Inappropriate Use of Antibiotic Prophylaxis to Prevent Infective Endocarditis in Obstetric Patients
Sean B. Pocock, MD, MPH1 and Katherine T. Chen, MD, MPH1
From the 1Department of Obstetrics and Gynecology and Epidemiology, Columbia University, New York, New York.
OBJECTIVE:
To evaluate infective endocarditis prophylaxis practices during the intrapartum period and to assess obstetric providers’ adherence to the American Heart Association and American College of Obstetrics and Gynecology guidelines for infective endocarditis prophylaxis.
METHODS:
We performed a chart review of pharmacy, electronic nursing, and physician records to report this case series of obstetric patients who received infective endocarditis prophylaxis during the intrapartum period at a single tertiary referral care center during a 1-year study period from August 1, 2004, to July 31, 2005.
RESULTS:
Fifty patients received antibiotics for infective endocarditis prophylaxis. Three of the 50 patients who received infective endocarditis prophylaxis had high-risk cardiac lesions and three other patients had moderate-risk cardiac lesions and evidence for intrapartum infection. Thus, only six patients (12.0%, 95% confidence interval 4.5%–24.3%) met the American Heart Association and American College of Obstetricians and Gynecologists criteria for an appropriate indication for infective endocarditis prophylaxis. Of these six patients who had an appropriate indication for infective endocarditis prophylaxis, only three (50.0%, 95% confidence interval 11.8%–88.2%) received appropriate antibiotic regimens.
CONCLUSION:
Antibiotics are frequently given to obstetric patients during pregnancy. Although many obstetric patients receive antibiotics for recommended indications, some patients, as our study shows, do not. A concerted effort by all practitioners and institutions to reduce the amount of inappropriate antibiotics given to obstetric patients will have positive public health effects in addition to benefiting individual mothers and neonates.
LEVEL OF EVIDENCE: II-3
Obstetrics & Gynecology
Wednesday, October 18, 2006
Friday, October 06, 2006
The dearth of new antibiotic development
The dearth of new antibiotic development: why we should be worried and what we can do about it.
eMJA The Medical Journal of Australia
Patrick G P Charles and M Lindsay Grayson
2004
Abstract
The emergence and spread of multidrug-resistant pathogens has increased substantially over the past 20 years.
Over the same period, the development of new antibiotics has decreased alarmingly, with many pharmaceutical companies pulling out of antibiotic research in favour of developing “lifestyle” drugs.
Reasons given for withdrawing from antibiotic development include poor “net present value” status of antibiotics, changes in regulations requiring larger drug trials and prolonged post-marketing surveillance, clinical preference for narrow-spectrum rather than broad-spectrum agents, and high new-drug purchase costs.
Major improvements in infection control in Australia are needed to prevent further spread of resistant clones, buying some time to develop urgently needed new antibiotic agents.
Perpetuating a culture of “pharma bashing” will simply lead to more pharmaceutical companies withdrawing from the market. A change in the health and research culture is needed to improve cooperation between public, academic and private sectors.
Article
Antibiotic resistance is a natural phenomenon — resistant strains of Staphylococcus aureus were encountered soon after the introduction of penicillin into clinical medicine in 1941 by Florey, Chain and colleagues.1-3 The story of penicillin’s discovery and then manufacture in sufficient quantities to treat injured troops at the D-Day landing in 1944 is also notable, because it was probably the last time an antimicrobial was developed to such an initial extent by anyone other than a large pharmaceutical company.4 To our knowledge, since the time of Florey, no government (regardless of its rhetoric) has developed a single new antimicrobial, and, while many clinicians criticise the activities of the big drug manufacturers, it is these companies that have been responsible for almost all new antimicrobial research and development during the past half-century.5 Although antibiotic development was rapid between the 1950s and the 1970s, with multiple new drugs being developed, many of these gains have been eroded over the past 30 years because of the rapid emergence of and spread of resistance to antimicrobials.6 Here, we explain what lies behind the developing resistance and why, despite a seemingly crowded current antibiotic market, the true picture is that our antibiotic development pipeline has been reduced to a trickle. We propose some problem-based solutions that could help prevent, or at least delay, a return to the dangers of the pre-antibiotic era.
Why do we need new antibiotics?
Burgeoning resistance
The increasing prevalence of resistant pathogens is mainly related to either the emergence of new strains or the spread of existing resistant clones. The specific mechanisms of drug resistance are important in determining its likely reversibility. For instance, plasmid-mediated resistance (eg, ampicillin resistance in Escherichia coli) is more likely to be reversible when exposure to the relevant antibiotic is withdrawn than chromosomally mediated resistance (eg, fluoroquinolone resistance in gram-negative bacteria), which is often a “one-way street”, with reversal much less likely.7
Although the emergence of resistant clones is crucial, the factor responsible for most resistance problems is patient-to-patient spread of existing resistant clones, usually on the hands of healthcare workers or on shared equipment in hospitals,8-11 aided by the increasing immunological frailty of many hospital inpatients.7
Inappropriate antibiotic use is a key driver of resistance, but the reasons for such use can be complex.7 In developed countries, the obsession with “zero risk” has distorted the decision-making process for many clinicians, with broad-spectrum antibiotics being used even when not indicated. Pharmaceutical marketing often targets such clinician insecurity, and rational debate is not always helped by the growing band of “microbiology accountants”, who report the percentage of resistant strains among their laboratory collections of pathogens rather than the likelihood of resistant pathogens among patients presenting with a particular disease.
Appropriate antibiotic prescribing has also been affected by the threat of bioterrorism.12 For instance, although the anthrax strain used in the 2001 US anthrax attacks was susceptible to both tetracyclines and penicillin, 32 000 government workers and other contacts were treated with oral ciprofloxacin for up to 60 days as prophylaxis, just in case the strain was capable of producing β-lactamase.13
Underpowered response?
The current antibiotic market is fairly crowded with agents, but many of these are “me-too” antibiotics — drugs from the same class developed by competing companies (eg, fluoroquinolones and third-generation cephalosporins). There has been a decline in registration of new antibiotics. A summary of new antibiotics and older antibiotics with new indications or treatment options is given in Box 1.
Several of the “new” antibiotics were actually discovered in the 1980s. Their development stalled because of poor initial results or problems with toxicity, but, more recently, desperation has led to renewed research interest in these drug classes, especially agents for treating gram-positive pathogens (Box 2). For example, daptomycin was initially studied in the early 1990s but was “shelved” due to toxicity, especially its potential to cause myositis. Its use at a lower dose has now been reassessed.18,19
Oritavancin, tigecycline and ramoplanin are the only truly new antibiotic agents that are likely to enter the Australian market in the next 5 years, with only tigecycline likely to be active against gram-negative bacteria.20,21 Because of this and the worsening problem of multiresistant Acinetobacter spp., Pseudomonas aeruginosa and Klebsiella spp., clinicians have been forced to use more toxic older agents such as colistin (Box 1).22
Why is the new-antibiotic pipeline running dry?
Large pharmaceutical companies are primarily responsible for new antibiotic development, with 93% of new agents developed between 1980 and 2003 coming from this source, rather than small biotechnology companies or small pharmaceutical manufacturers.5 The cost of researching and developing any new drug is generally in excess of US$500 million, and it usually takes about 8–10 years from the time a drug is first developed to the time it is released for sale.5,6 Naturally, pharmaceutical companies will only take this risk if there is reasonable likelihood of recouping development costs and making a profit. The pharmaceutical industry is under considerable financial pressure, with many companies believing they need to get bigger to survive and to afford the research needed for drug licensing. However, with more than 40 companies merging and consolidating over the past 20 years, there are now only about eight companies still undertaking some antibiotic research and development.23,24 This is because, during the past 10–15 years, a number of key factors (discussed below) have combined to reduce pharmaceutical companies’ interest in antibiotic development.
Relatively low “net present value”
For an increasing number of pharmaceutical companies, antibiotics are financially less attractive to develop than drugs for other indications (Box 3). Antibiotics are generally used for short periods for specific, relatively narrow indications. In comparison, other agents (eg, lipid-lowering agents) are often commenced at a relatively young age, are taken by a large proportion of the population for many years without much restriction, and are not subject to the emergence of resistance. Further, in contrast to the restrictions placed on antibiotics, there are few guidelines (or physician experts) advising against widespread use of these agents.25
Conducting clinical trials is one of the major expenditures in developing any new drug, and a separate clinical trial is needed for each potential indication for a drug. The complexity of conducting clinical trials for antibiotics adds to the costs associated with their development and licensure.
Such financial considerations are often summarised by a drug’s “net present value” (NPV). This is what the drug’s future is worth in today’s money. Usually, the NPV is then risk-adjusted (rNPV), based on the extent to which the drug has been developed. For instance, an antibiotic in Phase III trials carries less risk than one early in development (most antibiotics in Phase III trials have an 87% “success rate”).24 Thus, it is no surprise that antibiotics have a lower rNPV than many other drug classes. In fact, in some industry estimates, injectable antibiotics rank well behind musculoskeletal, neuroscience and oncology agents and vaccines in terms of rNPV.24
Stricter standards for equivalence
Most antibiotic trials are “equivalence” trials, whereby the new drug is required to have equivalent or similar efficacy to an older, comparator agent that is already licensed for the relevant indication. The amount to which the efficacy of the new agent can differ from the comparator and still be considered sufficiently similar to be “equivalent” is called the “delta” value. Until recently, the standard for most antibiotic trials in which a drug’s efficacy was estimated to be 80%–90% was a delta value of 15% — that is, as long as the new antibiotic was within 15% of the efficacy of the comparator (ie, no more than 15% better or worse) it was considered statistically equivalent. Such trials would generally be used to support the licensure of the new drug for the studied indication. Because of concerns about possible “downward” drift in efficacy over time, some regulatory authorities have proposed that the delta value be reduced to 10%. The effect of this proposal would be to more than double the number of patients who need to be enrolled in antibiotic trials to demonstrate the new standard of “equivalence” (eg, for a study of community-acquired pneumonia, 1500–2200 patients would be required instead of 600–1000).25 Increased patient recruitment would add to trial costs.
Further, for some relatively uncommon, but important, indications, this increase in required patient recruitment would be unachievable from a clinical perspective, or would result in the trial becoming so prolonged that the comparator drug may no longer be considered appropriate due to the emergence of antibiotic resistance. It is believed that the proposed change in the trial delta value was a key reason for at least two major manufacturers withdrawing from antibiotic research prior to 2002.26
Risk of rapidly emerging antibiotic resistance
While the presence of antibiotic resistance among key clinical pathogens can be an important driver of new antibiotic development, it can also be a disincentive. This is especially the case if resistance to a new agent is emerging quickly, so that clinical trials cannot be completed without a substantial number of the enrolled patients being infected with new, highly resistant strains. This mostly affects trials associated with relatively rare clinical conditions (eg, bacterial meningitis or endocarditis), for which trials may take many years and require many enrolment sites to complete. However, it is often these uncommon, clinically devastating diseases that most require the development of new antibiotics to overcome the reduced efficacy of older agents.
Cross-class resistance can be a particular problem, as the development of resistance to either the new agent or the older comparator during a trial can make the assessment of either equivalence or superiority clinically irrelevant, and thus devalue the trial.
Clinical preference for narrow-spectrum agents
Given the costs associated with drug development, many companies attempt to design agents with a broad antibacterial spectrum to make them more suitable for a wide variety of indications. However, to avoid rapid emergence of resistance, many infectious disease experts often prefer that new antibiotics be used for specific, narrow indications for which the efficacy of older agents has become a problem. Thus, while pharmaceutical companies are pressing for multi-indication use to recoup their development costs, regulatory authorities frequently limit a new drug’s indications.
Varying licensure regulations
Conducting clinical trials to obtain multi-indication licensure is complicated by the fact that licensing requirements can vary between the United States, the United Kingdom, Europe, Australia and South America. Although there have been attempts to streamline these regulatory requirements, differences remain, so that pharmaceutical companies invariably target their most profitable market (generally the United States) when designing trials, even though other markets may have a greater disease burden and clinical need for the new agent.7 The World Health Organization and other agencies have tried to help standardise regulatory requirements, but progress has been slow.
Relatively high purchase price
Invariably, new agents are more expensive to users than their older comparators, as they are still under patent protection, and companies attempt to recoup their development costs during the patent period. In Australia, the initial high cost of some agents often leads to restrictions on their use both in hospitals and by the Pharmaceutical Benefits Scheme. In some developing countries, this high cost of a new drug encourages pharmaceutical companies that make generic drugs to ignore patent law and produce the drug at reduced cost, thereby often further eroding the new drug’s market.7
Increased post-marketing surveillance
Post-marketing surveillance of new drugs has been a growing requirement of most regulatory authorities over the past 20 years. For some agents, this has been vital in identifying important toxicities (eg, hepatotoxicity associated with trovafloxacin), but, for others, it has identified potential adverse effects that, although important, would not overly limit use of the drug if the clinical indication were sufficiently worthy (eg, the possibility of elevated liver enzyme levels and some blurred vision associated with use of telithromycin).23,24 However, the requirement for companies to maintain detailed post-marketing surveillance programs adds to a drug’s development costs and reduces its NPV, as some commercial risk persists after a drug is licensed.
How can we improve the situation?
In the near future, there appears to be little that can be done to overcome the current and impending shortage of new agents. Instead, there must be a greater focus on appropriate infection control measures to limit the spread of resistant clones within hospitals and reduce the emergence of new resistant strains by restricting unnecessary antibiotic use in humans and in agriculture.7,27
In Australia, the current hyperendemic spread of methicillin-resistant S. aureus within most large hospitals is a reflection of past apathy and woeful infection control measures in the 1970s and 1980s. The same mistakes must not be repeated with vancomycin-resistant enterococci, S aureus with reduced vancomycin susceptibility, and multiresistant Acinetobacter.28-30
Governments need to prioritise funding for effective infection control measures, such as patient cohorting and isolation (ie, greater access to single rooms) and improved hand hygiene among healthcare workers through the use of alcohol/chlorhexidine-based handrub to minimise transmission of resistant pathogens.11 Neglecting these issues will inevitably undermine current healthcare gains.
To encourage renewed interest in antibiotic research and development, a number of approaches have been suggested, many of which we believe could be effective:
Standardise regulation and licensure. Standard requirements for drug regulation in the United States, United Kingdom, Europe and other regions could have substantial benefits by reducing the number of clinical trials needed to obtain widespread licensure.
Specify appropriate antibiotic comparators. The proposal for a 10% delta value arose in response to concerns about downward drift in comparator efficacy. An alternative way of reducing the likelihood of inadequate efficacy would be for regulatory agencies to specify the appropriate antibiotic comparator required for each indication. This approach would allow the 15% delta value (and thus the current number of patients required for each trial) to be maintained.
Broaden the funding base for drug research and development. To reduce the financial risk of developing new drugs, antibiotic research and development could be co-funded by pharmaceutical companies, governments and public academic institutions.27 Tax incentives for companies to perform work in identifying new drugs might help.7
Increase cooperation between academic institutions and pharmaceutical companies. More research into the mechanisms of antibiotic resistance and bacterial physiology would allow the development of antimicrobials with new mechanisms of action, as occurred with the recently discovered CBR703 class of molecules, which inhibit bacterial RNA polymerase.31
Fast-track drug licensure when needed. For high-priority diseases, where resistance is a major clinical problem, a new system of fast-tracking licensure of potential agents is necessary to enhance clinical availability while continuing to monitor potential adverse reactions. The current system of fast-tracking drugs for treating HIV could serve as a useful model.7
Extending the duration of patent protection (so-called “exclusivity”) has also been proposed as a way of encouraging antibiotic research and development. However, we believe this is unlikely to be particularly effective, as the later years of a drug’s patent are heavily discounted in the NPV calculation because of the emergence of resistance and higher likelihood of generic pharmaceutical companies ignoring patent regulations and producing the drug at lower cost.
Conclusion
Declining antibiotic research and development at a time of increasing emergence and spread of resistant pathogens poses a major challenge to our society if we are to avoid a return to the pre-antibiotic era for many infections. Perpetuating a culture of “pharma bashing” will simply lead to more pharmaceutical companies withdrawing from the market. Crucial to success will be a change in the health and research culture towards greater cooperation between the public, academic and private sectors. Improving infection control initiatives will buy some time, but, given the lag between antibiotic development and eventual availability, we need to develop a sensible strategy soon to avoid problems in the next one to two decades.
e Medical Journal of Australia
eMJA The Medical Journal of Australia
Patrick G P Charles and M Lindsay Grayson
2004
Abstract
The emergence and spread of multidrug-resistant pathogens has increased substantially over the past 20 years.
Over the same period, the development of new antibiotics has decreased alarmingly, with many pharmaceutical companies pulling out of antibiotic research in favour of developing “lifestyle” drugs.
Reasons given for withdrawing from antibiotic development include poor “net present value” status of antibiotics, changes in regulations requiring larger drug trials and prolonged post-marketing surveillance, clinical preference for narrow-spectrum rather than broad-spectrum agents, and high new-drug purchase costs.
Major improvements in infection control in Australia are needed to prevent further spread of resistant clones, buying some time to develop urgently needed new antibiotic agents.
Perpetuating a culture of “pharma bashing” will simply lead to more pharmaceutical companies withdrawing from the market. A change in the health and research culture is needed to improve cooperation between public, academic and private sectors.
Article
Antibiotic resistance is a natural phenomenon — resistant strains of Staphylococcus aureus were encountered soon after the introduction of penicillin into clinical medicine in 1941 by Florey, Chain and colleagues.1-3 The story of penicillin’s discovery and then manufacture in sufficient quantities to treat injured troops at the D-Day landing in 1944 is also notable, because it was probably the last time an antimicrobial was developed to such an initial extent by anyone other than a large pharmaceutical company.4 To our knowledge, since the time of Florey, no government (regardless of its rhetoric) has developed a single new antimicrobial, and, while many clinicians criticise the activities of the big drug manufacturers, it is these companies that have been responsible for almost all new antimicrobial research and development during the past half-century.5 Although antibiotic development was rapid between the 1950s and the 1970s, with multiple new drugs being developed, many of these gains have been eroded over the past 30 years because of the rapid emergence of and spread of resistance to antimicrobials.6 Here, we explain what lies behind the developing resistance and why, despite a seemingly crowded current antibiotic market, the true picture is that our antibiotic development pipeline has been reduced to a trickle. We propose some problem-based solutions that could help prevent, or at least delay, a return to the dangers of the pre-antibiotic era.
Why do we need new antibiotics?
Burgeoning resistance
The increasing prevalence of resistant pathogens is mainly related to either the emergence of new strains or the spread of existing resistant clones. The specific mechanisms of drug resistance are important in determining its likely reversibility. For instance, plasmid-mediated resistance (eg, ampicillin resistance in Escherichia coli) is more likely to be reversible when exposure to the relevant antibiotic is withdrawn than chromosomally mediated resistance (eg, fluoroquinolone resistance in gram-negative bacteria), which is often a “one-way street”, with reversal much less likely.7
Although the emergence of resistant clones is crucial, the factor responsible for most resistance problems is patient-to-patient spread of existing resistant clones, usually on the hands of healthcare workers or on shared equipment in hospitals,8-11 aided by the increasing immunological frailty of many hospital inpatients.7
Inappropriate antibiotic use is a key driver of resistance, but the reasons for such use can be complex.7 In developed countries, the obsession with “zero risk” has distorted the decision-making process for many clinicians, with broad-spectrum antibiotics being used even when not indicated. Pharmaceutical marketing often targets such clinician insecurity, and rational debate is not always helped by the growing band of “microbiology accountants”, who report the percentage of resistant strains among their laboratory collections of pathogens rather than the likelihood of resistant pathogens among patients presenting with a particular disease.
Appropriate antibiotic prescribing has also been affected by the threat of bioterrorism.12 For instance, although the anthrax strain used in the 2001 US anthrax attacks was susceptible to both tetracyclines and penicillin, 32 000 government workers and other contacts were treated with oral ciprofloxacin for up to 60 days as prophylaxis, just in case the strain was capable of producing β-lactamase.13
Underpowered response?
The current antibiotic market is fairly crowded with agents, but many of these are “me-too” antibiotics — drugs from the same class developed by competing companies (eg, fluoroquinolones and third-generation cephalosporins). There has been a decline in registration of new antibiotics. A summary of new antibiotics and older antibiotics with new indications or treatment options is given in Box 1.
Several of the “new” antibiotics were actually discovered in the 1980s. Their development stalled because of poor initial results or problems with toxicity, but, more recently, desperation has led to renewed research interest in these drug classes, especially agents for treating gram-positive pathogens (Box 2). For example, daptomycin was initially studied in the early 1990s but was “shelved” due to toxicity, especially its potential to cause myositis. Its use at a lower dose has now been reassessed.18,19
Oritavancin, tigecycline and ramoplanin are the only truly new antibiotic agents that are likely to enter the Australian market in the next 5 years, with only tigecycline likely to be active against gram-negative bacteria.20,21 Because of this and the worsening problem of multiresistant Acinetobacter spp., Pseudomonas aeruginosa and Klebsiella spp., clinicians have been forced to use more toxic older agents such as colistin (Box 1).22
Why is the new-antibiotic pipeline running dry?
Large pharmaceutical companies are primarily responsible for new antibiotic development, with 93% of new agents developed between 1980 and 2003 coming from this source, rather than small biotechnology companies or small pharmaceutical manufacturers.5 The cost of researching and developing any new drug is generally in excess of US$500 million, and it usually takes about 8–10 years from the time a drug is first developed to the time it is released for sale.5,6 Naturally, pharmaceutical companies will only take this risk if there is reasonable likelihood of recouping development costs and making a profit. The pharmaceutical industry is under considerable financial pressure, with many companies believing they need to get bigger to survive and to afford the research needed for drug licensing. However, with more than 40 companies merging and consolidating over the past 20 years, there are now only about eight companies still undertaking some antibiotic research and development.23,24 This is because, during the past 10–15 years, a number of key factors (discussed below) have combined to reduce pharmaceutical companies’ interest in antibiotic development.
Relatively low “net present value”
For an increasing number of pharmaceutical companies, antibiotics are financially less attractive to develop than drugs for other indications (Box 3). Antibiotics are generally used for short periods for specific, relatively narrow indications. In comparison, other agents (eg, lipid-lowering agents) are often commenced at a relatively young age, are taken by a large proportion of the population for many years without much restriction, and are not subject to the emergence of resistance. Further, in contrast to the restrictions placed on antibiotics, there are few guidelines (or physician experts) advising against widespread use of these agents.25
Conducting clinical trials is one of the major expenditures in developing any new drug, and a separate clinical trial is needed for each potential indication for a drug. The complexity of conducting clinical trials for antibiotics adds to the costs associated with their development and licensure.
Such financial considerations are often summarised by a drug’s “net present value” (NPV). This is what the drug’s future is worth in today’s money. Usually, the NPV is then risk-adjusted (rNPV), based on the extent to which the drug has been developed. For instance, an antibiotic in Phase III trials carries less risk than one early in development (most antibiotics in Phase III trials have an 87% “success rate”).24 Thus, it is no surprise that antibiotics have a lower rNPV than many other drug classes. In fact, in some industry estimates, injectable antibiotics rank well behind musculoskeletal, neuroscience and oncology agents and vaccines in terms of rNPV.24
Stricter standards for equivalence
Most antibiotic trials are “equivalence” trials, whereby the new drug is required to have equivalent or similar efficacy to an older, comparator agent that is already licensed for the relevant indication. The amount to which the efficacy of the new agent can differ from the comparator and still be considered sufficiently similar to be “equivalent” is called the “delta” value. Until recently, the standard for most antibiotic trials in which a drug’s efficacy was estimated to be 80%–90% was a delta value of 15% — that is, as long as the new antibiotic was within 15% of the efficacy of the comparator (ie, no more than 15% better or worse) it was considered statistically equivalent. Such trials would generally be used to support the licensure of the new drug for the studied indication. Because of concerns about possible “downward” drift in efficacy over time, some regulatory authorities have proposed that the delta value be reduced to 10%. The effect of this proposal would be to more than double the number of patients who need to be enrolled in antibiotic trials to demonstrate the new standard of “equivalence” (eg, for a study of community-acquired pneumonia, 1500–2200 patients would be required instead of 600–1000).25 Increased patient recruitment would add to trial costs.
Further, for some relatively uncommon, but important, indications, this increase in required patient recruitment would be unachievable from a clinical perspective, or would result in the trial becoming so prolonged that the comparator drug may no longer be considered appropriate due to the emergence of antibiotic resistance. It is believed that the proposed change in the trial delta value was a key reason for at least two major manufacturers withdrawing from antibiotic research prior to 2002.26
Risk of rapidly emerging antibiotic resistance
While the presence of antibiotic resistance among key clinical pathogens can be an important driver of new antibiotic development, it can also be a disincentive. This is especially the case if resistance to a new agent is emerging quickly, so that clinical trials cannot be completed without a substantial number of the enrolled patients being infected with new, highly resistant strains. This mostly affects trials associated with relatively rare clinical conditions (eg, bacterial meningitis or endocarditis), for which trials may take many years and require many enrolment sites to complete. However, it is often these uncommon, clinically devastating diseases that most require the development of new antibiotics to overcome the reduced efficacy of older agents.
Cross-class resistance can be a particular problem, as the development of resistance to either the new agent or the older comparator during a trial can make the assessment of either equivalence or superiority clinically irrelevant, and thus devalue the trial.
Clinical preference for narrow-spectrum agents
Given the costs associated with drug development, many companies attempt to design agents with a broad antibacterial spectrum to make them more suitable for a wide variety of indications. However, to avoid rapid emergence of resistance, many infectious disease experts often prefer that new antibiotics be used for specific, narrow indications for which the efficacy of older agents has become a problem. Thus, while pharmaceutical companies are pressing for multi-indication use to recoup their development costs, regulatory authorities frequently limit a new drug’s indications.
Varying licensure regulations
Conducting clinical trials to obtain multi-indication licensure is complicated by the fact that licensing requirements can vary between the United States, the United Kingdom, Europe, Australia and South America. Although there have been attempts to streamline these regulatory requirements, differences remain, so that pharmaceutical companies invariably target their most profitable market (generally the United States) when designing trials, even though other markets may have a greater disease burden and clinical need for the new agent.7 The World Health Organization and other agencies have tried to help standardise regulatory requirements, but progress has been slow.
Relatively high purchase price
Invariably, new agents are more expensive to users than their older comparators, as they are still under patent protection, and companies attempt to recoup their development costs during the patent period. In Australia, the initial high cost of some agents often leads to restrictions on their use both in hospitals and by the Pharmaceutical Benefits Scheme. In some developing countries, this high cost of a new drug encourages pharmaceutical companies that make generic drugs to ignore patent law and produce the drug at reduced cost, thereby often further eroding the new drug’s market.7
Increased post-marketing surveillance
Post-marketing surveillance of new drugs has been a growing requirement of most regulatory authorities over the past 20 years. For some agents, this has been vital in identifying important toxicities (eg, hepatotoxicity associated with trovafloxacin), but, for others, it has identified potential adverse effects that, although important, would not overly limit use of the drug if the clinical indication were sufficiently worthy (eg, the possibility of elevated liver enzyme levels and some blurred vision associated with use of telithromycin).23,24 However, the requirement for companies to maintain detailed post-marketing surveillance programs adds to a drug’s development costs and reduces its NPV, as some commercial risk persists after a drug is licensed.
How can we improve the situation?
In the near future, there appears to be little that can be done to overcome the current and impending shortage of new agents. Instead, there must be a greater focus on appropriate infection control measures to limit the spread of resistant clones within hospitals and reduce the emergence of new resistant strains by restricting unnecessary antibiotic use in humans and in agriculture.7,27
In Australia, the current hyperendemic spread of methicillin-resistant S. aureus within most large hospitals is a reflection of past apathy and woeful infection control measures in the 1970s and 1980s. The same mistakes must not be repeated with vancomycin-resistant enterococci, S aureus with reduced vancomycin susceptibility, and multiresistant Acinetobacter.28-30
Governments need to prioritise funding for effective infection control measures, such as patient cohorting and isolation (ie, greater access to single rooms) and improved hand hygiene among healthcare workers through the use of alcohol/chlorhexidine-based handrub to minimise transmission of resistant pathogens.11 Neglecting these issues will inevitably undermine current healthcare gains.
To encourage renewed interest in antibiotic research and development, a number of approaches have been suggested, many of which we believe could be effective:
Standardise regulation and licensure. Standard requirements for drug regulation in the United States, United Kingdom, Europe and other regions could have substantial benefits by reducing the number of clinical trials needed to obtain widespread licensure.
Specify appropriate antibiotic comparators. The proposal for a 10% delta value arose in response to concerns about downward drift in comparator efficacy. An alternative way of reducing the likelihood of inadequate efficacy would be for regulatory agencies to specify the appropriate antibiotic comparator required for each indication. This approach would allow the 15% delta value (and thus the current number of patients required for each trial) to be maintained.
Broaden the funding base for drug research and development. To reduce the financial risk of developing new drugs, antibiotic research and development could be co-funded by pharmaceutical companies, governments and public academic institutions.27 Tax incentives for companies to perform work in identifying new drugs might help.7
Increase cooperation between academic institutions and pharmaceutical companies. More research into the mechanisms of antibiotic resistance and bacterial physiology would allow the development of antimicrobials with new mechanisms of action, as occurred with the recently discovered CBR703 class of molecules, which inhibit bacterial RNA polymerase.31
Fast-track drug licensure when needed. For high-priority diseases, where resistance is a major clinical problem, a new system of fast-tracking licensure of potential agents is necessary to enhance clinical availability while continuing to monitor potential adverse reactions. The current system of fast-tracking drugs for treating HIV could serve as a useful model.7
Extending the duration of patent protection (so-called “exclusivity”) has also been proposed as a way of encouraging antibiotic research and development. However, we believe this is unlikely to be particularly effective, as the later years of a drug’s patent are heavily discounted in the NPV calculation because of the emergence of resistance and higher likelihood of generic pharmaceutical companies ignoring patent regulations and producing the drug at lower cost.
Conclusion
Declining antibiotic research and development at a time of increasing emergence and spread of resistant pathogens poses a major challenge to our society if we are to avoid a return to the pre-antibiotic era for many infections. Perpetuating a culture of “pharma bashing” will simply lead to more pharmaceutical companies withdrawing from the market. Crucial to success will be a change in the health and research culture towards greater cooperation between the public, academic and private sectors. Improving infection control initiatives will buy some time, but, given the lag between antibiotic development and eventual availability, we need to develop a sensible strategy soon to avoid problems in the next one to two decades.
e Medical Journal of Australia
Saturday, September 30, 2006
Antibiotic-Associated Colitis
Antibiotic-Associated Colitis
Antibiotic-associated colitis is inflammation of the large intestine caused by the growth of unusual bacteria that results from the use of antibiotics.
Many antibiotics alter the balance among the types and quantity of bacteria in the intestine, thus allowing certain disease-causing bacteria to multiply and replace other bacteria. The type of bacteria that most commonly overgrows and causes infection is Clostridium difficile. Clostridium difficile infection releases two toxins that can damage the protective lining of the large intestine.
Almost any antibiotic can cause this disorder, but clindamycinSome Trade Names CLEOCIN, penicillins such as ampicillinSome Trade Names OMNIPENPOLYCILLINPRINCIPEN, and cephalosporins such as cephalexinSome Trade Names KEFLEXare implicated most often. Other commonly involved antibiotics include erythromycinSome Trade Names E-MYCINERYTHROCINILOSONE, sulfonamides such as sulfamethoxazoleSome Trade Names GANTANOL, chloramphenicolSome Trade Names CHLOROMYCETIN, tetracyclineSome Trade Names ACHROMYCIN VTETRACYNSUMYCIN, and quinolones such as norfloxacinSome Trade Names NOROXIN.
Clostridium difficile infection is most common when an antibiotic is taken by mouth, but it also occurs when antibiotics are injected or administered intravenously. The risk of developing antibiotic-associated colitis increases with age.
Symptoms
Symptoms usually begin while the person is taking antibiotics. However, in one third of people who have this disorder, symptoms do not appear until 1 to 10 days after treatment has stopped, and in some people, symptoms do not appear for as long as 6 weeks afterward.
Symptoms vary according to the degree of inflammation caused by the bacteria, ranging from slightly loose stools to bloody diarrhea, abdominal pain, and fever. The most severe cases may involve life-threatening dehydration, low blood pressure, toxic megacolon (see Inflammatory Bowel Diseases: Complications), and perforation of the large intestine
Diagnosis
The diagnosis of antibiotic-associated colitis is confirmed when one of the toxins produced by Clostridium difficile is identified in a stool sample. A toxin is found in about 20% of people with mild antibiotic-associated colitis and in more than 90% of those with severe antibiotic-associated colitis. Sometimes two or three stool samples must be obtained before the toxin is detected.
A doctor can also diagnose antibiotic-associated colitis by inspecting the lower part of the inflamed large intestine (the sigmoid colon), usually through a sigmoidoscope (a rigid or flexible viewing tube). A colonoscope (a longer flexible viewing tube) is used to examine the entire large intestine if the diseased section of intestine is higher than the reach of the sigmoidoscope. These procedures, however, usually are not required.
Treatment
If a person with antibiotic-associated colitis has diarrhea while taking antibiotics, the drugs are discontinued immediately unless they are essential. Drugs that slow the movement of the intestine, such as diphenoxylate, generally are avoided because they may prolong the disorder by keeping the disease-causing toxin in contact with the large intestine. Antibiotic-induced diarrhea without complications usually subsides on its own within 10 to 12 days after the antibiotic has been stopped. When it does, no other therapy is required. However, if mild symptoms persist, cholestyramineSome Trade Names QUESTRANmay be effective, probably because it binds itself to the toxin.
For most cases of more severe antibiotic-associated colitis, the antibiotic metronidazoleSome Trade Names FLAGYLis effective against Clostridium difficile. The antibiotic vancomycinSome Trade Names VANCOCINis reserved for the most severe or resistant cases. Symptoms return in up to 20% of people with this disorder, and treatment with antibiotics is repeated. If diarrhea returns repeatedly, prolonged antibiotic therapy may be needed. Some people are treated with preparations of lactobacillus given by mouth or bacteroides given rectally to restock the intestine with normal bacteria; however, these treatments are not used routinely.
Rarely, antibiotic-associated colitis is so severe that the person must be hospitalized to receive intravenous fluids, electrolytes (such as sodium, magnesium, calcium, and potassium), and blood transfusions. A temporary ileostomy (a surgically created connection between the small intestine and an opening in the abdominal wall that diverts stool from the large intestine and rectum) or surgical removal of the large intestine occasionally is needed in these severe cases as a lifesaving measure.
Merck
Friday, September 22, 2006
Prophylactic antibiotic use in open fractures: an evidence-based guideline.
Prophylactic antibiotic use in open fractures: an evidence-based guideline.
Surg Infect (Larchmt). 2006 Aug;7(4):379-405
Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey.
Background:
Prolonged courses of broad-spectrum antibiotics are often cited as the standard of care for prevention of infective complications of open fractures. The origins of these recommendations are obscure, however, and multi-drug-resistant systemic infections attributable to antibiotic overuse are common life-threatening problems in current intensive care unit practice.
Objective:
To review systematically the effects of prophylactic antibiotic administration on the incidence of infections complicating open fractures.
Data Sources:
Computerized bibliographic search of published research and citation review of relevant articles.
Study Selection:
All published clinical trials claiming to evaluate, or cited elsewhere as being authoritative regarding, the role of antibiotics in open fracture management were identified and then evaluated according to published guidelines for evidence-based medicine. Only small studies (<20>
Data Extraction:
Information on demographics, study dates, fracture grade, antibiotic type, duration and route of administration, surgical interventions, infection-related outcomes, and the methodologic quality of the studies was extracted by the authors. The primary results were submitted to the Therapeutic Agents Committee of the Surgical Infection Society for review prior to creation of the final consensus document.
Data Synthesis:
Current antibiotic management of open fractures is based on a small number of studies that generally are more than 30 years old and do not reflect current management priorities in trauma and critical care. With a few noteworthy exceptions, these primary studies suffer from a variety of methodologic problems, including commingling of prospective and retrospective data sets, absence of or inappropriate statistical analysis, lack of blinding, or failure of randomization.
PMID: 16978082 [PubMed - in process]
Friday, September 15, 2006
A Non-Nephrotoxic Gentamicin Congener That Retains Antimicrobial Efficacy.
A Non-Nephrotoxic Gentamicin Congener That Retains Antimicrobial Efficacy.
Sept 13, 2006
Sandoval RM,
Reilly JP,
Running W,
Campos SB,
Santos JR,
Phillips CL,
Molitoris BA.
*Indiana University School of Medicine, Division of Nephrology, Indiana Center for Biological Microscopy, Indiana University Department of Pathology & Laboratory Medicine, and paragraph signRoudebush Veterans Administration Medical Center, Indianapolis, and Indiana University Department of Chemistry, Bloomington, Indiana.
Aminoglycoside antibiotics, although of major clinical importance in the treatment of serious Gram- negative infections and a potential therapeutic agent in the amelioration of diseases that are characterized by premature stop mutations, are associated with a high incidence of acute renal failure. With the use of HPLC techniques, the four components (congeners) of gentamicin, the most commonly used aminoglycoside, were isolated and characterized. Described here is a congener with minimal cytotoxicity in cell culture and animal studies that retained normal bactericidal properties in both Bacillus subtilis and a multidrug-resistant form of Klebsiella pneumoniae.
Furthermore, in animal studies, this congener failed to induce the functional and pathologic changes that are characteristic of gentamicin nephrotoxicity that is seen with the native compound. Finally, internalization of this non-nephrotoxic component was unaltered, but the subcellular distribution was different from native gentamicin or the other three cytotoxic congeners. These studies have identified a component of the native gentamicin congener mixture that retains its bactericidal properties with minimal or no apparent nephrotoxicity.
PMID: 16971659 [PubMed - as supplied by publisher]
Sept 13, 2006
Sandoval RM,
Reilly JP,
Running W,
Campos SB,
Santos JR,
Phillips CL,
Molitoris BA.
*Indiana University School of Medicine, Division of Nephrology, Indiana Center for Biological Microscopy, Indiana University Department of Pathology & Laboratory Medicine, and paragraph signRoudebush Veterans Administration Medical Center, Indianapolis, and Indiana University Department of Chemistry, Bloomington, Indiana.
Aminoglycoside antibiotics, although of major clinical importance in the treatment of serious Gram- negative infections and a potential therapeutic agent in the amelioration of diseases that are characterized by premature stop mutations, are associated with a high incidence of acute renal failure. With the use of HPLC techniques, the four components (congeners) of gentamicin, the most commonly used aminoglycoside, were isolated and characterized. Described here is a congener with minimal cytotoxicity in cell culture and animal studies that retained normal bactericidal properties in both Bacillus subtilis and a multidrug-resistant form of Klebsiella pneumoniae.
Furthermore, in animal studies, this congener failed to induce the functional and pathologic changes that are characteristic of gentamicin nephrotoxicity that is seen with the native compound. Finally, internalization of this non-nephrotoxic component was unaltered, but the subcellular distribution was different from native gentamicin or the other three cytotoxic congeners. These studies have identified a component of the native gentamicin congener mixture that retains its bactericidal properties with minimal or no apparent nephrotoxicity.
PMID: 16971659 [PubMed - as supplied by publisher]
Friday, September 08, 2006
Impact of piperacillin resistance on the outcome of Pseudomonas ventilator-associated pneumonia.
Impact of piperacillin resistance on the outcome of Pseudomonas ventilator-associated pneumonia.
Sept 7, 2006
Combes A,
Luyt CE,
Fagon JY,
Wolff M,
Trouillet JL,
Chastre J.
Groupe Hospitalier Pitie-Salpetriere, Assistance Publique, Hopitaux de Paris Universite Pierre et Marie Curie, Paris 6, Service de Reanimation Medicale, Institut de Cardiologie, 47, boulevard de l'Hopital, 75651, Paris Cedex 13, France, alain.combes@psl.aphp.fr.
BACKGROUND:
The impact of antibiotic resistance on the outcome of infections due to Gram-negative bacilli, especially Pseudomonas, remains highly controversial.
STUDY OBJECTIVE, DESIGN, AND PATIENTS:
We evaluated the impact of piperacillin resistance on the outcomes of Pseudomonas aeruginosa ventilator-associated pneumonia (VAP) for patients who had received appropriate empiric antibiotics before enrollment in the PNEUMA trial, a multicenter randomized study comparing 8 vs 15[Symbol: see text]days of antibiotics.
RESULTS:
Despite similar characteristics at intensive care unit (ICU) admission, patients infected with piperacillin-resistant Pseudomonas strains were more acutely ill at VAP onset and had a higher 28-day mortality rate (37 vs 19%; P[Symbol: see text]=[Symbol: see text]0.04) than those with piperacillin-susceptible Pseudomonas VAP. Factors associated with 28-day mortality retained by multivariable analysis were: age (OR: 1.07; 95% CI: 1.03-1.12); female gender (OR: 4.00; 95% CI: 1.41-11.11); severe underlying comorbidities (OR: 2.73; 95% CI: 1.02-7.33); and SOFA score (OR: 1.17; 95% CI: 1.03-1.32), but piperacillin resistance did not reach statistical significance (OR: 2.00; 95% CI: 0.72-5.61). The VAP recurrence rates, either superinfection or relapse, and durations of mechanical ventilation and ICU stay did not differ as a function of Pseudomonas-resistance status.
CONCLUSIONS:
For patients with Pseudomonas VAP benefiting from appropriate empiric antibiotics, piperacillin resistance was associated with increased disease severity at VAP onset and higher 28-day crude mortality; however, after controlling for confounders, piperacillin-resistance was no longer significantly associated with 28-day mortality. The VAP recurrence rates and durations of ICU stay and mechanical ventilation did not differ for susceptible and resistant strains.
PMID: 16957901 [PubMed - as supplied by publisher]
Sept 7, 2006
Combes A,
Luyt CE,
Fagon JY,
Wolff M,
Trouillet JL,
Chastre J.
Groupe Hospitalier Pitie-Salpetriere, Assistance Publique, Hopitaux de Paris Universite Pierre et Marie Curie, Paris 6, Service de Reanimation Medicale, Institut de Cardiologie, 47, boulevard de l'Hopital, 75651, Paris Cedex 13, France, alain.combes@psl.aphp.fr.
BACKGROUND:
The impact of antibiotic resistance on the outcome of infections due to Gram-negative bacilli, especially Pseudomonas, remains highly controversial.
STUDY OBJECTIVE, DESIGN, AND PATIENTS:
We evaluated the impact of piperacillin resistance on the outcomes of Pseudomonas aeruginosa ventilator-associated pneumonia (VAP) for patients who had received appropriate empiric antibiotics before enrollment in the PNEUMA trial, a multicenter randomized study comparing 8 vs 15[Symbol: see text]days of antibiotics.
RESULTS:
Despite similar characteristics at intensive care unit (ICU) admission, patients infected with piperacillin-resistant Pseudomonas strains were more acutely ill at VAP onset and had a higher 28-day mortality rate (37 vs 19%; P[Symbol: see text]=[Symbol: see text]0.04) than those with piperacillin-susceptible Pseudomonas VAP. Factors associated with 28-day mortality retained by multivariable analysis were: age (OR: 1.07; 95% CI: 1.03-1.12); female gender (OR: 4.00; 95% CI: 1.41-11.11); severe underlying comorbidities (OR: 2.73; 95% CI: 1.02-7.33); and SOFA score (OR: 1.17; 95% CI: 1.03-1.32), but piperacillin resistance did not reach statistical significance (OR: 2.00; 95% CI: 0.72-5.61). The VAP recurrence rates, either superinfection or relapse, and durations of mechanical ventilation and ICU stay did not differ as a function of Pseudomonas-resistance status.
CONCLUSIONS:
For patients with Pseudomonas VAP benefiting from appropriate empiric antibiotics, piperacillin resistance was associated with increased disease severity at VAP onset and higher 28-day crude mortality; however, after controlling for confounders, piperacillin-resistance was no longer significantly associated with 28-day mortality. The VAP recurrence rates and durations of ICU stay and mechanical ventilation did not differ for susceptible and resistant strains.
PMID: 16957901 [PubMed - as supplied by publisher]
Friday, September 01, 2006
Antibiotics and Severe pseudomonal infections.
Antibiotics and Severe pseudomonal infections.
Curr Opin Crit Care. 2006 Oct;12(5):458-63.
Mutlu GM,
Wunderink RG.
Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
PURPOSE OF REVIEW:
To review the most recent data on severe Pseudomonas aeruginosa infections. The focus will be on clinical studies with an emphasis on the critically ill.
RECENT FINDINGS:
The frequency of P. aeruginosa as the etiologic agent of infections associated with high morbidity and mortality in hospitalized patients continues to increase. Unfortunately, pan-resistant isolates are now emerging as a significant clinical problem. Highly or pan-resistant isolates are associated with more frequent inappropriate initial therapy and increased mortality. Prevention relies on limitation of antibiotic pressure. Unfortunately, antibiotic class rotation has not resulted in persistent decreases in resistant isolates and the increased use of treatment protocols may actually increase selection.
SUMMARY:
Because of the frequency of antibiotic resistance in clinical isolates of P. aeruginosa and the high associated mortality, combination, broad-spectrum antibiotic therapy should be used for empiric coverage of suspected P. aeruginosa infections. Accurate diagnostic testing can help to discontinue unnecessary antibiotics and decrease the overall selective pressure. Increasing resistance without new antibiotic classes on the horizon suggests the need for better use of available antibiotics and an emphasis on innovative treatment strategies in the future.
PMID: 16943726 [PubMed - in process]
Curr Opin Crit Care. 2006 Oct;12(5):458-63.
Mutlu GM,
Wunderink RG.
Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
PURPOSE OF REVIEW:
To review the most recent data on severe Pseudomonas aeruginosa infections. The focus will be on clinical studies with an emphasis on the critically ill.
RECENT FINDINGS:
The frequency of P. aeruginosa as the etiologic agent of infections associated with high morbidity and mortality in hospitalized patients continues to increase. Unfortunately, pan-resistant isolates are now emerging as a significant clinical problem. Highly or pan-resistant isolates are associated with more frequent inappropriate initial therapy and increased mortality. Prevention relies on limitation of antibiotic pressure. Unfortunately, antibiotic class rotation has not resulted in persistent decreases in resistant isolates and the increased use of treatment protocols may actually increase selection.
SUMMARY:
Because of the frequency of antibiotic resistance in clinical isolates of P. aeruginosa and the high associated mortality, combination, broad-spectrum antibiotic therapy should be used for empiric coverage of suspected P. aeruginosa infections. Accurate diagnostic testing can help to discontinue unnecessary antibiotics and decrease the overall selective pressure. Increasing resistance without new antibiotic classes on the horizon suggests the need for better use of available antibiotics and an emphasis on innovative treatment strategies in the future.
PMID: 16943726 [PubMed - in process]
Saturday, August 26, 2006
Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections.
Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections.
Li J,
Nation RL,
Turnidge JD,
Milne RW,
Coulthard K,
Rayner CR,
Paterson DL.
Facility for Anti-infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia.
Increasing multidrug resistance in Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago.
We summarise recent progress in understanding the complex chemistry, pharmacokinetics, and pharmacodynamics of colistin, the interplay between these three aspects, and their effect on the clinical use of this important antibiotic. Recent clinical findings are reviewed, focusing on evaluation of efficacy, emerging resistance, potential toxicities, and combination therapy.
In the battle against rapidly emerging bacterial resistance we can no longer rely entirely on the discovery of new antibiotics; we must also pursue rational approaches to the use of older antibiotics such as colistin.
PMID: 16931410 [PubMed - in process]
Related Articles
Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria.
Li J,
Nation RL,
Turnidge JD,
Milne RW,
Coulthard K,
Rayner CR,
Paterson DL.
Facility for Anti-infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia.
Increasing multidrug resistance in Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago.
We summarise recent progress in understanding the complex chemistry, pharmacokinetics, and pharmacodynamics of colistin, the interplay between these three aspects, and their effect on the clinical use of this important antibiotic. Recent clinical findings are reviewed, focusing on evaluation of efficacy, emerging resistance, potential toxicities, and combination therapy.
In the battle against rapidly emerging bacterial resistance we can no longer rely entirely on the discovery of new antibiotics; we must also pursue rational approaches to the use of older antibiotics such as colistin.
PMID: 16931410 [PubMed - in process]
Related Articles
Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria.
Sunday, August 20, 2006
Efficacy and safety of Sultamicillin and Amoxicillin/Clavulanic Acid in the treatment of upper respiratory tract infections
[Efficacy and safety of Sultamicillin (Ampicillin/Sulbactan) and Amoxicillin/Clavulanic Acid in the treatment of upper respiratory tract infections in adults: an open-label, multicentric, randomized trial.]
Feb 2006
Ferreira JB,
Rapoport PB,
Sakano E,
Kos AO,
Piltcher OB,
Pignatari SS,
Pinheiro SD,
Mocellin M.
Servico de Otorrinolaringologia, Depto. de Cirurgia, Faculdade de Medicina, UFG.
Upper respiratory tract infections are the most common causes of medical visits in children and adults, demanding massive use of antibiotics. Bacterial resistance caused by beta-lactamase is one of the most serious problems in this matter. Sultamicillin, a double pro-drug of Ampicillin/Sulbactan, is a potent beta-lactamase inhibitor which can face this challenge. AIM: evaluate efficacy, safety and tolerability of Ampicillin/Sulbactan compared to Amoxicillin/Clavulanate in upper respiratory tract infections in adults.
METHODS:
102 patients were enrolled and randomized to receive Ampicillin/Sulbactan or Amoxicillin/Clavulanate during 10 days. They were evaluated 10 and 30 days after treatment to learn about the therapeutic response.
RESULTS:
There were no differences between the two groups respecting cure at the end of treatment (visit 2) or at the end of the study (visit 3). Cure ratio was 61.7% and 93.2% (visits 2 and 3) in the Amoxicillin/Clavulanate group compared to 64.4% and 97.4%, respectively, in Ampicillin/Sulbactan group. The adverse events ratio for the two groups was the same (p=0.940). The number of patients with diarrhea was greater in the group of patients receiving Amoxicillin/Clavulanate (70.6%) than in the group receiving Ampicillin/Sulbactan (29.4%) (p=0.0164).
CONCLUSIONS:
Ampicillin/Sulbactan is as safe and efficient as Amoxicillin/Clavulanate in the empiric treatment of upper respiratory infections in adults. The low occurrence of diarrhea in the group receiving Ampicillin/Sulbactan needs confirmation in other studies.
PMID: 16917560 [PubMed - in process]
Monday, August 14, 2006
Antibiotics / anti-inflammatories for reducing acute inflammatory episodes in lymphoedema of the limbs.
Antibiotics / anti-inflammatories for reducing acute inflammatory episodes in lymphoedema of the limbs.
Badger C,
Seers K,
Preston N,
Mortimer P.
BACKGROUND: Lymphoedema is a chronic and progressive condition and current debate revolves around the best course of management for infective/inflammatory episodes.
OBJECTIVES: To determine whether antibiotic/anti-inflammatory drugs given prophylactically reduce the number and severity of infective/inflammatory episodes in patients with lymphoedema.
SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group register in September 2003, the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2003), CINAHL, MEDLINE, PASCAL, SIGLE, UnCover, reference lists produced by The British Lymphology Society, the National Research Register (NRR) and the International Society of Lymphology congress proceedings.
SELECTION CRITERIA: Types of studies considered for review were randomised controlled trials testing an antibiotic or anti-inflammatory drug against placebo (with or without physical therapies). DATA
COLLECTION AND ANALYSIS: Eligibility for inclusion was confirmed by two blinded reviewers who screened the papers independently using a checklist of criteria relating to the randomisation and blinding of a trial. Both reviewers extracted data from the eligible studies using a data extraction form.
MAIN RESULTS: Overall, four studies (364 randomised patients) were included. Two of these studied the effects of intensive physical treatment plus selenium or placebo in preventing AIE, and two studied the effects of Ivermectin, Diethylcarbamazine (DEC) (anti-filarial agents) and penicillin as prophylactic treatment for adeno lymphangitis(ADL) versus placebo.Both selenium trials reported no inflammatory episodes during the trial period in the treated group but one case of infection in the two placebo groups respectively during the first three weeks of each trial. Seven additional cases of infection in trial one and 14 cases in trial two required treatment in the three month follow up period.One anti filarial trial reported a total of 127 ADL episodes for all groups during the treatment year (compared with 684 episodes reported for the same participants during the pre-treatment year). Another 228 ADL episodes were reported during the trial follow-up year but no significant differences were found between the three groups. No apparent link was found between the grade of oedema and the frequency of ADL episodes. However, there was a significant link between increased episodes and the rainy season. In the penicillin group the mean number of inflammatory episodes was reduced from 4.6 to 0.5 after treatment and increased to 1.9 at the end of the follow-up year.
REVIEWERS' CONCLUSIONS: The effectiveness of selenium in preventing AIE in lymphoedema remains inconclusive in the absence of properly conducted randomised controlled trials. Anti-filarials (DEC and Ivermectin) do not appear to reduce ADL episodes in filarial lymphoedema. Foot care may be important in reducing ADL episodes, and penicillin appears to contribute to a significant reduction in ADL, when combined with foot-care. It seems reasonable to emphasise the importance of foot-care to patients and practitioners in preventing infection and this may also apply to care of the arm in women who develop lymphoedema following breast cancer treatment. However, properly conducted trials are needed to demonstrate any efficacy of these interventions.
PMID: 15106193 [PubMed - indexed for MEDLINE]
Badger C,
Seers K,
Preston N,
Mortimer P.
BACKGROUND: Lymphoedema is a chronic and progressive condition and current debate revolves around the best course of management for infective/inflammatory episodes.
OBJECTIVES: To determine whether antibiotic/anti-inflammatory drugs given prophylactically reduce the number and severity of infective/inflammatory episodes in patients with lymphoedema.
SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group register in September 2003, the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2003), CINAHL, MEDLINE, PASCAL, SIGLE, UnCover, reference lists produced by The British Lymphology Society, the National Research Register (NRR) and the International Society of Lymphology congress proceedings.
SELECTION CRITERIA: Types of studies considered for review were randomised controlled trials testing an antibiotic or anti-inflammatory drug against placebo (with or without physical therapies). DATA
COLLECTION AND ANALYSIS: Eligibility for inclusion was confirmed by two blinded reviewers who screened the papers independently using a checklist of criteria relating to the randomisation and blinding of a trial. Both reviewers extracted data from the eligible studies using a data extraction form.
MAIN RESULTS: Overall, four studies (364 randomised patients) were included. Two of these studied the effects of intensive physical treatment plus selenium or placebo in preventing AIE, and two studied the effects of Ivermectin, Diethylcarbamazine (DEC) (anti-filarial agents) and penicillin as prophylactic treatment for adeno lymphangitis(ADL) versus placebo.Both selenium trials reported no inflammatory episodes during the trial period in the treated group but one case of infection in the two placebo groups respectively during the first three weeks of each trial. Seven additional cases of infection in trial one and 14 cases in trial two required treatment in the three month follow up period.One anti filarial trial reported a total of 127 ADL episodes for all groups during the treatment year (compared with 684 episodes reported for the same participants during the pre-treatment year). Another 228 ADL episodes were reported during the trial follow-up year but no significant differences were found between the three groups. No apparent link was found between the grade of oedema and the frequency of ADL episodes. However, there was a significant link between increased episodes and the rainy season. In the penicillin group the mean number of inflammatory episodes was reduced from 4.6 to 0.5 after treatment and increased to 1.9 at the end of the follow-up year.
REVIEWERS' CONCLUSIONS: The effectiveness of selenium in preventing AIE in lymphoedema remains inconclusive in the absence of properly conducted randomised controlled trials. Anti-filarials (DEC and Ivermectin) do not appear to reduce ADL episodes in filarial lymphoedema. Foot care may be important in reducing ADL episodes, and penicillin appears to contribute to a significant reduction in ADL, when combined with foot-care. It seems reasonable to emphasise the importance of foot-care to patients and practitioners in preventing infection and this may also apply to care of the arm in women who develop lymphoedema following breast cancer treatment. However, properly conducted trials are needed to demonstrate any efficacy of these interventions.
PMID: 15106193 [PubMed - indexed for MEDLINE]
Thursday, August 10, 2006
WHO issues guidelines on use of cotrimoxazole prophylaxis
WHO issues guidelines on use of cotrimoxazole prophylaxis
Theo Smart, Thursday, August 10, 2006
Cotrimoxazole prophylaxis should be widely used by people with progressing HIV disease and by all HIV-infected or exposed infants (until it is clear that they are uninfected) according to guidelines issued this week by the World Health Organization (WHO).
In fact, where HIV prevalence is high, infectious diseases common and healthcare infrastructure is limited, governments may want to consider simply giving cotrimoxazole to everyone with HIV and to infants known or suspected of having been exposed to HIV, says WHO.
Background on cotrimoxazole prophylaxis Cotrimoxazole prophylaxis has long been part of the standard care for people living with advanced HIV disease in industrialised countries, where it is primarily used to prevent illnesses such as Pneumocystis jiroveci pneumonia (PCP) and toxoplasmosis. Studies have also shown that cotrimoxazole prophylaxis prevents infections and prolongs life in resource-limited settings. However, even though the treatment is simple, quite inexpensive and potentially life-saving, most countries have been slow to adopt or implement cotrimoxazole prophylaxis as a routine part of their HIV programmes for a number of reasons.
There were several reasons for this. Firstly, PCP and toxoplasmosis are not as common in resource-limited countries — where people with HIV usually first die from other illnesses. Also, there were concerns about fostering resistance to the drug (a widely used antibiotic) and cross-resistance to sulfadoxine/pyrimethamine (used to treat malaria). In fact, in some parts of Africa, there are already high levels of bacterial resistance to cotrimoxazole — until recently, there was little evidence to show that cotrimoxazole prophylaxis would be effective in such settings. Furthermore, clinical studies were needed to answer questions about the safety and practical aspects of using cotrimoxazole in infants or pregnant women.
Finally, although WHO had put out a provisional statement on the use of cotrimoxazole in 2000, it has never previously issued clear technical guidelines on the operational aspects of implementing cotrimoxazole prophylaxis, especially in the context of scaling up HIV care in resource-limited settings. However, over the last several years, the evidence base in support of cotrimoxazole prophylaxis has strengthened considerably. For instance, new studies have shown that PCP, which cotrimoxazole can prevent, is the leading cause of death in infants with HIV in all settings (and the incidence peaks during the first six months of life). Other new evidence has been drawn from recent clinical trials and observational cohort studies in a wide range of populations and settings, even in regions where malaria is endemic and background resistance to cotrimoxazole is common. Consistently, the studies have shown that cotrimoxazole prophylaxis reduces mortality and morbidity in adults, children and infants.
The new WHO guidelines review the clinical evidence as well as essential information needed to use cotrimoxazole safely; with annexes that summarise the criteria for recognising HIV-related clinical events used in the WHO staging system of HIV disease, as well as how to grade the seriousness of adverse events that may occur in persons taking cotrimoxazole.
Recommendations in infants and children It is especially important that infants with, or suspected of having, HIV receive cotrimoxazole during the first six months of their life. Cotrimoxazole prophylaxis is recommended for all HIV-exposed infants starting at 4–6 weeks of age (or at first encounter with the healthcare system) and should be continued until HIV infection can be excluded by HIV antibody testing (beyond 18 months of age) or virological testing (before 18 months of age) at least six weeks after complete cessation of breastfeeding.
Cotrimoxazole prophylaxis is recommended for all HIV-infected infants below one year of age regardless of symptoms or CD4 percentage. Treatment should continue until they are at least five years of age regardless of clinical symptoms or CD4 percentage or whether they have had a good immune response on antiretroviral therapy.
For children between one to four years old, cotrimoxazole prophylaxis is recommended for all children with WHO stage II, III or IV disease, or all children with a CD4 cell% <>
For children aged five or older, see adult recommendations in terms of starting or stopping cotrimoxazole prophylaxis. In settings with limited infrastructure and high child mortality and HIV prevalence — and where HIV screening may not be possible, WHO recommends a universal option: giving cotrimoxazole to all children born to mothers with or suspected of having HIV.
However, cotrimoxazole should not be given to young children who have (or have a history of) severe adverse reactions (grade 4 reactions) to cotrimoxazole or other sulfa-containing drugs and children with glucose-6-phosphate dehydrogenase (although WHO does not recommend routine screening for glucose-6-phosphate dehydrogenase deficiency in resource limited settings). If a child cannot take cotrimoxazole, dapsone 2 mg/kg once daily should be used. Recommendations in adolescents and adults Where CD4 cell counts are available, WHO recommends that everyone with CD4 cell counts below 350 should take cotrimoxazole prophylaxis whether they have symptoms or not. In addition, those with stage III and IV disease should take cotrimoxazole regardless of their CD4 cell count.
Where CD4 cell counts are not available, cotrimoxazole prophylaxis should be taken by everyone with mild, advanced or severe symptoms of HIV disease (WHO stage II, III or IV disease).
Where infrastructure is even more limited, and HIV prevalence is high, WHO says countries can consider offering cotrimoxazole to everyone who tests HIV-positive.
Cotrimoxazole is recommended to HIV-positive pregnant women, regardless of the stage of pregnancy and should continue while she is breastfeeding. Women with HIV who live in an area where there is malaria, should take cotrimoxazole rather than sulfadoxine/pyrimethamine–based intermittent presumptive therapy for malaria.
For people with HIV who qualify for antiretroviral therapy, WHO recommends that they start cotrimoxazole two weeks before their ART regimen — in case there is rash or any other adverse reaction.
In industrialised countries, it is considered safe to discontinue cotrimoxazole in response to effective antiretroviral treatment (that increases the CD4 cell count to over 200). However, in resource limited settings where the primary causes of mortality are malaria or bacterial infections that strike people down with much higher CD4 cell counts, WHO’s “general recommendation is to continue cotrimoxazole prophylaxis among adults living with HIV indefinitely.” Even so, the guidelines (perhaps prematurely considering the evidence base) discuss the alternatives, such as discontinuing cotrimoxazole once the CD4 cell count has been over 350 for at least six months. Recommended daily dosing: For infants below 6 months or <>30 kgs (800 mg/160 mg)
Cotrimoxazole suspension contains 200 mg/40 mg per 5 ml of syrup. Single strength tablets contain 400 mg/80 mg, double strength tablet twice that. It is possible to divide the tablets for children and infants.
Theo Smart, Thursday, August 10, 2006
Cotrimoxazole prophylaxis should be widely used by people with progressing HIV disease and by all HIV-infected or exposed infants (until it is clear that they are uninfected) according to guidelines issued this week by the World Health Organization (WHO).
In fact, where HIV prevalence is high, infectious diseases common and healthcare infrastructure is limited, governments may want to consider simply giving cotrimoxazole to everyone with HIV and to infants known or suspected of having been exposed to HIV, says WHO.
Background on cotrimoxazole prophylaxis Cotrimoxazole prophylaxis has long been part of the standard care for people living with advanced HIV disease in industrialised countries, where it is primarily used to prevent illnesses such as Pneumocystis jiroveci pneumonia (PCP) and toxoplasmosis. Studies have also shown that cotrimoxazole prophylaxis prevents infections and prolongs life in resource-limited settings. However, even though the treatment is simple, quite inexpensive and potentially life-saving, most countries have been slow to adopt or implement cotrimoxazole prophylaxis as a routine part of their HIV programmes for a number of reasons.
There were several reasons for this. Firstly, PCP and toxoplasmosis are not as common in resource-limited countries — where people with HIV usually first die from other illnesses. Also, there were concerns about fostering resistance to the drug (a widely used antibiotic) and cross-resistance to sulfadoxine/pyrimethamine (used to treat malaria). In fact, in some parts of Africa, there are already high levels of bacterial resistance to cotrimoxazole — until recently, there was little evidence to show that cotrimoxazole prophylaxis would be effective in such settings. Furthermore, clinical studies were needed to answer questions about the safety and practical aspects of using cotrimoxazole in infants or pregnant women.
Finally, although WHO had put out a provisional statement on the use of cotrimoxazole in 2000, it has never previously issued clear technical guidelines on the operational aspects of implementing cotrimoxazole prophylaxis, especially in the context of scaling up HIV care in resource-limited settings. However, over the last several years, the evidence base in support of cotrimoxazole prophylaxis has strengthened considerably. For instance, new studies have shown that PCP, which cotrimoxazole can prevent, is the leading cause of death in infants with HIV in all settings (and the incidence peaks during the first six months of life). Other new evidence has been drawn from recent clinical trials and observational cohort studies in a wide range of populations and settings, even in regions where malaria is endemic and background resistance to cotrimoxazole is common. Consistently, the studies have shown that cotrimoxazole prophylaxis reduces mortality and morbidity in adults, children and infants.
The new WHO guidelines review the clinical evidence as well as essential information needed to use cotrimoxazole safely; with annexes that summarise the criteria for recognising HIV-related clinical events used in the WHO staging system of HIV disease, as well as how to grade the seriousness of adverse events that may occur in persons taking cotrimoxazole.
Recommendations in infants and children It is especially important that infants with, or suspected of having, HIV receive cotrimoxazole during the first six months of their life. Cotrimoxazole prophylaxis is recommended for all HIV-exposed infants starting at 4–6 weeks of age (or at first encounter with the healthcare system) and should be continued until HIV infection can be excluded by HIV antibody testing (beyond 18 months of age) or virological testing (before 18 months of age) at least six weeks after complete cessation of breastfeeding.
Cotrimoxazole prophylaxis is recommended for all HIV-infected infants below one year of age regardless of symptoms or CD4 percentage. Treatment should continue until they are at least five years of age regardless of clinical symptoms or CD4 percentage or whether they have had a good immune response on antiretroviral therapy.
For children between one to four years old, cotrimoxazole prophylaxis is recommended for all children with WHO stage II, III or IV disease, or all children with a CD4 cell% <>
For children aged five or older, see adult recommendations in terms of starting or stopping cotrimoxazole prophylaxis. In settings with limited infrastructure and high child mortality and HIV prevalence — and where HIV screening may not be possible, WHO recommends a universal option: giving cotrimoxazole to all children born to mothers with or suspected of having HIV.
However, cotrimoxazole should not be given to young children who have (or have a history of) severe adverse reactions (grade 4 reactions) to cotrimoxazole or other sulfa-containing drugs and children with glucose-6-phosphate dehydrogenase (although WHO does not recommend routine screening for glucose-6-phosphate dehydrogenase deficiency in resource limited settings). If a child cannot take cotrimoxazole, dapsone 2 mg/kg once daily should be used. Recommendations in adolescents and adults Where CD4 cell counts are available, WHO recommends that everyone with CD4 cell counts below 350 should take cotrimoxazole prophylaxis whether they have symptoms or not. In addition, those with stage III and IV disease should take cotrimoxazole regardless of their CD4 cell count.
Where CD4 cell counts are not available, cotrimoxazole prophylaxis should be taken by everyone with mild, advanced or severe symptoms of HIV disease (WHO stage II, III or IV disease).
Where infrastructure is even more limited, and HIV prevalence is high, WHO says countries can consider offering cotrimoxazole to everyone who tests HIV-positive.
Cotrimoxazole is recommended to HIV-positive pregnant women, regardless of the stage of pregnancy and should continue while she is breastfeeding. Women with HIV who live in an area where there is malaria, should take cotrimoxazole rather than sulfadoxine/pyrimethamine–based intermittent presumptive therapy for malaria.
For people with HIV who qualify for antiretroviral therapy, WHO recommends that they start cotrimoxazole two weeks before their ART regimen — in case there is rash or any other adverse reaction.
In industrialised countries, it is considered safe to discontinue cotrimoxazole in response to effective antiretroviral treatment (that increases the CD4 cell count to over 200). However, in resource limited settings where the primary causes of mortality are malaria or bacterial infections that strike people down with much higher CD4 cell counts, WHO’s “general recommendation is to continue cotrimoxazole prophylaxis among adults living with HIV indefinitely.” Even so, the guidelines (perhaps prematurely considering the evidence base) discuss the alternatives, such as discontinuing cotrimoxazole once the CD4 cell count has been over 350 for at least six months. Recommended daily dosing: For infants below 6 months or <>30 kgs (800 mg/160 mg)
Cotrimoxazole suspension contains 200 mg/40 mg per 5 ml of syrup. Single strength tablets contain 400 mg/80 mg, double strength tablet twice that. It is possible to divide the tablets for children and infants.
Sunday, August 06, 2006
Carbapenems
Carbapenems
Carbapenems are a class of beta-lactam antibiotics.
The following drugs belong to the carbapenem class:
Imipenem (often given as part of Imipenem/cilastatin)
Meropenem
Ertapenem
Faropenem
Doripenem
External Links
Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD; beginning at pp131
Carbapenems
* * * * *
Carbapenems
Imipenem/Cilastatin(Primaxin)
Mechanism of action
Inhibits bacterial cell wall synthesis. Cilastatin blocks metabolism of imipenem.
Spectrum of activity
Gram-negative (including P aeruginosa); Gram-positive (including some enterococci); not MRSA; Anaerobes including Bacteroides fragilis
Half-life
1 h
Metabolism
In kidney by dehydropeptidase. Blocked by cilastatin
Excretion
70% unchanged in urine
Clinical Side effects
GI, phlebitis, neurologic (seizures <>
Laboratory abnormalities
Increased LFTs, other rare events
Mechanism of drug interactions
No CYP-450 interactions. Probenecid increases levels
Other considerations
Significant dosage adjustment in renal insufficincy
Approved indications
Intra-abdominal infection, lower respiratory tract infection, UTI, gynecologic infection, bacterial septicemia, bone, joint, and skin infections, endocarditis, polymicrobic infections
Usual Dose
500 mg q6h, adjusted for renal function
----------
Meropenem(Merrem)
Mechanism of action
Ertapenem(Invanz)
Mechanism of action
Carbapenems are a class of beta-lactam antibiotics.
The following drugs belong to the carbapenem class:
Imipenem (often given as part of Imipenem/cilastatin)
Meropenem
Ertapenem
Faropenem
Doripenem
External Links
Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD; beginning at pp131
Carbapenems
* * * * *
Carbapenems
Imipenem/Cilastatin(Primaxin)
Mechanism of action
Inhibits bacterial cell wall synthesis. Cilastatin blocks metabolism of imipenem.
Spectrum of activity
Gram-negative (including P aeruginosa); Gram-positive (including some enterococci); not MRSA; Anaerobes including Bacteroides fragilis
Half-life
1 h
Metabolism
In kidney by dehydropeptidase. Blocked by cilastatin
Excretion
70% unchanged in urine
Clinical Side effects
GI, phlebitis, neurologic (seizures <>
Laboratory abnormalities
Increased LFTs, other rare events
Mechanism of drug interactions
No CYP-450 interactions. Probenecid increases levels
Other considerations
Significant dosage adjustment in renal insufficincy
Approved indications
Intra-abdominal infection, lower respiratory tract infection, UTI, gynecologic infection, bacterial septicemia, bone, joint, and skin infections, endocarditis, polymicrobic infections
Usual Dose
500 mg q6h, adjusted for renal function
----------
Meropenem(Merrem)
Mechanism of action
Inhibits bacterial cell wall synthesis
Spectrum of activity
Gram-negative (including P aeruginosa); Gram-positive (including some enterococci); not MRSA; Anaerobes including Bacteriodes fragilis
Half-life
1-1.5 h
Metabolism
Minor hepatic to inactive metabolite
Excretion
75% unchanged in urine
Clinical Side effects
Headache, rash, GI, phlebitis, hypotension
Laboratory abnormalities
Increased LFTs, other rare events
Mechanism of drug interactions
No CYP-450 interactions. Probenecid increases levels
Other considerations
Dose adjustment necessary in renal insufficiency
Approved indications
Intra-abdominal infection, bacterial meningitis
Usual Dose
1 g q8h, adjusted for renal function
----------------Ertapenem(Invanz)
Mechanism of action
Inhibits bacterial cell wall synthesis
Spectrum of activityGram-negative—not P aeruginosa;Gram-positive, not enterococci, not MRSA; Anaerobes including Bacteriodes fragilis
Half-life
4h
Metabolism
Minor hepatic to inactive metabolite
Excretion
38% unchanged in urine; 37% inactive metabolite; 10% feces
Clinical Side effects
Headache, rash, GI, phlebitis, hypotension
Laboratory abnormalities
Increased LFTs, other rare events
Mechanism of drug interactions
No CYP-450 interactions. Probenecid increases levels.
Other considerations
Minor dose adjustment necessary in renal insufficiency
Approved indications
Intra-abdominal infection, skin and skin structure, community-acquired pneumonia, UTI, pelvic infections
Usual Dose
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