Mechanisms of Antibiotic Resistance

In the United States more than 2 million people are infected with antibiotic-resistant bacteria annually, with 23,000 deaths as a direct result. In addition to increased resistance to existing agents, there is a lack of new antibiotics in development. The word antibiotic has become synonymous with ‘antibacterial drug’: therefore, in this article the term antibiotic has been used throughout.

Bacteria can be intrinsically resistant to certain antibiotics but can also acquire resistance to antibiotics via mutations in chromosomal genes and by horizontal gene transfer. The intrinsic resistance of a bacterial species to a particular antibiotic is the ability to resist the action of that antibiotic as a result of inherent structural or functional characteristics. The simplest example of intrinsic resistance in an individual species results from the absence of a susceptible target of a specific antibiotic; for example, the biocide triclosan has broad efficacy against Gram-positive bacteria and many Gram-negative bacteria, but it is unable to inhibit growth of members of the Gram-negative genus Pseudomonas. Although this was initially thought to be due to active efflux, it has more recently been shown that it is instead due to the carriage of an insensitive allele of fabI that encodes an additional enoyl-ACP reductase enzyme — the target for triclosan in sensitive species. A second example relates to the lipopeptide daptomycin (first approved for clinical use in 2003), which is active against Gram-positive bacteria but is not effective against Gram-negative bacteria. This is due to an intrinsic difference in the composition of the cytoplasmic membrane; Gram-negative bacteria have a lower proportion of anionic phospholipids in the cytoplasmic membrane than do Gram-positive bacteria, which reduces the efficiency of the Ca2+-mediated insertion of daptomycin into the cytoplasmic membrane that is required for its antibacterial activity. The intrinsic resistance of some Gram-negative bacteria to many compounds is due to an inability of these agents to cross the outer membrane: for example, the glycopeptide antibiotic vancomycin inhibits peptidoglycan crosslinking by binding to target d-Ala-d-Ala peptides but is only normally effective in Gram-positive bacteria as, in Gram-negative organisms, it cannot cross the outer membrane and access these peptides in the periplasm…

To learn more about antibiotic resistance, take a look at the following paper in Nature.

Nature Reviews Microbiology13,42–51(2015)doi:10.1038/nrmicro3380

Antibiotic Resistance – National Action Plan

On the heels of recent concern for carbapenem-resistant enterobacteriaceae, President Obama announced the National Action Plan to reduce antibiotic resistance by 2020. The plan hopes to accomplish this goal through the following means:

National Strategy on Combating Antibiotic-Resistant Bacteria 

The National Strategy provides detailed actions for five interrelated national goals to be achieved by 2020 in collaboration with partners in healthcare, public health, veterinary medicine, agriculture, and food safety, as well as in academic, Federal, and industrial research and development.  The goals are:

  1. Slow the emergence and prevent the spread of resistant bacteria.
  2. Strengthen National efforts to identify and report cases of antibiotic resistance.
  3. Advance the development and use of rapid diagnostic tests for the identification and characterization of antibiotic-resistant bacteria.
  4. Accelerate basic and applied research and development for new antibiotics as well as other therapeutics and vaccines.
  5. Improve international collaboration, capacities for antibiotic-resistance prevention, surveillance, control, and antibiotic research and development.

(Fact Sheet: Obama Administration Takes Actions to Combat Antibiotic-Resistant Bacteria. http://www.whitehouse.gov, accessed March, 2015)

Through an executive order, the plan calls for collaboration between physicians, hospitals, and the federal government to establish a task force for combating multi-drug resistant (MDR) bacteria, improve antibiotic stewardship, strengthen national surveillance efforts for resistant bacteria, promote the development of new and next-generation antibiotics and diagnostics, and strengthen international cooperation.  Interestingly, similar efforts have been adopted in India and China, with some degree of success. Finally, the administration hopes to launch of a $20 million prize for new, rapid, point-of-care diagnostic tests.

 

 

Digoxin Toxicity – A Practical Review

CLINICAL FEATURES

  • Acute digoxin toxicity
    • Time course: initial toxic effects of nausea and vomiting occur at 2-4 hours, peak serum levels at 6 hours and life-threatening cardiovascular complications  at 8-12h
    • GI: anorexia, nausea, vomiting, diarrhoea, abdominal pain
    • Metabolic: hyperkalaemia (early sign of significant toxicity)
    • CVS: enhanced automaticity (atrial tachycardias (e.g. flutter, AF) with AV block, VF, VT, ventricular ectopic beats), bradyarrhythmias (Conduction delays / blocks, slow or regularised AF), hypotension, shock
    • CNS: lethargy, confusion
  • Chronic digoxin toxicity
    • Typically occurs  in the context of intercurrent illness, especially with impaired renal function
    • Clinical features are a combination of toxicity and the intercurrent illness
    • Symptoms may have an insidious onset over days to weeks
    • Features include those of acute digoxin toxicity as well as visual disturbances (e.g. reduced acuity, yellow halos (xanthopsia) and altered color perception (chromatopsia))

DIAGNOSIS

  • Urgent K level, creatinine
  • Serum digoxin level –  a steady state level 6 or more hours after the last dose; levels can be misleading as levels near the therapeutic range (0.6-1.3 nmol/L) correlate poorly with severity of intoxication
  • ECG

MANAGEMENT

  • ACUTE DIGOXIN TOXICITY
    • Digoxin-induced cardiotoxicity is refractory to standard measures
      • Bradyarrhythmias
        • Digibind is the definitive treatment
        • Atropine
        • Epinephrine (but may aggravate cardiac irritability)
        • Pacing (rarely effective)
      • Tachyarrhythmias
        • Digibind is the definitive treatment
        • MgSO4as an adjunctive measure
        • Often refractory to cardioversion
    • Hyperkalemia: Insulin and glucose, bicarbonate Calciumis traditionally contra-indicated due to the risk of precipitating a ‘stone heart’.
    • Activated charcoal if the patient presents <1h post-ingestion and not vomiting (unlikely to prevent severe toxicity in large ingestions)
  • CHRONIC DIGOXIN TOXICITY
    • Resuscitation as for acute digoxin toxicity
    • Renal replacement therapy may be indicated in the context of renal failure and hyperkalemia
    • Digibind!

Atrial Myxoma

General Information
  • Most common primary cardiac neoplasm
  • Prevalence of cardiac tumors at autopsy ranges from 0.001% to 0.3%
  • Thought to originate from entrapped entrapped embryonic foregut
  • Histologically, composed of scattered cells within a mucopolysaccharide stroma
  • Produce VEGF, which contributes to the induction of angiogenesis and the early stages of tumor growth
  • On a macroscopic level, typical myxomas are pedunculated and gelatinous in consistency; the surface may be smooth, villous, or friable.
  • 35 percent of myxomas are friable or villous, and these tend to present with emboli.
Clinical Manifestations
  • Symptoms:
    • Due to obstruction of blood flow, valvular regurgitation, impaired contractility
    • Can see dyspnea, orthopnea, paroxysmal nocturnal dyspnea, pulmonary edema, cough, hemoptysis, edema, and fatigue
    • Direct invasion of myocardium can cause arrhythmias, heart block, or pericardial effusion with or without tamponade
    • Left atrial tumors may release tumor fragments or thrombi into the systemic circulation, leading to embolization in multiple vascular territories
    • May be worse in certain body positions, due to motion of the tumor within the atrium
  • Signs:
    • On physical examination, a characteristic “tumor plop” may be heard early in diastole.
    • Constitutional symptoms (e.g., fever, weight loss) are seen in around 30 percent of patients.
    • Laboratory abnormalities (e.g., anemia and elevations in the ESR or CRP) are present in 35 percent, usually those with systemic symptoms].

 

Diagnostic Evaluation 
  • Echocardiography
    • Images both the myocardium and the cardiac chambers can usually identify the presence of a mass
    • In addition, echocardiography may provide information about any obstruction to the circulation, as well as the likelihood that the tumor could be a source of emboli
    • TTE is sufficient, but TEE may be better. The superior diagnostic utility of TEE is due to the proximity of the esophagus to the heart, the lack of intervening lung and bone, and the ability to use high-frequency imaging transducers that afford superior spatial resolution.
  • Cardiac MRI and Computerized Tomography
    • MRI is preferred. In addition to furnishing detailed anatomic images, the T1- and T2-weighted sequences reflect the chemical microenvironment within a tumor, thereby offering clues as to the type of tumor that is present.
    • However, CT scanning is still useful when MRI is not immediately available or is contraindicated.
  • PET scan
    • Useful in identifying cardiac involvement in patients with metastatic tumors, atrial myxoma or lipomatous septal hypertrophy.
  • Transvenous biopsy
    • Limited data is available on the risks and benefits of transvenous biopsy of suspected cardiac tumors.
    • Because myxomas may embolize, transvenous biopsy is not generally warranted if the appearance is typical on noninvasive imaging.
    • Biopsy is considered reasonable for other cardiac tumors if potential benefits are deemed sufficient to outweigh potential risks.

 

Treatment and Prognosis

 

  • Once a presumptive diagnosis of myxoma has been made on imaging studies, prompt resection is required because of the risk of embolization or cardiovascular complications, including sudden death.
  • The results of surgical resection are generally very good, with most series reporting an operative mortality rate under 5 percent.
  • Postoperative recovery is generally rapid.
  • Atrial arrhythmias or atrioventricular conduction abnormalities were present postoperatively in about 25% of patients
  • Approximately 5% risk for recurrence, suggesting the need for careful follow-up

Adapted from: Cohen et al. Atrial Myxoma: A Case Presentation and Review.Cardiology Research. 3 (1), 2012, 41-44. CC BY-SA 4.0

 

Answer to CC #9

Case Challenge #9 presented a 52 year old female with fever, new-onset weakness, and dyspnea on exertion associated with weight loss and a rash. She is afebrile, has petechiae on her fingertips, left-sided weakness. Heart sounds reveal a CARDIAC “PLOP.” MRI reveals multifocal acute CVA in different vascular distributions.

What is the most likely diagnosis?

  • Coxiella endocarditis
  • Hereditary hemorrhagic telangiectasia
  • Whipple’s disease
  • Rheumatic fever
  • Atrial myxoma

The patient has evidence of embolic disease, presumably from a cardiac source, as evidenced by the multifocal acute CVA. The key finding here is in the heart sounds. The atrial myxoma produces a diastolic sound that is referred to as a “tumor plop.” This sound arises from obstruction to ventricular in-flow that occurs as the tumor comes to rest over the mitral annulus. For more information, click the image below to hear a short podcast about atrial myxoma and the tumor plop.

LAMyxomaDiagram

 

FAQ: The House Passes A Bill To Fix Medicare’s Doctor Payments. What’s In It?

By Mary Agnes Carey

The troubled payment formula for Medicare physicians is one step closer to repeal.

The House Thursday overwhelmingly passed legislation to scrap Medicare’s troubled physician payment formula, just days before a March 31 deadline when doctors who treat Medicare patients will see a 21 percent payment cut. Senate action could come this week as well, but probably not until the chamber completes a lengthy series of votes on the GOP’s fiscal 2016 budget package.

According to a summary of the bill, unveiled by Republican and Democratic committee leaders earlier this week, the current system would be scrapped and replaced with payment increases for doctors for the next five years as Medicare transitions to a new system focused “on quality, value and accountability.”

There’s enough in the wide-ranging deal for both sides to love or hate.

Senate Democrats have pressed to add to the proposal four years of funding for an unrelated program, the Children’s Health Insurance Program, or CHIP. The House package extends CHIP for two years. In a statement Saturday, Senate Finance Democrats said they were “united by the necessity of extending CHIP funding for another four years” but others have suggested they may support the package.

Some senators have also raised concerns about asking Medicare beneficiaries to pay for more of their medical care, the impact of the package on women’s health services and cuts to Medicare providers.

In a letter to House members before Thursday’s vote, the seniors group AARP said the legislation places “unfair burdens on beneficiaries. AARP and other consumer and aging organizations remain concerned that beneficiaries account for the largest portion of budget offsets (roughly $35 billion) through greater out-of-pocket expenses” on top of higher Part B premiums that beneficiaries will pay to prevent the scheduled cut in Medicare physician payments.

Some Democratic allies said the CHIP disagreement should not undermine the proposal. After the House approved the SGR package by a vote of 392-37, Ron Pollack, executive director of the consumers group Families USA, urged the Senate to “adopt a CHIP funding bill as soon as possible. Families USA believes that a four-year extension is preferable to two years. We also know that time is of the essence, and it is crucial that the Senate act quickly.”

Some GOP conservatives and Democrats are unhappy that the package isn’t fully paid for, with policy changes governing Medicare beneficiaries and providers paying for only about $70 billion of the approximately $200 billion package. The Congressional Budget Office Wednesday said the bill would add $141 billion to the federal deficit.

For doctors, the package offers an end to a familiar but frustrating rite. Lawmakers have invariably deferred the cuts prescribed by a 1997 reimbursement formula, which everyone agrees is broken beyond repair. But the deferrals have always been temporary because Congress has not agreed to offsetting cuts to pay for a permanent fix. In 2010, Congress delayed scheduled cuts five times. In a statement Sunday, the American Medical Association urged Congress “to seize the moment” to enact the changes.

Here are some answers to frequently asked questions about the proposal and the congressional ritual known as the doc fix.

Q: How did this become an issue?

Today’s problem is a result of efforts years ago to control federal spending – a 1997 deficit reduction law that called for setting Medicare physician payment rates through a formula based on economic growth, known as the “sustainable growth rate” (SGR). For the first few years, Medicare expenditures did not exceed the target and doctors received modest pay increases. But in 2002, doctors were furious when their payments were reduced 4.8 percent. Every year since, Congress has staved off the scheduled cuts. But each deferral just increased the size of the fix needed the next time.

The Medicare Payment Advisory Commission (MedPAC), which advises Congress, says the SGR is “fundamentally flawed” and has called for its repeal. The SGR provides “no incentive for providers to restrain volume,” the agency said.

Q. Why haven’t lawmakers simply eliminated the formula before?

Money is the biggest problem. An earlier bipartisan, bicameral SGR overhaul plan produced jointly by three key congressional committees would cost $175 billion over the next decade, according to the Congressional Budget Office. While that’s far less than previous estimates for SGR repeal, it is difficult to find consensus on how to finance a fix.

For physicians, the prospect of facing big payment cuts is a source of mounting frustration. Some say the uncertainty has led them to quit the program, while others are threatening to do so. Still, defections have not been significant to date, according to MedPAC.

In a March 2014 report, the panel stated that beneficiaries’ access to physician services is “stable and similar to (or better than) access among privately insured individuals ages 50 to 64.” Those findings could change, however, if the full force of SGR cuts were ever implemented.

“The flawed Sustainable Growth Rate (SGR) formula and the cycle of patches to keep it from going into effect have created an unstable environment that hinders physicians’ ability to implement new models of care delivery that could improve care for patients,” said Dr. Robert M. Wah, president of the American Medical Association. “We support the policy to permanently eliminate the SGR and call on Congress to seize the moment and finally put in place reforms that will foster innovation and put us on a path towards a more sustainable Medicare program.”

Q: What are the options that Congress is looking at?

The House package would scrap the SGR and give doctors a 0.5 percent bump for each of the next five years as Medicare transitions to a payment system designed to reward physicians based on the quality of care provided, rather than the quantity of procedures performed, as the current payment formula does.

The measure, which builds upon last year’s legislation from the House Energy and Commerce and Ways and Means Committees and the Senate Finance Committee, would encourage better care coordination and chronic care management, ideas that experts have said are needed in the Medicare program. It would give a 5 percent payment bonus to providers who receive a “significant portion” of their revenue from an “alternative payment model” or patient-centered medical home. It would also allow broader use of Medicare data for “transparency and quality improvement” purposes.

“The SGR has generated repeated crises for nearly two decades,” Energy and Commerce Committee Chairman Fred Upton, R-Mich., one of the bill’s drafters, said in a statement. “We have a historic opportunity to finally move to a system that promotes quality over quantity and begins the important work of addressing Medicare’s structural issues.”

The package, which House Speaker John Boehner, R-Ohio, and Minority Leader Nancy Pelosi, D-Calif., began negotiating weeks ago, also includes an additional $7.2 billion for community health centers over the next two years. NARAL Pro-Choice America denounced the deal because the health center funding would be subject to the Hyde Amendment, a common legislative provision that says federal money can be used for abortions only when a pregnancy is the result of rape, incest or to save the life of the mother.

In a letter to Democratic colleagues, Pelosi said the funding would occur “under the same terms that Members have previously supported and voted on almost every year since 1979.” In a statement, the National Association of Community Health Centers said the proposal “represents no change in current policy for Health Centers, and would not change anything about how Health Centers operate today.”

A summary of the House plan says the package also includes other health measures – known as extenders – that Congress has renewed each year during the SGR debate. The list includes funding for therapy services, ambulance services and rural hospitals, as well as continuing a program that allows low-income people to keep their Medicaid coverage as they transition into employment and earn more money. The deal also would permanently extend the Qualifying Individual, or QI program, which helps low-income seniors pay their Medicare premiums.

Q. What is the plan for CHIP?

The House plan would add two years of funding for CHIP, a federal-state program that provides insurance for low-income children whose families earned too much money to qualify for Medicaid. While the health law continues CHIP authorization through 2019, funding for the program has not been extended beyond the end of September.

The length of the proposed extension could cause strains with Senate Democrats beyond those on the Finance panel who have raised objections to the House package. Last month, the Senate Democratic caucus signed on to legislation from Sen. Sherrod Brown, D-Ohio, calling for a four-year extension of the current CHIP program.

Q: How would Congress pay for all of that?

The measure the House passed does not. That is a major departure from the GOP’s mantra that all legislation must be financed. Tired of the yearly SGR battle, veteran members in both chambers may be willing to repeal the SGR on the basis that it’s a budget gimmick – the cuts are never made – and therefore financing is unnecessary. But that strategy could run into stiff opposition from Republican lawmakers and some Democrats.

Most lawmakers feel the need to find financing for the Medicare extenders, the CHIP extension and any increase in physician payments over the current pay schedule. Those items account for about $70 billion of financing in the approximately $200 billion package.

Conservative groups are urging Republicans to fully finance any SGR repeal. “Americans didn’t hand Republicans a historic House majority to engage in more deficit spending and budget gimmickry,” Dan Holler, communications director for Heritage Action for America, said earlier this month.

Q. Will seniors and Medicare providers have to help pay for the plan?

Starting in 2018, wealthier Medicare beneficiaries (individuals with incomes between $133,500 to $214,000, with thresholds likely higher for couples) would pay more for their Medicare coverage, a provision impacting just 2 percent of beneficiaries, according to the summary.

Starting in 2020, “first-dollar” supplemental Medicare insurance known as “Medigap” would not be able to cover the Part B deductible for new beneficiaries, which is currently $147 per year but has increased in past years.

But the effect of that change may be mitigated, according to one analysis.

“Because Medigap policies would no longer pay the Part B deductible, Medigap premiums for the affected policies would go down. Most affected beneficiaries would come out ahead — the drop in their Medigap premiums would exceed the increase in their cost sharing for health services,” according to an analysis from the Center on Budget and Policy Priorities, a left-leaning think tank. “Some others would come out behind. In both cases, the effect would be small — generally no more than $100 a year.”

Experts contend that the “first-dollar” plans, which cover nearly all deductibles and co-payments, keep beneficiaries from being judicious when making medical decisions. According to lobbyists and aides, an earlier version of the “doc fix” legislation that negotiators considered would have prohibited “first dollar” plans from covering the first $250 in costs for new beneficiaries.

Post-acute providers, such as long-term care and inpatient rehabilitation hospitals, skilled nursing facilities and home health and hospice organizations, would help finance the repeal, receiving base pay increases of 1 percent in 2018, about half of what was previously expected.

Other changes include phasing in a one-time 3.2 percentage-point boost in the base payment rate for hospitals currently scheduled to take effect in fiscal 2018. The number of years of the phase-in isn’t specified in the bill summary.

Scheduled reductions in Medicaid “disproportionate share” payments to hospitals that care for large numbers of people who are uninsured or covered by Medicaid would be delayed by one year to fiscal 2018 but extended for an additional year to fiscal 2025.

Q. How quickly could the Senate act?

The wide margin of passage in the House, plus the Obama administration’s support of the measure, may put pressure on senators to pass the bill once they conclude work on the chamber’s fiscal 2016 budget resolution later Thursday or early Friday morning. But Senate Democrats and Republicans may want to offer amendments to the House bill, which could mean that the chamber does not resolve the SGR issue before the Senate’s two-week break, which is scheduled to begin March 30.

If the SGR issue can’t be resolved by March 31, Congress could pass a temporary patch as negotiations continue or ask the Centers for Medicare and Medicaid Services, which oversees Medicare, to hold the claims in order to avoid physicians seeing their payments cut 21 percent. However, Speaker Boehner has said the House will not consider a temporary patch before leaving for its break Thursday.

Kaiser Health News (KHN) is a nonprofit national health policy news service. Creative Commons CC BY 4.0 license.

Pulmonary Hypertension Primer

OVERVIEW

  • Pulmonary hypertension is present when mean pulmonary artery pressure exceeds 25 mm Hg at rest or 30 mm Hg with exercise.

CAUSES

  • Mediator induced or hypoxic vasoconstriction
    • Post-transplant
    • ARDS
    • OSA
    • Sepsis
    • Post cardiac surgery
    • Kyphoscoliosis
    • Loss of vascular architecture in chronic lung disease (emphysema, COPD, CF)
  • Obstruction of vessels
    • PA: thromboembolism, vasculitis, mediastinal tumour or fibrosis
    • PV: pulmonary venocclusive disease
  • Acute cardiac conditions
    • Mitral Stenosis or regurgitation
    • VSD
    • LV infarct

PATHOPHYSIOLOGY

  • Cardiac causes
    • LV disease -> ↑ LA pressure -> ↑ pulmonary venous pressure -> ↑ PAP -> ↑PVR
    • L to right shunt will also cause high PVP
  • Respiratory causes
    • Hypoxic vasoconstriction -> PHT
  • Which leads to:
    • Vasoconstriction
    • Altered vascular endothelium and smooth muscle function
    • Cellular remodelling
    • Increased vascular contractility
    • Lack of relaxation in response to various endogenous vasodilators
    • Fibrosis of vascular tissue

HISTORY

  • Progressive SOB
  • Fatigue
  • Chest pain (like angina)
  • Syncope
  • Interrogate for conditions that can produce pulmonary hypertension (murmurs, collagen disease, valve pathology, VTE, OSA, alcohol consumption, chronic respiratory disease)

EXAMINATION

  • Prominent ‘a’ wave
  • Palpable P2
  • Right heart failure – increased JVP, (large V waves), parasternal heave, TR murmur, hepatomegaly, peripherial edema
  • Other signs of CHF
  • Hypoxaemia

DIAGNOSIS

  • Right-heart cath: mean pulmonary artery pressure > 25mmHg @ rest and > 30mmHg with exercise
    • Mild = 25-40mmHg
    • Moderate = 41-55mmHg
    • Severe = > 55mmHg
  • Functional assessment
    • I – no limitation on physical activity (no SOB, fatigue, chest pain or syncope)
    • II – minimal limitation of physical activity (comfortable @ rest, but develop symptoms on normal physical activity)
    • III – marked limitation of physical activity (comfortable @ rest but symptoms on less than normal activity)
    • IV – unable to perform any physical activity, RHF, symptoms @ rest

ADDITIONAL INVESTIGATIONS

  • ECG: RVH, RAD, p-pulmonale, tall R waves in V1, right ventricular strain
  • CXR: RVH on lateral (loss of retrosternal space), prominent pulmonary vascular
  • ECHO: RVH, estimation of PAP
  • Pulmonary function tests
  • DLCO: low
  • ABG
  • V/Q scan
  • High resolution CT: parenchymal disease suspected
  • Serology testing
  • LFT’s – hepatic congestion, end-stage disease
  • iNO provocation test: if lowers PA pressure -> Ca2+ antagonists may be helpful

MANAGEMENT

  • Goals
  1. Optimize PAP
  2. Optimize RV preload
  3. Avoid RV ischemia and failure
  • Chronic Pulmonary Hypertension
    • General:
      • Warfarin: in CTEPH, improved survival, INR 1.5-2.5
      • O2, diuretics, digoxin
      • vaccination to prevent respiratory infections (influenza, pneumococcal)
    • Specific
      • Calcium channel blockers: small proportion of patients respond well
      • Prostanoids: prostacyclin, epoprostenol, treprostinil, inhaled iloprost, beraprost
      • Endothelin receptor antagonists: bosentan
      • Phosphodiesterase inhibitors: ino-dilators, dipyridamole, sildenafil
    • Definitive: lung transplant

UTSW Internal Medicine

%d bloggers like this: