Background Many studies associated nosocomial infections with increased hospital costs due to extra days in hospital, staff time, extra investigations and drug treatment. The cost of antibiotic treatment for these infections represents a significant part of hospital expenditure. This prospective observational study was designed to determine the daily antibiotic cost of nosocomial infections per infected adult patient in Akdeniz University Hospital.
Background
Many studies associated nosocomial infections with increased hospital costs due to extra days in hospital, staff time, extra investigations and drug treatment. The cost of antibiotic treatment for these infections represents a significant part of hospital expenditure. This prospective observational study was designed to determine the daily antibiotic cost of nosocomial infections per infected adult patient in Akdeniz University Hospital.Methods All adult patients admitted to the ICUs between January 1, 2000, and June 30, 2003 who had only one nosocomial infection during their stay were included in the study. Infection sites and pathogens, antimicrobial treatment of patient and it's cost were recorded. Daily antibiotic costs were calculated per infected patient.
Methods
All adult patients admitted to the ICUs between January 1, 2000, and June 30, 2003 who had only one nosocomial infection during their stay were included in the study. Infection sites and pathogens, antimicrobial treatment of patient and it's cost were recorded. Daily antibiotic costs were calculated per infected patient.Results Among the 8460 study patients, 817 (16.6%) developed 1407 episodes of nosocomial infection. Two hundred thirty three (2.7%) presented with only one nosocomial infection. Mean daily antibiotic cost was $89.64. Daily antibiotic cost was $99.02 for pneumonia, $94.32 for bloodstream infection, $94.31 for surgical site infection, $52.37 for urinary tract infection, and $162.35 for the other infections per patient. The treatment of  Pseudomonas aeruginosa  infections was the most expensive infection treated. Piperacillin-tazobactam and amikacin were the most prescribed antibiotics, and meropenem was the most expensive drug for treatment of the nosocomial infections in the ICU.
Results
Among the 8460 study patients, 817 (16.6%) developed 1407 episodes of nosocomial infection. Two hundred thirty three (2.7%) presented with only one nosocomial infection. Mean daily antibiotic cost was $89.64. Daily antibiotic cost was $99.02 for pneumonia, $94.32 for bloodstream infection, $94.31 for surgical site infection, $52.37 for urinary tract infection, and $162.35 for the other infections per patient. The treatment of  Pseudomonas aeruginosa  infections was the most expensive infection treated. Piperacillin-tazobactam and amikacin were the most prescribed antibiotics, and meropenem was the most expensive drug for treatment of the nosocomial infections in the ICU.Pseudomonas aeruginosaConclusions Daily antibiotic cost of nosocomial infections is an important part of extra costs that should be reduced providing rational antibiotic usage in hospitals.
Conclusions
Daily antibiotic cost of nosocomial infections is an important part of extra costs that should be reduced providing rational antibiotic usage in hospitals.

Background Nosocomial infections are frequent complications of hospitalization and also an important public health problem in developing countries, as well as in developed ones. The socioeconomic impact, ie, prolongation of hospitalization, mortality, and cost of these infections adversely effects patients and nations' economic well-being [ 1 ]. The cost of nosocomial infections includes increased length of hospital stay, staff time, laboratory cultures of pathogens and antimicrobial treatment [ 2 - 4 ]. Although, cost of antimicrobial treatment is an important part of health expenditure, data on this subject are extremely limited in Turkey. The aim of our study was to determine daily antibiotic cost of nosocomial infection per infected patient in a university hospital.
Background
Nosocomial infections are frequent complications of hospitalization and also an important public health problem in developing countries, as well as in developed ones. The socioeconomic impact, ie, prolongation of hospitalization, mortality, and cost of these infections adversely effects patients and nations' economic well-being [ 1 ]. The cost of nosocomial infections includes increased length of hospital stay, staff time, laboratory cultures of pathogens and antimicrobial treatment [ 2 - 4 ]. Although, cost of antimicrobial treatment is an important part of health expenditure, data on this subject are extremely limited in Turkey.The aim of our study was to determine daily antibiotic cost of nosocomial infection per infected patient in a university hospital.Methods The hospital setting Akdeniz University Hospital is a 600-bed tertiary referral centre in Antalya, Turkey, treating 27 000 patients per year. The study was conducted in six adult medical and surgical intensive care units (ICUs) with a total of 51 ICU beds. Neonatal ICU was not included in the study. Since 1993, the institutional policies of hospital infection control have been implemented by infection control team. Definitions and study population In our hospital, routine prospective, active surveillance of nosocomial infections in all ICUs is performed by one infection control nurse, supervised by an infection control physician. Nosocomial infections are defined using the Centers for Disease Control and Prevention criteria [ 5 , 6 ]. We do not follow patients for signs of infection after discharge unless they are readmitted to the hospital. Between January 1, 2000 and June 30, 2003, all inpatients hospitalized in one of the adult ICUs were included in this study. Data on antimicrobial treatment were recorded for patients aged 15 or above presenting with only one nosocomial infection. For all patients included in the study, the following were recorded: age, sex, infection site, microbiologic data, antimicrobial therapy and antibiotic cost. Measurement of costs In our ICUs, all antimicrobial prescriptions are recommended by an infectious disease consultant. Antimicrobial agents prescribed only for therapeutic indications were recorded. The daily antibiotic cost was calculated in US dollars based on June 2003 prices of antimicrobial agents provided by the hospital pharmacy. The daily antibiotic cost per infected patient was calculated by the multiplication of box price and number of daily doses that was used for that infection. Two costs were calculated for each antimicrobial; the minimal cost (min) was based on the lowest recommended parenteral daily dose and the maximal cost (max) was based on the highest recommended parenteral daily dose.
Methods
The hospital setting Akdeniz University Hospital is a 600-bed tertiary referral centre in Antalya, Turkey, treating 27 000 patients per year. The study was conducted in six adult medical and surgical intensive care units (ICUs) with a total of 51 ICU beds. Neonatal ICU was not included in the study. Since 1993, the institutional policies of hospital infection control have been implemented by infection control team.
The hospital setting
Akdeniz University Hospital is a 600-bed tertiary referral centre in Antalya, Turkey, treating 27 000 patients per year. The study was conducted in six adult medical and surgical intensive care units (ICUs) with a total of 51 ICU beds. Neonatal ICU was not included in the study. Since 1993, the institutional policies of hospital infection control have been implemented by infection control team.Definitions and study population In our hospital, routine prospective, active surveillance of nosocomial infections in all ICUs is performed by one infection control nurse, supervised by an infection control physician. Nosocomial infections are defined using the Centers for Disease Control and Prevention criteria [ 5 , 6 ]. We do not follow patients for signs of infection after discharge unless they are readmitted to the hospital. Between January 1, 2000 and June 30, 2003, all inpatients hospitalized in one of the adult ICUs were included in this study. Data on antimicrobial treatment were recorded for patients aged 15 or above presenting with only one nosocomial infection. For all patients included in the study, the following were recorded: age, sex, infection site, microbiologic data, antimicrobial therapy and antibiotic cost.
Definitions and study population
In our hospital, routine prospective, active surveillance of nosocomial infections in all ICUs is performed by one infection control nurse, supervised by an infection control physician. Nosocomial infections are defined using the Centers for Disease Control and Prevention criteria [ 5 , 6 ]. We do not follow patients for signs of infection after discharge unless they are readmitted to the hospital.Between January 1, 2000 and June 30, 2003, all inpatients hospitalized in one of the adult ICUs were included in this study. Data on antimicrobial treatment were recorded for patients aged 15 or above presenting with only one nosocomial infection. For all patients included in the study, the following were recorded: age, sex, infection site, microbiologic data, antimicrobial therapy and antibiotic cost.Measurement of costs In our ICUs, all antimicrobial prescriptions are recommended by an infectious disease consultant. Antimicrobial agents prescribed only for therapeutic indications were recorded. The daily antibiotic cost was calculated in US dollars based on June 2003 prices of antimicrobial agents provided by the hospital pharmacy. The daily antibiotic cost per infected patient was calculated by the multiplication of box price and number of daily doses that was used for that infection. Two costs were calculated for each antimicrobial; the minimal cost (min) was based on the lowest recommended parenteral daily dose and the maximal cost (max) was based on the highest recommended parenteral daily dose.
Measurement of costs
In our ICUs, all antimicrobial prescriptions are recommended by an infectious disease consultant. Antimicrobial agents prescribed only for therapeutic indications were recorded. The daily antibiotic cost was calculated in US dollars based on June 2003 prices of antimicrobial agents provided by the hospital pharmacy. The daily antibiotic cost per infected patient was calculated by the multiplication of box price and number of daily doses that was used for that infection. Two costs were calculated for each antimicrobial; the minimal cost (min) was based on the lowest recommended parenteral daily dose and the maximal cost (max) was based on the highest recommended parenteral daily dose.Results Between January 1, 2000, and June 30, 2003, a total of 8460 patients were admitted to the adult ICUs. Overall, 817 patients developed 1407 episodes of nosocomial infections, accounting for an infection rate of 16,6%. Among them, 233 patients (mean age:50,1; sex ratio female:male 0,49) had only one nosocomial infection. Mean daily antibiotic cost was found $89,64 per infected patient ($8,56 to $359,28). Among the sites of nosocomial infections, urinary tract infections had the lowest daily antibiotic cost per infected patient (Table  1 ). The mean daily antibiotic cost for pneumonia was the highest of all sites, but patients with bloodstream infection reached the highest range of daily cost ($31,31 to $359,28). In addition, mean daily antibiotic cost was found $162,35 for seventeen other infections including postoperative meningitis, mediastinitis, and empyema. Table 1 Daily antibiotic costs according to the sites of nosocomial infections. Site of nosocomial infections Number of patients Range of daily cost per infected (US$) Mean (US$) Pneumonia 111 10,02–250,74 99,02 Bloodstream infections 28 31,31–359,28 94,32 Surgical site infections 11 17,12–204,74 94,31 Urinary tract infections 66 8,56–228,68 52,37 Out of 233 patients, 206 patients had microbiologically documented infections, 177 patients were infected by a single pathogen while 29 patients were diagnosed as having polymicrobial infections (Table  2 ).  Pseudomonas aeruginosa  was the most prevalent bacteria followed by  Klebsiella  spp. and  Acinetobacter  spp..  P. aeruginosa  infections had the highest overall daily antibiotic cost per infected patient than other pathogens. Among 21  Staphylococcus aureus  strains 15 (72%) were resistant to methicillin. The overall daily antibiotic cost of methicillin resistant  S. aureus  (MRSA) infections was two to three times higher than infections with susceptible strains. However, median daily cost per infected patient for MRSA infections were lower than susceptible strain infections. Table 2 Daily antibiotic cost according to the pathogens. Pathogens No. Overall daily cost (US$) Range of daily cost per pathogen (US$) Median (US$) Pseudomonas aeruginosa 60 5567,06 17,98–204,74 100,04 Acinetobacter  spp 36 4951,06 17,98–359,28 92,47 Stenotrophomonas maltophilia 4 310,99 31,31–100,04 89,82 Klebsiella  spp 37 3104,22 10,02–179,64 79,6 Enterobacter  spp 10 961,79 60,42–139,08 77,28 Escherichia coli 23 1652,57 10,02–179,64 60,41 Proteus  spp 3 49,04 13,24–49,04 49,04 Staphylococcus aureus Methicillin-susceptible (MS) 6 476,22 10,02–142,2 74,52 Methicillin-resistance (MR) 15 1188,1 35,88–142,2 71,1 CoNS* MS-CoNS 1 49,64 16,34–49,64 49,64 MR-CoNS 3 148,92 17,52–49,64 49,64 Enterococcus  spp 16 1141,25 32,29–142,2 49,64 Candida  spp 21 235,52 8,56–38,64 8,56 No pathogen identified 27 3166,75 10,02–359,28 114,6 * Coagulase negative  Staphylococcus Among the 350 antibiotic prescriptions for nosocomial infections, piperacillin-tazobactam and amikacin were the most prescribed antibiotics (Table  3 ). Carbapenems especially meropenem were the most expensive drugs. Table 3 Daily cost of antimicrobial agents for nosocomial infections. Antimicrobial agents Number of prescriptions Daily cost per infected (US$) Min Max Betalactams Ampicillin-sulbactam 20 23,92 71,76 Piperacillin-tazobactam 48 85,95 114,6 Ticarcillin-clavulanate 4 14,9 22,35 Carbapenems  Imipenem 31 100,04 150,06  Meropenem 23 179,64 359,28 Cephalosporins  Cefepime 26 38,64 77,28  Ceftazidime 18 35,82 71,64  Cefoperazone-sulbactam 16 40,28 80,56  Cefazoline 10 10,02 20,04  Ceftriaxone 3 19,7 39,4 Aminoglycosides*  Amikacin 52 - 7,96  Netilmicin 21 - 24,48  Tobramycin 3 - 18,56 Fluoroquinolones  Ciprofloxacin 18 49,04 98,08  Ofloxacin 2 25,74 51,48  Levofloxacin 1 41,07 82,14 Glycopeptides  Vancomycin 13 49,64 87,27  Teicoplanin 12 71,1 142,2 Other antibiotics  Clarithromycin 4 11,57 23,14  Trimethoprim-sulphamethoxazole 2 4,48 8,96  Metronidazole 2 5,51 10,04 Antifungal agents  Fluconazole 21 8,56 34,24 Total 350 8,56 359,28 * dosage given as once-daily.
Results
Between January 1, 2000, and June 30, 2003, a total of 8460 patients were admitted to the adult ICUs. Overall, 817 patients developed 1407 episodes of nosocomial infections, accounting for an infection rate of 16,6%. Among them, 233 patients (mean age:50,1; sex ratio female:male 0,49) had only one nosocomial infection. Mean daily antibiotic cost was found $89,64 per infected patient ($8,56 to $359,28).Among the sites of nosocomial infections, urinary tract infections had the lowest daily antibiotic cost per infected patient (Table  1 ). The mean daily antibiotic cost for pneumonia was the highest of all sites, but patients with bloodstream infection reached the highest range of daily cost ($31,31 to $359,28). In addition, mean daily antibiotic cost was found $162,35 for seventeen other infections including postoperative meningitis, mediastinitis, and empyema.Daily antibiotic costs according to the sites of nosocomial infections.Out of 233 patients, 206 patients had microbiologically documented infections, 177 patients were infected by a single pathogen while 29 patients were diagnosed as having polymicrobial infections (Table  2 ).  Pseudomonas aeruginosa  was the most prevalent bacteria followed by  Klebsiella  spp. and  Acinetobacter  spp..  P. aeruginosa  infections had the highest overall daily antibiotic cost per infected patient than other pathogens. Among 21  Staphylococcus aureus  strains 15 (72%) were resistant to methicillin. The overall daily antibiotic cost of methicillin resistant  S. aureus  (MRSA) infections was two to three times higher than infections with susceptible strains. However, median daily cost per infected patient for MRSA infections were lower than susceptible strain infections.Pseudomonas aeruginosaKlebsiellaAcinetobacterP. aeruginosaStaphylococcus aureusS. aureusDaily antibiotic cost according to the pathogens.Pseudomonas aeruginosaAcinetobacterStenotrophomonas maltophiliaKlebsiellaEnterobacterEscherichia coliProteusStaphylococcus aureusEnterococcusCandida* Coagulase negative  StaphylococcusStaphylococcusAmong the 350 antibiotic prescriptions for nosocomial infections, piperacillin-tazobactam and amikacin were the most prescribed antibiotics (Table  3 ). Carbapenems especially meropenem were the most expensive drugs.Daily cost of antimicrobial agents for nosocomial infections.* dosage given as once-daily.Disscussion Cost is an important factor which determines the physician's choice of medication to treat patients in spesific stiuations. In this study, we tried to demonstrate the daily cost of antimicrobial treatment of nosocomial infections according to site of infection, pathogen and antimicrobial agent. In different studies, economical analysis regarding costs attributable to nosocomial infections has been evaluated and reported between $1018 to 2280 per infected patient [ 7 - 9 ]. Jarvis et al reported that the estimated average costs of nosocomial infections were $558 to 593 for each urinary tract infection, $2734 for each surgical site infection, $3061 to 40000 for each bloodstream infection, and $4947 for each pneumonia [ 1 ]. Daily cost of antimicrobial treatment has been reported to be a significant extra cost attributable to nosocomial infections. In this study, we found an average daily antibiotic cost of $89,64 per nosocomial infection. It is clear that cost of overall antibiotic treatment for a period of approximately 10–15 days is $900 to $1350. Prolongation of hospital stay has been the major extra cost attributable to nosocomial infections in many reports [ 2 - 4 ], but in comparative case-control study from our country, Yalcin et al. [ 8 ] found that cost of antibiotic therapy of $1190 per infected patient, accounted for about 75% of the total extra cost. This finding may be due to the high prices of antibiotics in Turkey. To calculate the true costs of antibiotic therapy, hidden costs arising from intravenous administration, labor, serum antibiotic assay, monitoring hematological and biochemical indices and adverse effects of antibiotics must be considered [ 10 ]. The present study does not include these relevant "hidden costs" that could substantially modify the total cost of an antibiotic treatment. Although, hidden costs were not calculated, an average daily antibiotic cost of a single nosocomial infection is found to be markedly high in our hospital. This result is within the limits reported by other large economic studies, suggesting that our data is comparable to those found in other countries and with other assessment methods. In a French prevalence survey, Astagneau et al.[ 11 ] reported an average daily antibiotic cost between FF 520 to 1085 (about $86 to $160) per nosocomial infection. French et al.[ 12 ] and Haley et al.[ 13 ] reported an average cost of antibiotic treatment of $190 and between $72 to $128 per nosocomial infection, respectively. In Turkey, Yalcin et al.[ 14 ] found that daily antibiotic cost of nosocomial infections was $70 per patient. The daily antibiotic cost varies markedly according to site of infection. Our study has demonstrated that pneumonia and bloodstream infections were associated with the highest daily antibiotic costs as reported in other studies [ 11 , 13 , 14 ]. Surgical site infections had also high daily antibiotic cost in our study. In their case-control study, Coello et al. reported that antibiotic therapy for surgical patients was the second most significant contributor to cost [ 15 ]. In the present study, nosocomially infected patients that had only one nosocomial infection were considered for analysis. Clearly, antimicrobial treatment of patients with multiple nosocomial infections might be much more expensive. P. aeruginosa  infections had the highest daily antibiotic cost followed by other non-fermentative bacilli. Infections caused by  P. aeruginosa  are difficult to treat because of its virulence and relatively limited choice of effective antimicrobial agents, so, these infections often require combination therapy. Emergence of resistance in  P. aeruginosa  has been associated with increased morbidity, mortality, and costs [ 16 ]. On the other hand, although the overall antibiotic cost of MRSA infections was higher than infections with susceptible strains, the daily antibiotic cost per infected patient with MRSA was lower with susceptible strain infections. MRSA infections are treated by glycopeptides which cost less than beta-lactams in our country. Astagneau et al reported that the daily antibiotic cost of multi-resistant bacterial infections such as multi-resistant  P. aeruginosa  infections, was 20% higher than susceptible infections, but the daily antibiotic cost per infected patient for MRSA infections was not higher than for susceptible strain infections [ 11 ]. Expensive antibiotics, such as piperacillin-tazobactam, carbapenems, cefepime, ciprofloxacin, teicoplanin were prescribed more commonly than the cheaper agents such as ampicillin-sulbactam, ceftriaxone or ofloxacin in our ICUs. These expensive antibiotics were mainly prescribed for resistant and severe gram-negative nosocomial infections, such as ventilator-associated pneumonia and postneurosurgical meningitis in ICU. Physicians may be forced to choose empirical antibiotic therapy with broad spectrum antimicrobials by increasing bacterial multi-resistance. In conclusion, mean daily antibiotic cost was found $89,64 per nosocomial infection in our ICUs and nosocomial pneumonia had the highest daily antibiotic cost per infected patient. It is clear that cost of antibiotic therapy of nosocomial infections is an important part of extra cost attributable to nosocomial infection. Approximately one third of nosocomial infections are preventable by full implementation of the current infection control guideline recommendations [ 17 ]. Each institution should develope empirical antibiotic guidelines according to its own local nosocomial infections data. Infection control measures, such as education of health care workers regarding antimicrobial agents and resistance; isolation of patients infected with multi-resistant organisms, should be implemented to reduce infections and expensive antibiotic prescriptions.
Disscussion
Cost is an important factor which determines the physician's choice of medication to treat patients in spesific stiuations. In this study, we tried to demonstrate the daily cost of antimicrobial treatment of nosocomial infections according to site of infection, pathogen and antimicrobial agent.In different studies, economical analysis regarding costs attributable to nosocomial infections has been evaluated and reported between $1018 to 2280 per infected patient [ 7 - 9 ]. Jarvis et al reported that the estimated average costs of nosocomial infections were $558 to 593 for each urinary tract infection, $2734 for each surgical site infection, $3061 to 40000 for each bloodstream infection, and $4947 for each pneumonia [ 1 ].Daily cost of antimicrobial treatment has been reported to be a significant extra cost attributable to nosocomial infections. In this study, we found an average daily antibiotic cost of $89,64 per nosocomial infection. It is clear that cost of overall antibiotic treatment for a period of approximately 10–15 days is $900 to $1350. Prolongation of hospital stay has been the major extra cost attributable to nosocomial infections in many reports [ 2 - 4 ], but in comparative case-control study from our country, Yalcin et al. [ 8 ] found that cost of antibiotic therapy of $1190 per infected patient, accounted for about 75% of the total extra cost. This finding may be due to the high prices of antibiotics in Turkey. To calculate the true costs of antibiotic therapy, hidden costs arising from intravenous administration, labor, serum antibiotic assay, monitoring hematological and biochemical indices and adverse effects of antibiotics must be considered [ 10 ]. The present study does not include these relevant "hidden costs" that could substantially modify the total cost of an antibiotic treatment. Although, hidden costs were not calculated, an average daily antibiotic cost of a single nosocomial infection is found to be markedly high in our hospital.This result is within the limits reported by other large economic studies, suggesting that our data is comparable to those found in other countries and with other assessment methods. In a French prevalence survey, Astagneau et al.[ 11 ] reported an average daily antibiotic cost between FF 520 to 1085 (about $86 to $160) per nosocomial infection. French et al.[ 12 ] and Haley et al.[ 13 ] reported an average cost of antibiotic treatment of $190 and between $72 to $128 per nosocomial infection, respectively. In Turkey, Yalcin et al.[ 14 ] found that daily antibiotic cost of nosocomial infections was $70 per patient.The daily antibiotic cost varies markedly according to site of infection. Our study has demonstrated that pneumonia and bloodstream infections were associated with the highest daily antibiotic costs as reported in other studies [ 11 , 13 , 14 ]. Surgical site infections had also high daily antibiotic cost in our study. In their case-control study, Coello et al. reported that antibiotic therapy for surgical patients was the second most significant contributor to cost [ 15 ]. In the present study, nosocomially infected patients that had only one nosocomial infection were considered for analysis. Clearly, antimicrobial treatment of patients with multiple nosocomial infections might be much more expensive.P. aeruginosa  infections had the highest daily antibiotic cost followed by other non-fermentative bacilli. Infections caused by  P. aeruginosa  are difficult to treat because of its virulence and relatively limited choice of effective antimicrobial agents, so, these infections often require combination therapy. Emergence of resistance in  P. aeruginosa  has been associated with increased morbidity, mortality, and costs [ 16 ]. On the other hand, although the overall antibiotic cost of MRSA infections was higher than infections with susceptible strains, the daily antibiotic cost per infected patient with MRSA was lower with susceptible strain infections. MRSA infections are treated by glycopeptides which cost less than beta-lactams in our country. Astagneau et al reported that the daily antibiotic cost of multi-resistant bacterial infections such as multi-resistant  P. aeruginosa  infections, was 20% higher than susceptible infections, but the daily antibiotic cost per infected patient for MRSA infections was not higher than for susceptible strain infections [ 11 ].P. aeruginosaP. aeruginosaP. aeruginosaP. aeruginosaExpensive antibiotics, such as piperacillin-tazobactam, carbapenems, cefepime, ciprofloxacin, teicoplanin were prescribed more commonly than the cheaper agents such as ampicillin-sulbactam, ceftriaxone or ofloxacin in our ICUs. These expensive antibiotics were mainly prescribed for resistant and severe gram-negative nosocomial infections, such as ventilator-associated pneumonia and postneurosurgical meningitis in ICU. Physicians may be forced to choose empirical antibiotic therapy with broad spectrum antimicrobials by increasing bacterial multi-resistance.In conclusion, mean daily antibiotic cost was found $89,64 per nosocomial infection in our ICUs and nosocomial pneumonia had the highest daily antibiotic cost per infected patient. It is clear that cost of antibiotic therapy of nosocomial infections is an important part of extra cost attributable to nosocomial infection. Approximately one third of nosocomial infections are preventable by full implementation of the current infection control guideline recommendations [ 17 ]. Each institution should develope empirical antibiotic guidelines according to its own local nosocomial infections data. Infection control measures, such as education of health care workers regarding antimicrobial agents and resistance; isolation of patients infected with multi-resistant organisms, should be implemented to reduce infections and expensive antibiotic prescriptions.Competing interests The author(s) declare that they have no competing interests.
Competing interests
The author(s) declare that they have no competing interests.Authors' conributions DI collated and analyzed the data, participated in the study design and was principal writer of manuscript. ANY conceived the study. GO carried out the laboratory studies. RS, FG, OT and LM participated in the patient management. All authors read and approved the final manuscript.
Authors' conributions
DI collated and analyzed the data, participated in the study design and was principal writer of manuscript. ANY conceived the study. GO carried out the laboratory studies. RS, FG, OT and LM participated in the patient management. All authors read and approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


Cell and molecular biologists have a good start at understanding the adult salamander's enviable ability to completely regrow a lost limb or jaw. (Salamanders can even regenerate portions of their eyes and heart.) Happily, mammals share many of the required cellular skills—though in an untapped form. In response to injury, fully differentiated salamander muscle cells can produce less specialized cells that are capable of multiplying and recreating lost tissue. In this month's  PLoS Biology , biochemist Jeremy Brockes and his colleagues at University College London tie this muscle cell de-differentiation to expression of a single gene,  Msx1 , a player in limb development and regeneration across species.PLoS BiologyMsx1The protein encoded by  Msx1  appears at the borders of maturing tissues in salamanders, chickens, and mice, and represses differentiation of muscle cells (called myofibers) during development.  Msx1  promotes amphibian limb and tail regeneration, zebrafish fin repair, and regrowth of the tips of digits in mice. Here, Anoop Kumar et al. clarify the gene's role in muscle repair by demonstrating that  Msx1  expression is required for de-differentiation of salamander myofibers—mature muscle tissue without the ability to produce new cells—into cells with single nuclei (mononucleate cells) that are able to multiply.Msx1Msx1Msx1Large, elongated cells, myofibers are distinguished by a striped pattern of actin and myosin, the proteins that produce muscle contractions. They develop from precursor cells, which proliferate and fuse together into multinucleate intermediates called myotubes. As myotubes bulk up on actin and myosin, pushing their many nuclei to the cell periphery, they mature into myofibers. Once differentiated, myofibers are committed to the life of a muscle workhorse. They cannot divide; mature muscle in mammals adds strength and repairs injury by accumulating more actin and myosin, and by fusing single-nucleus “satellite” cells into new or existing myofibers.Unlike their mammalian counterparts, salamander and newt myofibers respond to injury by splitting into several multinucleated fragments, or by budding off several of their nuclei to create individual cells. These mononucleate progeny multiply and develop to replace lost tissue. Kumar et al. found that more than half of salamander myofibers spontaneously fragment and bud when dissected and placed in cell culture. Prior study has shown that mouse myofibers don't normally behave this way, although cultured mouse myotubes can imitate amphibian myofibers if given a push, in the form of  Msx1 . A fraction of mouse myotubes made to express  Msx1  break off mononucleate cells that can be induced to express markers for bone, cartilage, fat, or muscle.Msx1Msx1In the salamander cells,  Msx1  RNA and protein appeared in actively fragmenting and budding myofibers, especially in and around their nuclei. When Kumar et al. blocked the translation of  Msx1  mRNA, the myofibers did not generate new cells.Msx1Msx1The results confirm  Msx1  as a pivotal regulator of muscle cell re-entry into the cycle of cell division and tissue growth. In this context, it doesn't drive cell division—on the contrary, the authors showed that  Msx1  induced cell splitting without DNA replication. The gene drove committed muscle cells to donate nuclei, creating a pool of new cells to divide, differentiate, and repair damage. Given what it can do for mouse cells in culture, the question remains whether  Msx1  might help awaken a latent capacity for regeneration in living mammals.Msx1Msx1Msx1