Antibiotic Resistance: Why the Urgency?
Antibiotic resistance has been declared a crisis by the World Health Organization, the Centers for Disease Control and Prevention (CDC), the Institute of Medicine, the Infectious Diseases Society of America, and virtually all other relevant organizations.
Contributing to this urgency are the following facts:
• Pharmaceutical companies are no longer developing new antibiotics because they “can’t break even.” The last new antibiotic class for gram-negative bacteria was the quinolones, developed 4 decades ago.
• Antibiotic abuse in the United States is widespread. We have only 4.6% of the global population but we have 46% of the global antibiotic market.
• Our prevention record is dismal. A patient entering a US hospital is 40 times more likely to acquire methicillin-resistant Staphylococcus aureus (MRSA) bacteremia than a patient entering a hospital in The Netherlands.
What Are the Solutions for Antibiotic Resistance?
1. Collect Data
The European Union has detailed, 15-year data on antibiotic use by drug, and resistance data by microbe, covering 26 countries. They know what and where the problems are. For example, Greece has the highest per capita use of antibiotics, and The Netherlands has among the lowest. The proportion of Klebsiella isolates that are carbapenemase-producing in Greece is 38%, and in The Netherlands it is 0.2%. The proportion of S aureusisolates that are methicillin-resistant is 58% in Greece and 1.6% in The Netherlands. These data are strong testimony supporting the acknowledged association between antibiotic abuse and resistance, and they identify areas of great need for corrective intervention. In the United States, we have no comparable data.
2. Stop Antibiotic Use on the Farm
A full 80% of antibiotic use in the United States is for growth promotion and disease prevention in farm animals. Resistant bacteria and resistance genes can be traced from the chickens to the chicken meat in grocery stores and, finally, to blood cultures in patients (The “farm to fork” phenomenon). The practice of antibiotics for growth promotion on the farm was stopped in Denmark many years ago, with no apparent economic or animal health consequences.
3. Practice Antibiotic Stewardship
Antibiotic stewardship has many elements:
• Use a procalcitonin level as a biomarker for infection to avoid unnecessary antibiotic use, as has been shown to be successful in nearly every well-controlled trial.
• Short courses of antibiotics are virtually always effective in well-controlled trials.[3,8]
• Switch antibiotics from intravenous (IV) to oral formulations to hasten discharge and reduce risks associated with IV catheters. This switch is easily done with many antibiotics (linezolid, metronidazole, fluoroquinolones, some cephalosporins, fluconazole, etc).
• Use colistin carefully. Colistin, available since 1961, is increasingly needed but is saddled with dosing errors because the recommendations in the package insert are wrong.
• Avoid antibiotic redundancy, as illustrated by the report that 23% of 782,821 patients were given metronidazole on top of another agent for anaerobic bacteria.
4. Reduce Inappropriate Antibiotic Use in Outpatients
The abuse of antibiotics is well known and in large part reflects consumer demand because the patient expects to walk out of the clinic with a prescription for that viral respiratory tract infection. A Cochrane review of all methods to reduce antibiotic abuse in the clinic concluded that the “3-day prescription” was the only method with documented success. This means telling the patients with “sinusitis” that they probably have a viral infection that is likely to get better within 3 days, and providing a prescription that is dated 3 days later for use if the patient is not better or is getting worse at that time.
Public campaigns can work but they are costly. France conducted a national campaign to convince patients and providers to do better, with a target of a 25% reduction in antibiotic prescriptions in the entire country. They achieved a 26% reduction! We also need to communicate better via modern technologies such as Twitter. For example, a tweet that proclaimed “Finally over my cold, thank God for Z-pack” had 850,375 followers. We need to do better in social networking arenas to reach that audience.
Information from the microbiome could be particularly important. This is in very early development, but initial studies show that antibiotics such as ciprofloxacin, commonly prescribed for 1 week, have a profound and sometimes lasting effect on the colonic microbiome. Furthermore, excessive antibiotics in childhood have been associated strongly with subsequent obesity and inflammatory bowel disease.
Despite these concerns, we need to be careful with an anti-antibiotic campaign that goes too far, because antibiotics are great drugs when indicated.
5. Adopt Rapid Diagnostic Tests
Molecular methods are coming fast. We now have a polymerase chain reaction test for the detection of MRSA, vancomycin-resistant Enterococcus, Neisseria gonorrhoeae, Chlamydia trachomatis, group B Streptococcus, tuberculosis, Candida albicans, and many others. Coming soon are tests that will detect practically every bacterium as well as other pathogens, making an etiologic diagnosis to facilitate antibiotic decision-making within 1-2 hours of collecting the culture. Interpretation will be tricky, however, because many specimens will need quantitation and there will be a predictable need for substantial stewardship.
6. Develop New Drugs
“Big pharma” previously developed new antibiotics in response to the continuing development of resistance. They no longer do this because they cannot regain their investment as a result of idiosyncrasies of short-term use, low price standards, and the antiquated model of the US Food and Drug Administration (FDA). Does anyone think that it would be possible to conduct a 2000-patient study with, for example, pneumonia caused by multidrug-resistant bacteria?
We need a novel method to deal with antibiotic development and its related costs. Possibilities include:
• A public-private partnership such as the combined resources of the Bill & Melinda Gates Foundation, Janssen Pharmaceuticals, and the TB Alliance, which has now produced bedaquiline, the first new FDA-approved drug for tuberculosis in the past 40 years ;
• Federal support for this effort, such as use of Biomedical Advanced Research and Development Authority (BARDA) funds that originally targeted only bioterrorism; and
• The need for a novel system for testing drugs and diagnostics, such as the new National Institutes of Health-funded Antibiotic Resistance Network.
7. Integrate Antibiotic Resistance Initiatives Into Healthcare Reform
We need convincing evidence of the benefit of infection-prevention initiatives in the context of healthcare reform, with the goal of saving both lives and money. An example of success with this strategy is the “5-step plan to prevent central line bacteremia.” The plan was logical, but it needed verification. It was tested in 103 intensive care units in Michigan, with the anticipated impressive results. Subsequently the plan was introduced in the CDC network, with the study authors’ conclusion that “If every hospital did this, it would annually save 27,000 lives and $1.8 billion.”
Healthcare reform priorities are ripe for similar prevention methods, including MRSA bacteremia, Clostridium difficile infection, surgical-site infection, and catheter-associated urinary tract infections. Caution must be used to prevent “gaming the system,” however, as illustrated by the experience with central line bacteremia. When financial penalties were instituted, national rates of central line bacteremia declined by 25% within 1 week!
8. Create a Plan for the United States
We need a comprehensive plan for the United States that includes some or all of the points listed above. The European Union has a plan with identified priorities to address antibiotic resistance, supported by funding of $220 million per year. It is humbling that although we recognize the crisis of antibiotic resistance and our role in producing it, the United States has no comparable plan in place for resolving it
a si� ia`K�`�ter change from baseline in respiratory rate, which decreased by 3.5 breaths per minute vs. a decrease of 2.8 breaths per minute in the midazolam group (P = 0.04). There were no significant differences in the overall blood pressure score—which compares intra-procedure SBP with pre-procedure SBP—in the midazolam group compared with the diazepam group (P = 0.38). The time to nadir SBP following sedative administration was also similar between the two groups (44 vs. 47 min for the midazolam and diazepam groups, respectively; P = 0.46).
We also compared outcomes in patients on PI-based ART vs. non-PI-based ART. There were no significant differences between these groups in terms of age, sex, liver disease, baseline SBP, or concomitant use of CYP 3A4 inhibitors, chronic opioids or chronic benzodiazepines. There were no significant differences between the four treatment groups (PI/midazolam; PI/diazepam; non-PI/midazolam; non-PI/diazepam) in the outcomes of lowest SBP, heart rate, nadir oxygen saturation, nadir respiratory rate, consciousness score < 2, sedation duration, or newly abnormal change in cardiac rhythm.
We performed multivariate analysis for four discrete outcomes – attainment of consciousness score < 2, sedation duration, nadir SBP, and cardiac rhythm score – adjusting for possible confounders based on clinical relevance and significance in univariate analysis. In adjusted analyses, we found that midazolam use (vs.diazepam use) was significantly associated with a consciousness score < 2 (odds ratio = 3.80; 95% confidence interval 1.33; 10.88) but not with cardiac rhythm score, nadir SBP, or sedation duration (data not shown).
Most endoscopic procedures are performed with the patient under moderate (‘conscious’) sedation, during which the patient is able to respond purposefully to verbal or tactile stimulation. Adequate sedation can both facilitate successful completion of the procedure and increase patient tolerability by decreasing anxiety and pain.
In this retrospective analysis of 136 adult HIV-positive patients on ART who underwent a colonoscopy, we assessed the safety of midazolam vs. diazepam based on multiple physiological outcomes. We found that the patients in our cohort safely received midazolam-based sedation, with comparable haemodynamic, cardiac, and respiratory outcomes compared with patients who received diazepam. We did observe a difference in consciousness score between the midazolam and diazepam groups, consistent with the known interaction between midazolam and ART. However, no patient suffered an outcome indicative of over-sedation, such as requirement for reversal of sedation, hospitalization or unresponsiveness. It is notable that more patients in the diazepam group compared with the midazolam group (26% vs. 9%, respectively) were awake and oriented during the procedure. Had patients in the diazepam group been given more diazepam to achieve a level of moderate sedation, it is likely that the duration of sedation would have been longer in the diazepam group.
Concerns regarding the safety of midazolam use in HIV-positive patients on ART arise from the possibility of drug interactions resulting in increased levels of midazolam.[6–8] Metabolism of midazolam is almost entirely dependent on hydroxylation by CYP 3A4. Guidelines indicate that iv midazolam can be co-administered with ART with close clinical monitoring.[9–11] In addition, it has been demonstrated in a number of small studies that, with careful titration, drugs such as fentanyl, meperidine and midazolam, can be administered safely for short-term procedures in HIV-positive patients on ART.[12–15]
Previous studies investigating the clinical impact of co-administration of midazolam and ART have yielded conflicting results. In a cohort of 143 ambulatory patients undergoing bronchoscopy and receiving midazolam (total doses ranged from 2 to 15 mg; average 7.5 mg), no patient suffered an adverse outcome or required intubation. By contrast, in a recent study of 241 HIV-positive in-patients who received iv midazolam prior to bronchoscopy, the incidence of prolonged sedation (defined as > 90 minutes) was 9.8% in patients receiving PIs compared with 1.58% in those not taking ART. One possible reason for the difference between these findings and our results is the fact that the previous cohort consisted of in-patients, in whom concomitant comorbidities may have predisposed patients to complications from sedation; indeed, 10% of the patients in the PI group had pre-existing respiratory distress or altered mental status prior to the procedure and 29% were diagnosed with Pneumocystis jirovecii pneumonia. By contrast, we examined only ambulatory patients and compared outcomes between patients on ART receiving iv midazolam and those receiving iv diazepam. It is important to acknowledge that the risks of iv midazolam may differ by procedure and the presence of medical comorbidities.
In our institution, based on pharmacokinetic principles and available evidence, we generally do not empirically reduce the dose of midazolam for HIV-positive patients undergoing procedural sedation. Peak benzodiazepine concentrations after a single dose or multiple doses over a very short period of time (e.g. 20 minutes) are not affected by drug half-life or clearance. Furthermore, in the context of short-term use, the recovery time for benzodiazepines is mainly dependent on redistribution kinetics rather than half-life.
Limitations of this study include its retrospective design and the limited sample size. To address the possibility of confounding, we conducted a multivariable analysis adjusting for variables such as age, sex, liver disease, and concomitant medications including CYP 3A4 inhibitors and chronic opioid use. We also examined outcomes in four different subgroups – midazolam- and diazepam-based sedation with and without concomitant PIs – and could not detect an association between the treatment groups and any of the outcomes. An additional limitation is that our institutional endoscopic anaesthesia scoring system may not be sensitive enough to detect the optimal level of sedation.
In conclusion, we demonstrated that HIV-positive out-patients undergoing colonoscopy who received iv midazolam for procedural sedation had similar clinical outcomes to those who received diazepam. Based on these findings, we conclude that the use of iv midazolam can be considered for HIV-positive patients on ART with close clinical monitoring. These findings should be confirmed in prospective studies or in a randomized controlled trial.