceae , full clinical resistance is not always seen . mics and carbapenem resistance were established by microbroth dilution ( phoenix ) , british society for antimicrobial chemotherapy agar dilution or disc diffusion and interpreted according to clinical and laboratory standards institute ( clsi ) guidelines . carbapenem resistant bacteria detected by mic method should be further explored for carbapenemase production by phenotypical methods . several phenotypic methods to detect mbl production have been developed , including the modified hodge test ( mht ) , the double - disk synergy tests ( ddsts ) , combined disk tests and e - test . the mht is the only clsi - recommended carbapenemase - screening method and has been widely used because of the direct analysis of the carbapenemase activity . the advantage of this method is that even the weak carbapenemase activity enzyme can be detected . however , it shows a low sensitivity of 11% when ndm carbapenemase is tested by the mht according to clsi . and many ndm - positive bacteria give negative results in particularly in acinetobacter baumannii , whereas strains with high levels of ampc can give false positives , confusing interpretation . mbl inhibitors used in these methods include the metal - chelating agent ethylenediaminetetraacetic acid ( edta ) , thiol compounds ( mercaptopropionic acid or sodium mercaptoacetic acid ) , and dipicolinic acid . the different formats include the ddsts using 2-mercaptoacetic acid or edta , combined disk tests with dipicolinic acid or edta , and ipm / ipm - edta e - test strips . in laboratories , where molecular methods are not available , the ddsts would serve as a useful screening technique . the ddst using -lactamase and -lactamase - inhibitor disks is a convenient method of detecting extended spectrum -lactamase ( esbl)-producing gram - negative bacilli . the e - test mbl strip is one of the recommended tests for detection of ndm based on inhibition of mbl activity by edta . however , false - negative results had been reported for the e - test when an isolate had an ipm mic of 4 g / ml . edta alone has inhibitory action against some bacteria and can lead to false - positive results . the e - test mbl may be used in labs that do not screen for mbl producers on a daily basis , or in those which perform susceptibility testing using liquid medium techniques and rarely use disk diffusion susceptibility techniques . in addition , the combined disk test is also based on inhibition of mbl activity by edta . ndm-1 producers are positively detected by this technique , which is reliable for detecting mbl producers on a daily basis . the gold standard for the identification of carbapenemase producers and for specific detection of blandm is molecular techniques , mostly based on pcr , ideally followed by sequencing . when the presence of a carbapenemase is suspected , pcr is the fastest way to detect blandm genes . other molecular techniques , including real - time pcr and commercial dna arrays ( check - points ) , are useful alternatives . while these assays for rapid , sensitive , and specific detection appear to be promising , pcr requires specialized high - cost instruments and consumables . some laboratories have used colony blot hybridizations to efficiently screen large numbers of clinical isolates for carbapenemase genes . and a novel nucleic acid amplification method , designated loop - mediated isothermal amplification ( lamp ) , had been well established and documented . the lamp method is demonstrated to be a potentially valuable means for the detection of blandm and rapid clinical diagnosis , being fast , simple , and low in cost . in infection due to highly resistant pathogens such as ndm - positive bacteria , antimicrobial choice is limited and requires a considered analysis of risk and benefit of available agents . ndm - producing organisms frequently carry other resistance enzymes including esbl and ampc -lactamases , rendering most available antibiotics inactive . nevertheless , these organisms are usually susceptible to polymyxin ( including colistin and polymuxin b ) and tigecycline . however , colistin has uncertain efficacy in pulmonary infections , and its use has always been hampered by the occurrence of renal toxicity , and to a lesser extent , neurological adverse effects . more importantly , carbapenem resistant bacteria such as blandm-1 e. coli and blandm-1 k. pneumoniae have become resistant to colistin . tigecycline is a glycylcycline with a wide spectrum of activity against aerobic and anaerobic gram - positive and gram - negative bacteria . though it is useful in tissue infections , it is less useful in systemic infections . in addition , tigecycline is probably not appropriate in urinary infections owing to largely biliary excretion and low urinary levels . to the best of our knowledge , albur 's research indicated that adding tigecycline to colistin does not produce increased bacterial killing . development of molecular strategies that can rehabilitate the  old antibiotics  and halt the antibiotic resistance is a promising approach to target them . reported that membrane - active macromolecules restore the antibacterial efficacy of tetracycline antibiotics toward blandm-1 k. pneumonia and blandm-1 e. coli clinical isolates . these findings have potentially important therapeutic implications in the management of patients with infections caused by ndm - producing pathogen . fosfomycin might be useful as a last - resort option as part of combination regimens . it is mainly used in the treatment of utis , particularly those caused by e. coli and enterococcus faecalis . intravenous fosfomycin has been administered in critically ill patients with sepsis or nosocomial - acquired infections due to carbapenem - resistant k. pneumoniae , in combination with other antibiotics , due to its unique mechanism of action and its protective effect against nephrotoxicity induced by aminoglycosides or colistin . many mbls - producing enterobacteriaceae additionally carry esbls or other resistant determinants that confer resistance to aztreonam . there are no published clinical data as yet to support the use of aztreonam for the treatment of infections with mbl - producing enterobacteriaceae . however , the combination of aztreonam and avibactam , a non--lactam -lactamase inhibitor , may provide a much - needed therapeutic alternative . but a four - amino - acid insertion in penicillin - binding protein 3 had reduced susceptibility to aztreonam / avibactam according to alm et al . another finding is api88 , which is a novel , highly promising , 18-residue peptide lead compound with favorable in vitro and in vivo properties including a promising safety margin . starting from the antibacterial peptide apidaecin 1b , we can treat systemic infections with the most threatening human pathogens , such as e. coli , k. pneumoniae , pseudomonas aeruginosa , and a. baumannii . new carbapenemases such as ndm-1 enzyme are surfacing , resulting in almost total resistance to -lactam antibiotics . table 2 shows 22 cases related to the infection caused by ndm - producing bacteria . facing with this serious situation , we are in urgent need of new therapeutic options . one approach to combat this growing problem is the use of combination drug antibiotic adjuvant therapy . antibiotic adjuvants include not only antibiotics but also other bioactive molecules according to the study of lindsay and gerard . it was reported that aspergillomarasmine a ( ama ) , a naturally occurring fungal product , is a rapid and potent inhibitor of ndm-1 enzyme and another clinically relevant mbl , vim-2 . another promising strategy to target ndm - positive bacteria is using combination of two antibiotics . combination therapy has two desired outcomes : ( 1 ) improved treatment efficacy , and ( 2 ) reduction in the rate of mutations that result in resistance . reported in vivo activity using ceftazidime and ceftazidime - avibactam combination against ndm - producing isolates . in a case reported by honore et al . , wound cultures of a patient grew several types of bacteria including blandm-1 e. coli . but acute respiratory muscle weakness and apnea in the critically ill patient was induced by colistin neurotoxicity . worldwide reports of the ndm cases * the critically ill patient got acute respiratory muscle weakness and apnea that were induced by colistin neurotoxicity ; the final diagnosis of this patient was toxic metabolic leukoencephalopathy , probably related to sepsis . tec : teicoplanin ; tgc : tigecycline ; men : meropenem ; cip : ciprofloxacin ; va : vancomycin ; tzp : piperacillin / tazobactam ; atm : aztreonam ; cl : colistin ; mtz : metronidazole ; chl : chloramphenicol ; f / m : nitrofurantoin ; cc : clindamycin ; imp : imipenem ; co - trimoxazole : trimethoprim - sulfamethoxazole ; ndm : new delhi metallo--lactamase . with limited treatment options available , slowing and preventing the spread of blandm is essential . they reported that risk factors for hospital - associated infection include presence of co - morbid disease , mechanical ventilation and antibiotic exposure . in conclusion , we think that all necessary measures should be taken to reduce risks . first , the blandm gene has been identified in not a single species but in unrelated species ( including acinetobacter spp . ) . second , it is present not only in k. pneumoniae , but also in e. coli , which is also a major community - acquired pathogen . third , e. coli is also the number one cause of diarrhea in children in india and pakistan . the blandm gene spreading in enterobacteriaceae is an alarming risk because these novel multidrug - resistant bacteria could disseminate worldwide very quickly . in addition , the ndm-1 encoding gene is located on different large plasmids ( a 180-kb plasmid for k. pneumoniae and a 140-kb plasmid for e. coli ) that are easily transferable to susceptible e. coli j53 at a high frequency . the rapid dissemination of ndm-1 in clinically relevant bacteria has become a serious threat for therapy . a recent report indicated that in healthcare settings with source patients infected or colonized with ndm - producing bacteria , infection prevention control strategies and attention to colonization pressure will be key factors in minimizing the spread of blandm-1 plasmids in defined geographic units . the current diffusion of carbapenemase genes ( especially blandm gene ) in gram - negative rods is now a serious public health issue , and in the near future , could lead back to the preantibiotic era . the major cause of the development of drug resistance is widespread antibiotic usage , which may provide a selection force for antibiotic - resistant . in many developing countries such as india , antibiotic prescriptions are not properly followed by patients , either due to a lack of awareness about the side effects of incomplete treatment or to low socioeconomic status . apart from this , antibiotic are used widely in food animals , aquaculture , and for some commercial plants . in 2001 , the world health organization ( who ) launched a strategy to curb antibiotic resistance . the recommendations included banning the use of nonprescribed antibiotics , initiating prudent antibiotic formularies in hospitals , implementing stringent infection control policies , establishing national surveillance programs , and collaborating with international groups for better understanding of antibiotic resistance . in addition , a recent who report also recommends reducing antimicrobial use in animal husbandry . thus , antibiotic stewardship activities should be undertaken in order to reduce inappropriate use of cephalosporins , fluoroquinolones , -lactam/-lactamase inhibitor combinations , aminoglycosides , fosfomycin , tigecycline and polymyxins . measurement of the use of these antibiotics should be performed as well . in consideration of the serious situation currently , the focus must be on the following 4 aspects in the near term : ( 1 ) providing clean water and basic sanitation in the areas where the environment is already contaminated or at high risk for becoming contaminated with ndm - producing bacteria ; ( 2 ) identifying those who carry these bacteria ; ( 3 ) controlling widespread , indiscriminate use of antibiotics ; ( 4 ) preventing spread through the basic approaches of infection control . we should adherence to the standard precautions including hand hygiene , environmental cleaning and disinfecting to prevent transmission of this newest  superbug . " indeed , many countries around the world have adopted some important measures according to the above principles . for example , enhanced environmental cleaning , and active surveillance of high - risk patients with electronic tagging of colonized patient 's medical records was introduced in singapore , with isolation and cohorting of identified patients . but the lack of basic hygiene facilities in many countries has substantially exacerbated this problem . to avoid the risk of hospital acquired and patient to patient spread of these pathogens , regular training of nursing staff should be practiced so the spread of pathogens can be decreased . strict infection - control measures were effective in controlling the potential spread of this resistance at a local level . patients with a history of travel to high - risk areas and carriage of these bacteria should be sought in all hospital admissions and renal clinic attendees . at the international level , the response to the growing multidrug resistance in gram - negative bacteria should be based on implementing a worldwide surveillance network to discover and report emerging resistance traits , whether to carbapenems or to other drugs . in 2007 , a clinical isolate klebsiella pneumoniae was derived from a urinary culture of a 59-year - old male patient , who was hospitalized in ludhiana and new dehli . testing of this isolate suggested that the carbapenem resistance was due to the production of a novel mbl , designated ndm-1 , as the authors of the report believed the resistance originated from india . the same year , blandm was identified in 143 patients from multiple sites in the indian subcontinent . the infection caused by ndm - producing bacteria it has spread worldwide due to travel ,  medical tourism  and the ability of the genetic element to transfer between bacteria . antimicrobial use while traveling was an independent risk for acquisition and prolonged carriage of such organisms . the ndm-1 was found in many species of bacteria , predominantly k. pneumoniae and escherichia coli , collected in an extended survey in the uk , india , pakistan and bangladesh in 20082009 . recent reports have indicated the spread of ndm-1 and its variants in many different countries [ table 1 ] including the united states , austria , australia , norway , belgium , canada , denmark , france , germany , kenya , the netherlands , the sultanate of oman , china , hong kong , taiwan , singapore , sweden , egypt , japan , switzerland , morocco , kuwait , italy , south korea , ireland , czech republic , guatemala , new zealand , israel , iran , russia , colombia , malaysia , sri lanka , algeria , mexico , tunisia , reunion island , nepal , mauritius and honduras . in addition , the balkans region such as montenegro , serbia , bosnia  herzegovina and kosovo , and the middle east ( oman and iraq ) , may constitute an additional reservoir for ndm-1 producers , which may or may not initially have reached these countries from the indian subcontinent . in view of this situation , we believe that an immediate response to the emergence of ndm - producing bacteria should be an urgent priority worldwide . at a local level , patients with a history of travel to or originating from high - risk countries or areas should be screened for ndm - producing bacteria . initial reports of the ndm-1 and its variants * ndm-11 is assigned without any information in genbank ; the articles about ndm-10 , ndm-11 , ndm-12 and ndm-13 remain unpublished . e. coli : escherichia coli ; k. pneumonia : klebsiella pneumonia ; a. baumannii : acinetobacter baumannii ; a. lwoff ii : acinetobacter lwoffii . the problem of ndm-1 was not confined to hospital strains of bacteria but was widespread in the community environment in india . given that ndm - positive bacteria are common in the environment that many infections in india are community acquired , and that these bacteria can colonize the gastrointestinal tract , it is likely that fecal - oral transmission plays a major role in transmission occurring through contaminated food , water , and hands . detected ndm-1 carbapenemase - producing acinetobacter calcoaceticus and acinetobacter junii in environmental samples from livestock farms in china . these findings highlighted the need for improvements in sanitary conditions as a key public health intervention . recently , a novel bleomycin resistance protein has been characterized , which was associated with the blandm-1 gene as part of the same operon . walsh and colleagues hypothesized that bleomycin or bleomycin - like molecules exert a selective pressure on the large spread of the blandm-1 gene in the environment . it is possible that bleomycin - like molecules contribute to selective pressure , leading to the further spread of ndm producers in the environment . rapid detection of mbl - producing strains , including ndm producers , is necessary to prevent their dissemination and associated nosocomial infections . identification of the microorganism bacteria isolated from patients were identified via the phoenix automated phenotypic identification criteria ( becton dickinson , oxford , uk ) or with api 20e strips ( biomerieux , basingstoke , uk ) . detection of carbapenemase minimum inhibitory concentrations the first cause for suspicion that a carbapenemase is involved in a clinical infection is an elevated carbapenem minimum inhibitory concentration ( mic ) . however , elevated carbapenem mics are generally predictive of carbapenemase production in the enterobacteriaceae , full clinical resistance is not always seen . mics and carbapenem resistance were established by microbroth dilution ( phoenix ) , british society for antimicrobial chemotherapy agar dilution or disc diffusion and interpreted according to clinical and laboratory standards institute ( clsi ) guidelines . carbapenem resistant bacteria detected by mic method should be further explored for carbapenemase production by phenotypical methods . several phenotypic methods to detect mbl production have been developed , including the modified hodge test ( mht ) , the double - disk synergy tests ( ddsts ) , combined disk tests and e - test . the mht is the only clsi - recommended carbapenemase - screening method and has been widely used because of the direct analysis of the carbapenemase activity . the advantage of this method is that even the weak carbapenemase activity enzyme can be detected . however , it shows a low sensitivity of 11% when ndm carbapenemase is tested by the mht according to clsi . and many ndm - positive bacteria give negative results in particularly in acinetobacter baumannii , whereas strains with high levels of ampc can give false positives , confusing interpretation . mbl inhibitors used in these methods include the metal - chelating agent ethylenediaminetetraacetic acid ( edta ) , thiol compounds ( mercaptopropionic acid or sodium mercaptoacetic acid ) , and dipicolinic acid . the different formats include the ddsts using 2-mercaptoacetic acid or edta , combined disk tests with dipicolinic acid or edta , and ipm / ipm - edta e - test strips . in laboratories , where molecular methods are not available , the ddsts would serve as a useful screening technique . the ddst using -lactamase and -lactamase - inhibitor disks is a convenient method of detecting extended spectrum -lactamase ( esbl)-producing gram - negative bacilli . the e - test mbl strip is one of the recommended tests for detection of ndm based on inhibition of mbl activity by edta . however , false - negative results had been reported for the e - test when an isolate had an ipm mic of 4 g / ml . edta alone has inhibitory action against some bacteria and can lead to false - positive results . the e - test mbl may be used in labs that do not screen for mbl producers on a daily basis , or in those which perform susceptibility testing using liquid medium techniques and rarely use disk diffusion susceptibility techniques . in addition , the combined disk test is also based on inhibition of mbl activity by edta . ndm-1 producers are positively detected by this technique , which is reliable for detecting mbl producers on a daily basis . the gold standard for the identification of carbapenemase producers and for specific detection of blandm is molecular techniques , mostly based on pcr , ideally followed by sequencing . when the presence of a carbapenemase is suspected , pcr is the fastest way to detect blandm genes . other molecular techniques , including real - time pcr and commercial dna arrays ( check - points ) , are useful alternatives . while these assays for rapid , sensitive , and specific detection appear to be promising , pcr requires specialized high - cost instruments and consumables . some laboratories have used colony blot hybridizations to efficiently screen large numbers of clinical isolates for carbapenemase genes . and a novel nucleic acid amplification method , designated loop - mediated isothermal amplification ( lamp ) , had been well established and documented . the lamp method is demonstrated to be a potentially valuable means for the detection of blandm and rapid clinical diagnosis , being fast , simple , and low in cost . in infection due to highly resistant pathogens such as ndm - positive bacteria , antimicrobial choice is limited and requires a considered analysis of risk and benefit of available agents . ndm - producing organisms frequently carry other resistance enzymes including esbl and ampc -lactamases , rendering most available antibiotics inactive . nevertheless , these organisms are usually susceptible to polymyxin ( including colistin and polymuxin b ) and tigecycline . however , colistin has uncertain efficacy in pulmonary infections , and its use has always been hampered by the occurrence of renal toxicity , and to a lesser extent , neurological adverse effects . more importantly , carbapenem resistant bacteria such as blandm-1 e. coli and blandm-1 k. pneumoniae have become resistant to colistin . tigecycline is a glycylcycline with a wide spectrum of activity against aerobic and anaerobic gram - positive and gram - negative bacteria . though it is useful in tissue infections , it is less useful in systemic infections . in addition , tigecycline is probably not appropriate in urinary infections owing to largely biliary excretion and low urinary levels . to the best of our knowledge , albur 's research indicated that adding tigecycline to colistin does not produce increased bacterial killing . instead , it may cause antagonism at lower concentrations . based on these issues , development of molecular strategies that can rehabilitate the old antibiotics  and halt the antibiotic resistance is a promising approach to target them . reported that membrane - active macromolecules restore the antibacterial efficacy of tetracycline antibiotics toward blandm-1 k. pneumonia and blandm-1 e. coli clinical isolates . these findings have potentially important therapeutic implications in the management of patients with infections caused by ndm - producing pathogen . fosfomycin might be useful as a last - resort option as part of combination regimens . it is mainly used in the treatment of utis , particularly those caused by e. coli and enterococcus faecalis . intravenous fosfomycin has been administered in critically ill patients with sepsis or nosocomial - acquired infections due to carbapenem - resistant k. pneumoniae , in combination with other antibiotics , due to its unique mechanism of action and its protective effect against nephrotoxicity induced by aminoglycosides or colistin . many mbls - producing enterobacteriaceae additionally carry esbls or other resistant determinants that confer resistance to aztreonam . there are no published clinical data as yet to support the use of aztreonam for the treatment of infections with mbl - producing enterobacteriaceae . however , the combination of aztreonam and avibactam , a non--lactam -lactamase inhibitor , may provide a much - needed therapeutic alternative . but a four - amino - acid insertion in penicillin - binding protein 3 had reduced susceptibility to aztreonam / avibactam according to alm et al . another finding is api88 , which is a novel , highly promising , 18-residue peptide lead compound with favorable in vitro and in vivo properties including a promising safety margin . starting from the antibacterial peptide apidaecin 1b , we can treat systemic infections with the most threatening human pathogens , such as e. coli , k. pneumoniae , pseudomonas aeruginosa , and a. baumannii . new carbapenemases such as ndm-1 enzyme are surfacing , resulting in almost total resistance to -lactam antibiotics . table 2 shows 22 cases related to the infection caused by ndm - producing bacteria . facing with this serious situation , we are in urgent need of new therapeutic options . one approach to combat this growing problem is the use of combination drug antibiotic adjuvant therapy . antibiotic adjuvants include not only antibiotics but also other bioactive molecules according to the study of lindsay and gerard . it was reported that aspergillomarasmine a ( ama ) , a naturally occurring fungal product , is a rapid and potent inhibitor of ndm-1 enzyme and another clinically relevant mbl , vim-2 . ama also fully restored the activity of meropenem against enterobacteriaceae , acinetobacter spp . and pseudomonas spp . another promising strategy to target ndm - positive bacteria is using combination of two antibiotics . combination therapy has two desired outcomes : ( 1 ) improved treatment efficacy , and ( 2 ) reduction in the rate of mutations that result in resistance . reported in vivo activity using ceftazidime and ceftazidime - avibactam combination against ndm - producing isolates . in a case reported by honore et al . , wound cultures of a patient grew several types of bacteria including blandm-1 e. coli . but acute respiratory muscle weakness and apnea in the critically ill patient was induced by colistin neurotoxicity . worldwide reports of the ndm cases * the critically ill patient got acute respiratory muscle weakness and apnea that were induced by colistin neurotoxicity ; the final diagnosis of this patient was toxic metabolic leukoencephalopathy , probably related to sepsis . tec : teicoplanin ; tgc : tigecycline ; men : meropenem ; cip : ciprofloxacin ; va : vancomycin ; tzp : piperacillin / tazobactam ; atm : aztreonam ; cl : colistin ; mtz : metronidazole ; chl : chloramphenicol ; f / m : nitrofurantoin ; cc : clindamycin ; imp : imipenem ; co - trimoxazole : trimethoprim - sulfamethoxazole ; ndm : new delhi metallo--lactamase . with limited treatment options available , slowing and preventing the spread of blandm is essential . they reported that risk factors for hospital - associated infection include presence of co - morbid disease , mechanical ventilation and antibiotic exposure . in conclusion , we think that all necessary measures should be taken to reduce risks . first , the blandm gene has been identified in not a single species but in unrelated species ( including acinetobacter spp . ) . second , it is present not only in k. pneumoniae , but also in e. coli , which is also a major community - acquired pathogen . third , e. coli is also the number one cause of diarrhea in children in india and pakistan . the blandm gene spreading in enterobacteriaceae is an alarming risk because these novel multidrug - resistant bacteria could disseminate worldwide very quickly . in addition , the ndm-1 encoding gene is located on different large plasmids ( a 180-kb plasmid for k. pneumoniae and a 140-kb plasmid for e. coli ) that are easily transferable to susceptible e. coli j53 at a high frequency . the rapid dissemination of ndm-1 in clinically relevant bacteria has become a serious threat for therapy . a recent report indicated that in healthcare settings with source patients infected or colonized with ndm - producing bacteria , infection prevention control strategies and attention to colonization pressure will be key factors in minimizing the spread of blandm-1 plasmids in defined geographic units . the current diffusion of carbapenemase genes ( especially blandm gene ) in gram - negative rods is now a serious public health issue , and in the near future , could lead back to the preantibiotic era . the major cause of the development of drug resistance is widespread antibiotic usage , which may provide a selection force for antibiotic - resistant . in many developing countries such as india , antibiotic prescriptions are not properly followed by patients , either due to a lack of awareness about the side effects of incomplete treatment or to low socioeconomic status . apart from this , antibiotic are used widely in food animals , aquaculture , and for some commercial plants . in 2001 , the world health organization ( who ) launched a strategy to curb antibiotic resistance . the recommendations included banning the use of nonprescribed antibiotics , initiating prudent antibiotic formularies in hospitals , implementing stringent infection control policies , establishing national surveillance programs , and collaborating with international groups for better understanding of antibiotic resistance . in addition , a recent who report also recommends reducing antimicrobial use in animal husbandry . thus , antibiotic stewardship activities should be undertaken in order to reduce inappropriate use of cephalosporins , fluoroquinolones , -lactam/-lactamase inhibitor combinations , aminoglycosides , fosfomycin , tigecycline and polymyxins . measurement of the use of these antibiotics should be performed as well . in consideration of the serious situation currently , the focus must be on the following 4 aspects in the near term : ( 1 ) providing clean water and basic sanitation in the areas where the environment is already contaminated or at high risk for becoming contaminated with ndm - producing bacteria ; ( 2 ) identifying those who carry these bacteria ; ( 3 ) controlling widespread , indiscriminate use of antibiotics ; ( 4 ) preventing spread through the basic approaches of infection control . we should adherence to the standard precautions including hand hygiene , environmental cleaning and disinfecting to prevent transmission of this newest  superbug . " indeed , many countries around the world have adopted some important measures according to the above principles . for example , enhanced environmental cleaning , and active surveillance of high - risk patients with electronic tagging of colonized patient 's medical records was introduced in singapore , with isolation and cohorting of identified patients . but the lack of basic hygiene facilities in many countries has substantially exacerbated this problem . to avoid the risk of hospital acquired and patient to patient spread of these pathogens regular training of nursing staff should be practiced so the spread of pathogens can be decreased . strict infection - control measures were effective in controlling the potential spread of this resistance at a local level . patients with a history of travel to high - risk areas and carriage of these bacteria should be sought in all hospital admissions and renal clinic attendees . at the international level , the response to the growing multidrug resistance in gram - negative bacteria should be based on implementing a worldwide surveillance network to discover and report emerging resistance traits , whether to carbapenems or to other drugs . the most important identified reservoirs are colonized or infected individuals from endemic areas or centers with outbreaks , but the contaminated goods from these endemic areas also play a part . an international effort is needed to control the spread of these multiresistant pathogens . with limited treatment options , scientists need to develop new antibiotics and novel molecules to treat ndm - positive bacterial infections . there is an urgent need for infection control and continued global monitoring of isolates that harbor the ndm enzyme , as evidenced by recent outbreaks .
objective : to review the origin , diagnosis , treatment and public health concern of new delhi metallo--lactamase ( ndm)-producing bacteria.data sources : we searched database for studies published in english . 
 the database of pubmed from 2007 to 2015 was used to conduct a search using the keyword term  ndm and acinetobacter or enterobacteriaceae or pseudomonas aeruginosa.study selection : we collected data including the relevant articles on international transmission , testing methods and treatment strategies of ndm - positive bacteria . 
 worldwide ndm cases were reviewed based on 22 case reports.results:the first documented case of infection caused by bacteria producing ndm-1 occurred in india , in 2008 . since then , 13 blandm variants have been reported . 
 the rise of ndm is not only due to its high rate of genetic transfer among unrelated bacterial species , but also to human factors such as travel , sanitation and food production and preparation . with limited treatment options 
 , scientists try to improve available therapies and create new ones.conclusions:in order to slow down the spread of these ndm - positive bacteria , a series of measures must be implemented . the creation and transmission of blandm 
 are potentially global health issues , which are not issues for one country or one medical community , but for global priorities in general and for individual wound care practitioners specifically .