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Chronic Obstructive Lung Disease Medications
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The widespread use of inhaled corticosteroids for COLD patients is under debate, particularly since other agents are equally -- or more -- effective. Studies are mixed on whether long-term use improves lung function. They also can have some significant adverse effects over time, particularly in reducing bone density, which weakens bones. Combination inhalers that contain both a corticosteroid and a long-acting beta2-agonist may prove to be a good option.
Common side effects of inhaled steroids are throat irritation, hoarseness, and dry mouth. Other possible but less common adverse effects include rashes, wheezing, facial swelling (edema), fungal infections (thrush) in the mouth and throat, and bruising.
Inhaled steroids are generally considered safe and effective. They rarely cause any of the more serious side effects reported with prolonged use of oral steroids. There are some risks with long-term use, however. A 2001 study reported a higher risk for cataracts in patients over age 40. Others are reporting a higher risk for bone loss in patients who take inhaled steroids regularly. Several bone-preserving medications are now available that might safely offset this effect. There is also some concern that the more potent agents, particularly fluticasone, may suppress the adrenal system (which secretes natural steroids) to a greater degree than other steroid inhalants. This is a serious side effect of oral steroids.
Antibiotics
Treating Acute Bronchitis or Pneumonia in COLD Patients. People with COLD are at heightened risk for pneumonia, but any lung infection can worsen symptoms and is dangerous in COLD patients. Aggressive therapy using powerful antibiotics is usually called for when acute bronchitis or pneumonia occurs. The most common organisms causing pneumonia in people with chronic obstructive lung disease include Streptococcus pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, and Legionella pneumophila. Of some concern is the increase in infection rates by more unusual and difficult-to-treat organisms known as gram-negative bacteria.
The primary choice of medicine still includes the less expensive antibiotics, such as amoxicillin/clavulanate, doxycycline, and trimethoprim-sulfamethoxazole. Antibiotic classes known as macrolides and quinolones appear to be beneficial as well. Detecting the specific organism causing the lung infection is often difficult. [For more information, see In-DepthReport #64: Pneumonia.]
Preventive (Prophylactic) Antibiotics in COLD Patients. In the past, antibiotics were given daily for patients with even mild COLD until studies found that they did not alter progression of either the disorder or the disabilities associated with it. Preventive antibiotics may be given for 1 week per month, alternating the medications that are used. They are now prescribed only for COLD patients with one or more of the following conditions:
- Four or more episodes a year of acute infection with intensified COLD symptoms, including worsened shortness of breath and mucus production
- Deficient immune systems
- Bronchiectasis, an irreversible lung disease in which the airways in the lung are always dilated
Antibiotic Options
Beta-Lactams
The beta-lactam antibiotics include penicillins, cephalosporins, and some newer, similar agents. Their primary action is interfering with bacterial cell walls.
Penicillins. Penicillin was the first antibiotic that was discovered. There are many forms to this still-important agent:
- Natural penicillins include penicillin G (for intravenous use) and V (for oral use).
- Penicillin derivatives called aminopenicillins, particularly amoxicillin (Amoxil, Polymox, Trimox, Wymox, or any generic formulation), are now the most common penicillins used. Amoxicillin is inexpensive and at one time was highly effective against the S. pneumoniae bacteria. Unfortunately, bacterial resistance to amoxicillin has increased significantly, both among S. pneumoniae and H. influenzae. Ampicillin is similar, and an alternative, to amoxicillin, but requires more doses and has more severe gastrointestinal side effects than amoxicillin.
- Amoxicillin-clavulanate (Augmentin) is known as augmented penicillin, which works against a wide spectrum of bacteria. An extended release form has been approved for treating adults with community-acquired pneumonia caused by bacterial strains that have become resistant to penicillin.
- Antistaphylococcal penicillins were developed to treat Staphylococcus aureus. The standard agent was methicillin, but it is no longer used very much because of very high rates of resistance in hospital-acquired pneumonias. Resistance in community-acquired Staphylococcus aureus infections is increasing. Alternatives include vancomycin and linezolid.
- Certain penicillins are used against Pseudomonas aeruginosa, including ticarcillin and piperacillin. Piperacillin is the most effective of these medicines for this dangerous organism.
Many people have a history of an allergic reaction to penicillin, but some evidence suggests that the allergy may not persist in a significant number of adults. Skin tests are available to help determine if some people previously considered allergic could use these important antibiotics.
Cephalosporins. Most of these medicines are not very effective against bacteria that have developed resistance to penicillin. They are often classified as follows:
- First generation includes cephalexin (Keflex), cefadroxil (Duricef, Ultracef), and cephradine (Velosef).
- Second generation includes cefaclor (Ceclor), cefuroxime (Ceftin), cefprozil (Cefzil), and loracarbef (Lorabid).
- Third generation includes cefpodoxime (Vantin), cefdinir (Omnicef) cefditoren (Spectracef), cefixime (Suprax), and ceftibuten (Cedex). Ceftriaxone (Rocephin) is an injected cephalosporin. These are effective against a wide range of gram-negative bacteria.
Other Beta-Lactam Agents. Carbapenems (also known as thienamycins) include meropenem (Merrem), biapenem, faropenem, ertapenem (Invanz) and combinations (imipenem/cilastatin [Primaxin]). These agents cover a wide spectrum of bacteria. They are now used for serious hospital-acquired infection and for bacteria that have become resistant to other beta-lactam bacteria. Imipenem has serious side effects when used alone, so it is given in combination with another medicine, cilastatin, to offset these adverse effects. The newer medicines are less toxic, although they may not be as potent.
Sanfetrinem, a novel beta-lactam antibiotic known as a trinem, is proving to be effective against S. pneumoniae,H. influenzae, and M. catarrhalis.
Fluoroquinolones (Quinolones)
Fluoroquinolones (also simply called quinolones) interfere with the bacteria's ability to reproduce, preventing the copying of bacterial DNA (genetic material).
- Ciprofloxacin (Cipro), a second-generation quinolone, remains the most potent antipseudomonal quinolone against Pseudomonas aeruginosa bacteria, but is not very effective for gram-positive bacteria.
- Newer third-generation quinolones are the most effective agents against a wider range of common bacteria. They include levofloxacin (Levaquin), sparfloxacin (Zagam), gemifloxacin (Factive), and gatifloxacin (Tequin). Levofloxacin is the first drug approved specifically for penicillin-resistant S. pneumoniae. Some of the newer fluoroquinolones also need to be taken only once a day, making compliance easier. Some, but not all, quinolones cause photosensitivity (making it easier to become sunburned).
- A fourth generation includes moxifloxacin (Avelox), trovafloxacin, and clinafloxacin, which are proving to be effective against anaerobic bacteria. Studies suggest that taking the moxifloxacin once a day offered fast relief for patients with acute exacerbations of chronic bronchitis.
S. pneumoniae strains resistant to the quinolones have been uncommon in the U.S., but resistance has dramatically increased in the past few years, particularly with ciprofloxacin.
In February 2006, Bristol-Myers Squibb notified the FDA it is changing its prescription information for gatifloxacin (Tequin). Because of reports of serious changes in blood sugar levels in vulnerable people, the company says diabetics should not use this antibiotic. In addition, the company says that elderly people, people with kidney problems, and those taking medications that affect blood sugar levels should be watched carefully while taking Tequin.
Macrolides, Azalides, and Ketolides
Macrolides and azalides are antibiotics that also affect the genetics of bacteria. They include erythromycin, azithromycin (Zithromax), clarithromycin (Biaxin), and roxithromycin (Rulid). These antibiotics are effective against S. pneumoniae and M. catarrhalis, but bacterial resistance to these medicines is increasing.
In one study, patients who took erythromycin during a common cold had a lower risk for worsened COLD symptoms than those not taking the antibiotic.
Ketolides are derived from erythromycin. They were developed to combat organisms that have become resistant to macrolides. Telithromycin (Ketek), the first antibiotic in the ketolide class, was approved by the FDA in 2004 for treating community-acquired pneumonia (CAP), acute bacterial exacerbation of chronic bronchitis, and acute sinusitis.
In January 2006, the FDA issued a Public Health Advisory for health care providers and patients using Ketek. Patients treated with this antibiotic should stop using it if jaundice (yellowing of the skin or whites of the eyes) develops. The FDA issued this advisory after three cases of severe liver injury in patients treated with Ketek. In June 2006, the FDA reported that four people had died after taking the drug. In December 2006, the FDA recommended that Ketek should not be used in patients with sinusitis or bronchitis. The FDA panel also recommended that the drug should carry a black box warning noting the potentially serious side effects, including liver failure, vision problems, loss of consciousness, and neuromuscular problems.
Early studies of Ketek did not reveal any significant risks of liver injury, compared with other antibiotics.
Tetracyclines
Tetracyclines inhibit bacterial growth. They include doxycycline, tetracycline, and minocycline. Doxycycline can be effective for COLD patients, but bacteria that are resistant to penicillin are also often resistant to doxycycline. Tetracyclines have unique side effects among antibiotics, including skin reactions to sunlight, possible burning in the throat, and tooth discoloration.
Aminoglycosides
Aminoglycosides (gentamicin, kanamycin, tobramycin, amikacin) are given by injection for very serious bacterial infections. They can be given only in combination with other antibiotics. Some are available in inhaled forms or by irrigation (applying a solution directly to mucous membranes, skin, or body cavity). They can have very serious side effects, including damage to hearing, sense of balance, and kidneys.
Lincosamide
Lincosamides prevent bacteria from reproducing. The most common lincosamide is clindamycin (Cleocin). This antibiotic is useful against S. pneumoniae and S. aureus but not against H. influenzae.
Glycopeptides
Glycopeptides (vancomycin, teicoplanin) is used for Staphylococcus aureus that have become resistant to standard antibiotics. They are available in intravenous and oral forms.
Trimethoprim-Sulfamethoxazole
Trimethoprim-sulfamethoxazole (Bactrim, Cotrim, Septra) is less expensive than amoxicillin and particularly useful for adults with mild bacterial upper respiratory infections who are allergic to penicillin. It is no longer effective, however, against certain streptococcal strains. It should not be used in patients whose infections occur after dental work or in patients allergic to sulfa drugs. Allergic reactions can be very serious.
Oxazolidinone
Linezolid (Zyvox) is the first antibacterial drug in a new class of synthetic antibiotics called oxazolidinones. It has been proven effective against certain aerobic gram-positive bacteria, including Staphylococcus aureus (MRSA).
Others
Streptogrammins (quinupristin/dalfopristin [Synercid]). In a major 2001 study of S. pneumonia resistance to antibiotics, there were no reports of resistance to this agent.
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Treatment for AAT Deficiency
Replacement Treatment. Augmentation or replacement therapy supplements the existing alpha 1-antitrypsin (AAT) levels in the blood. The replacement AAT is derived from human blood, which has been screened for viruses and is injected weekly or bimonthly. One study reported that patients taking this supplement had a mortality rate that was two thirds of those not on this therapy. Replacement therapy may also reduce the severity and frequency of lung infections. Therapy is life-long. Patients with inherited AAT deficiency, regardless of their smoking history, are eligible for this therapy. Unfortunately, this therapy is in short supply.
An inhaled AAT replacement treatment produced from the milk of genetically bred sheep is under investigation. An oral form is also under investigation.
Other Investigative Treatments for AAT Deficiency. Aerosolized hyaluronic acid may protect lungs from injury by elastase. Elastase is the enzyme that causes lung tissue to lose elasticity. A clinical trial is underway.
Medicines That Loosen Lung Secretions
Patients with persistent coughing and sputum often use agents that loosen secretions and help move them out of the lungs. However, it is not clear if these agents offer any important benefits.
Expectorants. Expectorants, such as guaifenesin (found in common cough remedies), stimulate the flow of fluid in the airways and help move secretions using cilia motion (the hair-like structures in the lung) and coughing.
Mucolytics. Mucolytics contain ingredients that make sputum more watery and easier to cough up. One of these ingredients, acetylcysteine, also acts as an antioxidant, which could provide additional benefit to people with COLD. Although there is some controversy over their value, an analysis of many studies indicated that oral mucolytics reduce the number of symptoms in patients with severe chronic bronchitis, and have a small but significant effect on breathing function. They should not be used, however, during an acute attack, since they may worsen lung function. They also do not appear to be very helpful for patients with mild COLD.
Experimental Therapies
Selective Phosphodiesterase 4 Inhibitors. Cilomilast (Ariflo) and roflumilast (Daxas) are selective phosphodiesterase 4 (PDE4) inhibitors. They block PDE4, an enzyme that is overproduced in COLD and asthma and causes inflammation in the airways. Studies are very promising. A 2003 report on reflumilast, for example, found significant improvement in lung function and quality of life compared to placebo. The drugs can cause diarrhea and nausea, which may limit their tolerability.
Leukotriene-Antagonists. Leukotriene-antagonists (also called anti-leukotrienes) are oral medications that block leukotrienes. These are powerful chemicals in the immune system that, in excess, produce inflammation and spasms in the airways. Agents include zafirlukast (Accolate), montelukast (Singulair), zileuton (Ziflo), and pranlukast (Ultair, Onon). They are currently used for preventing asthma attacks. Studies indicate that they also have benefits for people with COLD, although it is not clear if they have advantages over standard COLD agents.
Retinoic Acid. All-trans retinoic acid (ATRA), a derivative of vitamin A, may reverse some of the damage that occurs in emphysema. One such agent is being developed; researchers hope it will grow new air sacs in the lungs.
Sildenafil. In 2005, the FDA approved sildenafil citrate (the active ingredient in Viagra) to treat pulmonary hypertension, a serious complication of chronic obstructive lung disease (COLD).
Testosterone Replacement. People with COLD tend to have low levels of testosterone. Researchers are investigating testosterone replacement in both men and women with COLD for increasing muscle strength and function.
P2Y(2) Receptor Agonists. P2Y(2) receptor agonists are experimental agents that increase the action of the cilia (hair-like structures) in the lung and clear out mucus. The most promising agent to date is currently referred to as INS37217.
Other Investigative Agents. A number of agents are in very early stages of investigation. They include drugs called antiproteases (e.g., sivelestat ONO-6818. batimastat), new antioxidants, and many others.
Review Date: 04/28/2006
Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of
Medicine, Harvard Medical School; Physician, Massachusetts General
Hospital
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