In response to decreasing penicillin coverage of Staph Aureus Boston City Hospital no longer exists on it’s own. It has become part of Boston Medical Center.
Penicillins and other beta lactams inhibit cell wall synthesis by preventing synthesis of the peptidoglycan layer. They bind transpeptidases and stop production of the wall.
The two major forms of beta lactam resistance are altered penicillin binding proteins, also known as PBPs or transpeptidases, or by the production of hydrolytic enzymes. These enzymes degrade the beta lactam ring, making the drugs ineffective. Alteration of the PBPs also gives bacteria an advantage against the antibiotics.
Penicilloic acid, the deactivated form of penicillin, is incapable of forming hydrogen bonds, so it is rendered ineffective by beta lactamase. The other resistance mechanism is in the form of PBPs. They are selected for by genetic pressures to both retain function in creating a cell wall and deny access to beta-lactams.
These numbers equate to 27% and 1.3% of the United States population.
New inventions intended to decrease infection have helped, but minimally. These include safer needles and anti-bacterial coatings. Changes in hospital staff behavior have had a larger impact on decreasing staph and other bacteria transmission rates.
Contact precautions, generally, involve handwashing before and after patient contact and to wear gowns and gloves when providing direct patient care.
Few prospective studies exist on the efficacy of decreasing bacterial transmission. Jernigan and others found that contact precautions decreased transmission from 0.14 transmissions per day to 0.009 transmissions per day. This 16 fold decrease during a MRSA outbreak was no doubt statistically significant.
Jernigan’s article was informative and, to a degree, shocking, but articles like that are few and far between. This is Duke University, home of Kathryn Kirkland. Her name has occurred frequently to speak of the negatives of contact precautions. Most notably, she found in 1999 that healthcare workers spend exactly half the amount of time with CP patients as they do with non-CP patients.
Most research looks like this. Kirkland and Weinstein had their famous study in 1999, Saint showed that attending physicians only see 35% of CP patients while seeing 73% of non-CP patients. Of course, residents always have to see everybody, so their rate didn’t change. Stelfox had a great study as well. They looked at a general cohort and a congestive heart failure cohort. The contact precaution patients in both groups had statistically significant longer hospital stays, more adverse events, and more preventable adverse events. There were also more deaths in the CP groups, though the study was not powerful enough to make that conclusion.
Active surveillance cultures, according to SHEA (the society for healthcare epidemiology of america) guidelines, need to be used to keep track of patients who are colonizers. These are generally in the form of nasal swabs.
Ceftobiprole has no new mechanism of action, rather it works like other cephalosportins but binds to the mutated 2a PBP which other cephalosporins cannot. Because it isn’t a new MOA, bacteria could become resistant to it relatively quickly. It is also not FDA approved because they stated that Johnson and Johnson and Basilea Pharmaceuticals both interfered with the phase 1 and 2 efficacy trials.
In 2008, the FDA requested further phase 3 studies, specifically for the treatment of MRSA. A new study was finally published in 2011, but there is no word yet on FDA approval. It’s MOA is different than other drugs, however. It both disrupts the cell membrane of gram positive bacteria and inhibits transpeptidases.
In mutated, or resistant, organisms, Iclaprim has an additional cyclopropane ring. This is the active structure of the molecule and can still produce hydrogen bonds with dihyrdofolate reductase, inhibiting folate synthesis.
According to the Healthcare Associated Infection forum, for every death from MRSA, the US government only awards $570. In comparison, every death from AIDs, the government gives out $69,000. The grant funding is not being provided for antibiotic research, so companies have more risk in developing drugs that may not pan out. MRSA kills 19,000 people per year. And is responsible for higher rates of infection than pneumococcal, invasive group A strep, meningococcal, and Haemophilus influenzae infections combioned, but there are still very few new antibiotics on the horizon.
PDF is an enzyme involved in bacterial protein synthesis, specifically in transforming methionine. We don’t use PDF, even in our mitochondria, so it is a very nice target. The non-mevalonate pathway is a backdoor for bacteria to create G3P, pyruvate, and isoprenoids, which are essential to bacteria. If this pathway is blocked, bacteria can’t survive. In bacteria, bacterial fatty acids are synthesized by several, individual enzymes, while mammals possess just one larger “fatty acid synthase.” any of those enzymes could become future targets. And finally, bacterial virulence factors, like adhesion, invasion, and evasion of host processes may be genetically alterable. These drugs, however, would be very narrow spectrum in that they target genes of bacteria. Even still, bacteria can become resistant. Staph aureus’s generation time or doubling rate is 27-30 minutes, so large amounts of mutations can occur over a relatively brief timeframe.
Contact Precautions and MRSA
A teaching hospital of Harvard Medical School Current Concepts: Methicillin resistant staphylococcus aureus Andrew BernhardKent State University College of Podiatric MedicineDepartment of Podiatry, Medical Student Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA
Methicillin Resistant Staph. Aureus• Methicillin was first produced in 1959• During the 1960s, infrequent MRSA outbreaks occurred in Europe and Australia.• In 1968, Boston City Hospital reported the first case in America. Harvard Medical School
MRSA Considerations • S. aureus is traditionally sensitive to beta-lactam antibiotics. • These antibiotics inhibit cell wall synthesis, which results in bacteriocidal performance. Harvard Medical School
β-Lactam Resistance• The key to MRSA virulence is its resistance, which can be due to production of hydrolytic enzymes, like β-Lactamase and penicillinase, or altered penicillin binding proteins. Harvard Medical School
Resistance MechanismsFigure 1, above, depicts the conversion ofpenicillin to penicilloic acid, an inactivecompound.Figure 2, right, depicts mecA encoded PBPs,which do not bind β-Lactam antibiotics. Harvard Medical School
What does this mean?• MRSA rates are generally considered • High school athletes to have been • Dutch animal farmers increasing. • Young Ohioans• Large, generalized • Hospitalized patients population studies are rare, but studies • Nursing home workers specifically show • College students increased incidence in the following: Harvard Medical School
Further statistics • According to the CDC: – 79 million Americans are colonized with staph aureus – 4.1 million are colonized with MRSA – The prevalence of MRSA has increased from 2% of staph infections in 1974 to 64% in 2004.Thankfully, some newer research shows a decrease in MRSA rates Harvard Medical School
Why the downward trend?• Needles with safety features and antimicrobial coated catheters have offered minimal infection control.• Improvements in hospital staff behavior have proven more effective. Harvard Medical School
What about contact precautions?• We are all familiar with them but what does the research say? Harvard Medical School
Contact Precaution Efficacy on MRSA • Few prospective studies exist. • The good news is that several studies show a correlation between contact precautions and decreased MRSA transmission, most notably Jernigan in 1996. Harvard Medical School
On the down side, • There are many studies which also demonstrate non- superiority of contact precautions, though they are older. • More commonly, current literature speaks to adverse effects. Harvard Medical School
• From Morgan’s comprehensive literature review Harvard Medical School
How does this affect MRSA?• Most patients under contact precautions are there because they are MRSA colonizers.• Active surveillance cultures are a great tool for identifying these patients.• But what new treatments are in the pipeline? Harvard Medical School
Ceftobiprole• New 5th generation cephalosporin• Broad spectrum and bacteriocidal• No safety concerns• Efficacy trials were potentially biased• Currently only available in Switzerland Harvard Medical School
Oritavancin • A glycopeptide antibiotic, like Vanco • Seemingly bacteriocidal against MRSA, VRE, C. diff, and Anthrax • Has had less ADRs then comparable drugs, but studies were not powerful enough for FDA. Harvard Medical School
Iclaprim• Diaminopyrimidine dihydrofolate reductase inhibitor• Similar to trimethoprim, but active against MRSA, VRSA, S. pneumonia, and gram –• Has been granted fast- track FDA status Harvard Medical School
The State of Antibiotic Research• Most sources say that antibiotic development is currently very underfunded.• New classes of drugs are more likely to be successful than newer versions of older drugs. Harvard Medical School
New Drug Targets• Yoneyama and Katsumata offer a review of potential new drug targets: – Peptide deformylase – Non-mevalonate pathway – Bacterial fatty acid synthesis – Bacterial virulence factors Harvard Medical School
References• Albrich WC, Harbarth S. Health-care workers: source, vector, or victim of MRSA?. The Lancet Infectious Diseases (2008) 8(5), 289-301.• Tacconelli E, De Angelis G, Cataldo MA, Pozzi E and Cauda R. Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) isolation? A systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy (2008) 61, 26–38.• Kirkland KB. Taking Off the Gloves: Toward a Less Dogmatic Approach to the Use of Contact Isolation. Clinical Infectious Diseases (2009) 48, 766–771.• Kirkland KB, Weinstein JM. Adverse effects of contact isolation. The Lancet (1999) 354, 1177-1178.• Muto CA, Jernigan JA, Ostrowsky BE, Richet HM, Jarvis WR, Boyce JM, Farr BM. SHEA Guideline for Preventing Nosocomial Transmission of Multidrug-Resistant Strains of Staphylococcus aureus and Enterococcus. Infection Control and Hospital Epidemiology (2003) 24(5), 362-386.• Morgan DJ, Diekema DJ, Sepkowitz K, Perencevich EN. Adverse outcomes associated with contact precautions: A review of the literature. American Journal of Infection Control (2009) 37(2), 85-93.• Catalano G, Houston SH, Catalano MC, Butera AS, Jennings SM, Hakala SM, Burrows SL, Hickey MG, Duss CV, Skelton DN, Laliotis GJ. Anxiety and Depression in Hospitalized Patients in Resistant Organism Isolation. Southern Medical Journal (2003) 96(2), 141-145.• Murray-Leisure KA, Geib S, Graceley D, et al. Control of epidemic methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol 1990; 11:343-50.• Bogdanovich T, Ednie LM, Shapiro S, Appelbaum PC. Antistaphylococcal Activity of Ceftobiprole, a New Broad-Spectrum Cephalosporin. Antimicrobial Agents and Chemotherapy (2005) 49(10), 4210-4219. Harvard Medical School
References• Kallen AJ, Mu Y, Bulens S, Reingold A, Petit S, Gershman K, Ray SM, Harrison LH, Lynfield R, Dumyati G, Townes JM, Schaffner W, Patel PR, Fridkin SK. Health Care-Associated Invasive MRSA Infections, 2005-2008. JAMA (2010) 304(6), 641-648.• MRSA History Timeline: The First Half-Century, 1959–2009. MRSA Research Center at The University of Chicago Medical Center. Available: http://mrsa-research-center.bsd.uchicago.edu/timeline.html• Buss BF, Mueller SW, Theis M, KeyserA, Safranek TJ. Population-Based Estimates of Methicillin- Resistant "Staphylococcus aureus" (MRSA) Infections among High School Athletes--Nebraska, 2006-2008. Journal of School Nursing (2009) 25(4), 282-291.• Van Rijen MML, Van Keulen PH, Kluytmans JA. Increase in a Dutch Hospital of Methicillin-Resistant Staphylococcus aureus Related to Animal Farming. Clinical Infectious Disease (2008) 46(2), 261-263.• Nasr P, Delorme T, Rose S, Senita J, Callahan C. Methicillin-resistant Staphylococcus aureus among younger population in Northeastern Ohio. The Ohio Journal of Science (2008) 108(3).• Cohen PR, Kurzrock R. Community-acquired methicillin-resistant Staphylococcus aureus skin infection: an emerging clinical problem. Journal of the American Academy of Dermatology (2004) 50(2), 277-280.• Burton DC, Edwards JR, Horan TC,; Jernigan JA, Fridkin SK. Methicillin-Resistant Staphylococcus aureus Central Line–Associated Bloodstream Infections in US Intensive Care Units, 1997-2007. JAMA (2009) 301(7), 727-736.• Reboli AC, John JF, Levkoff AH. Epidemic methicillin-gentamicin-resistant Staphylococcus aureus in a neonatal intensive care unit Am J Dis Control 1989; 143:34-9.• Yoneyama H, Katsumata R. Antibiotic Resistance in Bacteria and its Future for Novel Antibiotic Development. Bioscience, Biotechnology, and Biochemistry (2006) 70(5), 1060-1075. Harvard Medical School
References• Stelfox HT, Bates DW, Redelmeier DA. Safety of Patients Isolated for Infection Control. JAMA (2003) 290(14), 1899-1905.• Burke JP. Infection Control – A Problem for Patient Safety. New England Journal of Medicine (2003) 348(7), 651-658.• Jain R, Kralovic SM, Evans ME, Ambrose M, Simbartl LA, Obrosky DS, Render ML, Freyberg RW, Jernigan JA, Muder RR, Miller LJ, Roselle GA. Veterans Affairs Initiative to Prevent Methicillin-Resistant Staphylococcus aureus Infections. New England Journal of Medicine (2011) 364(7), 1419-1430.• Jernigan JA, Titus MG, Groschel DHM, Getchell-White SI, Farr BM. Effectiveness of Contact Isolation during a Hospital Outbreak of Methicillin Resistant Staphylococcus aureus. American Journal of Epidemiology (1996) 143(5), 496-504.• Boyce JM, Havill NL, Kohan C, Dumigan DG, Ligi CE. Do Infection Control Measures Work for Methacillin Resistant Staphylococcus Aureus? Infection Control and Hospital Epidemiology (2004) 25(5), 395-401.• Law MR, Gill ON, Turner A. Methicillin-resistant Staphylococcus aureus: associated morbidity and effectiveness of control measures. Epidemiol Infect 1988;101:301-9.• Cohen SH, Morita MM, Bradford M. A seven-year experience with methicillin resistant Staphylococcus aureus. Am J Med 1991;91(suppl 3B):233S-237S.• Rao N, Jacobs S, Joyce L. cost-effective eradication of an outbreak of methicillin-resistant Staphylococcus aureus in a community teaching hospital. Infect Control Hosp Epidemiol 1988;9:255-6O. Harvard Medical School