Cystic Fibrosis Infection Control

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The CF Center at Stanford has an infection control policy that seeks to reduce the risks to people with CF from potential cross infection. We strive actively to protect our patients by following the guidelines set out by CFF in their consensus statement on infection control.

The articles on this page describe general aspects of lung infections, the meaning of bacterial resistance, and what an allergic reaction to a CF drug really means.






Cystic Fibrosis Lung Infections and Infection Control
by Jane L. Burns, M.D.

Cystic fibrosis lung infections

Know Your Bugs

Viruses

Pseudomonas aeruginosa

Burkholderia cepacia complex

Staphylococcus aureus

Haemophilus influenzae (H. flu)

Other Bacteria

Non-tuberculous mycobacteria

Aspergillus

How  are  germs  spread?

PREVENTION

CFF Consensus conference on Infection Control

Standard Precautions

To summarize…

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Bacterial Resistance and Infection Control
by Richard Moss, M.D.
Many patients and families are concerned about infection control and the measures taken at our CF Center to reduce the risk of transmission of resistant bacteria while continuing to foster a sense of community and support. Here are some relevant facts which may help explain our policies and procedures.

First, it is essential to understand what we mean when we talk about resistance of bacteria to antibiotics. What does it really mean?

There are 4 categories of bacterial sensitivity to antibiotics:

CASE STUDY

Here is an example of an antibiotic sensitivity report for fictional patient Jane Smith on a clinic visit expectorated sputum culture that grew three strains of Pseudomonas aeruginosa, one strain of Stenotrophomonas maltophilia, and Staphylococcus aureus. What is listed is the antibiotic sensitivity pattern for 1 of the 3 strains of Pseudomonas, i.e., just one of 5 lists of antibiotic sensitivities we would get from this single culture report on this patient on this day:

"3+ mucoid Pseudomonas aeruginosa
Method Kirby Bauer
Ticarcillin Resistant
Piperacillin Resistant
Ceftazidime Intermediate
Ciprofloxacin Resistant
Imipenem Resistant
Gentamicin Resistant
Tobramycin Resistant
Amikacin Resistant
Aztreonam Intermediate
Cefepime Sensitive
Meropenem Resistant

Tobramycin E test (not yet FDA approved)
MIC 32 No interpretation"

What is your categorization of this bug, and how should Jane Smith be approached regarding infection control on a clinic visit? You wouldn't be expected to know the answer without a lot more knowledge of how the tests are done and what they mean. Here are several points about this culture result:

THE CONCEPT OF RESISTANCE - A RED HERRING IN CF?

We have problems even defining and understanding what resistance means in the world of CF. The word resistance refers to lab tests done in a liquid suspension with a conventional set "dose" of bacteria and cutoffs between "sensitive" and "resistant" refer to levels of that antibiotic traditionally associated with curing systemic (i.e, blood) infections.

We know in CF that the conventional term "resistance" is questionable clinically. For example, if your Pseudomonas is called "resistant" because tobramycin does not kill it at the conventional testing cutoff level of 8 mcg/ml, this is not very relevant in a disease where the bug is living in the mucus rather than tissue or blood, and we can deliver 1,000 mcg/ml Tobi® to the mucus by aerosol. Moreover, the way the bug lives in your lung is as a mucoid biofilm-a gigantic communal mass of bacteria (up to one billion bacteria in one gram of sputum!) stuck together by a slimy material called alginate or mucoid exopolysaccharide. This is much different than the way lab antibiotic testing is done with individual bugs swimming around freely in liquid suspension.

INFECTION CONTROL

We rely on universal direct and indirect contact precautions for ALL patients to reduce transmission of bacteria. The simplest way to describe this is to imagine a three foot zone around your body that should ideally not be entered by another patient (unless you live with them), and no shared object use without proper cleaning in between. All contacts by caregivers should be preceded by handwashing and cleaning of multi-use instruments such as stethoscopes.

We are concerned about acquisition and spread of Pseudomonas, and the infection control measures are designed to reduce the chance of spread. For multiresistant and panresistant bugs, we add restrictions on the patient such as use of mask when coming to clinic, and isolation when hospitalized. This is done to reduce the chance of transmission, not because the patient is sicker! The mask is an additional level of precaution but contact precautions are the key element for ALL patients.

In the near future the CFF Consensus Conference report on Infection Control will be published and available for detailed reading.

REPORTING CULTURE RESULTS TO PATIENTS

Ideally, we would like to track levels of resistance in all cultures and inform all patients promptly. In practice, this is a very difficult task. In our center we see over 200 patients a year, on average 4 times, yielding at least 800 "surveillance" bacterial cultures alone. Add to this cultures obtained when the patient is sick, and when hospitalized. Each specimen may contain multiple bacterial strains that are each tested for antibiotic sensitivities. And this is just for bacteria; often further cultures are also obtained for molds, mycobacteria, and so on. Finally, many other tests (bloodwork, x-rays, PFTs) are also being monitored.

Given our staff resources we have in the past focused on the priority of promptly informing people who are culture negative for Pseudomonas when they pick up Pseudomonas because we want to try to eradicate it early. Later on this becomes impossible, so that most people who have years of carrying mucoid Pseudomonas cannot achieve eradication by any known treatment. We do not routinely inform patients of each culture result in that instance. Besides the impracticality of the numbers, we know that typically a strain may go from "resistant" to "sensitive" and back and forth over time, confusing many people and raising needless anxiety. Instead, we focus on dealing with the situation at each clinic visit as well as of course during hospitalizations.

The infection control guidelines currently being prepared for publication do not distinguish between patients with sensitive or resistant Pseudomonas outside health care settings, but rather recommend a uniform set of infection control behaviors for all persons with CF. Thus, we have no specific reason to routinely inform patients with long-term Pseudomonas carriage of culture-to-culture changes in their resistance pattern with regard to their outside the health care system interactions, but urge adherence to the general recommendations. Cultures are checked before the next clinic visit so we can institute appropriate infection control for that visit.

Recently, our staff met and decided to go beyond current standard practice and monitor sensitivity results for long-term Pseudomonas patients, and send a letter out informing patients with resistant organisms of the mask requirement for clinic. We hope this system minimizes surprises about our infection control measures in the clinic and hospital. It is critical to remember that a "resistant" bug report does not and should not be taken as a bad thing in and of itself, and that our main interest as to timing use of this information focuses on our health-care facility setting, and early monitoring of new Pseudomonas. Now, in addition, we will attempt to track long-term carriers and provide "early warning" infection control letters.

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CF Drug Allergies
by Richard Moss, M.D.
Antibiotics are essential part of treatment for cystic fibrosis lung disease. Most patients receive numerous courses of oral, iv or inhaled antibiotics for symptoms and many patients are maintained on long-term "suppressive" regimes of oral or inhaled antibiotics. It is not surprising that given this enormous exposure a substantial problem with allergic reactions exists. Most reactions and reports of sensitization have been to the class of antibiotics derived from penicillin that are effective against Pseudomonas aeruginosa, the major bacterial infection in CF. These are called anti-pseudomonal b-lactam antibiotics [BLA]. Allergy to aminoglycosides such as tobramcyin and quinolones such as ciprofloxacin are very rare.

A general principle of allergy is that reactions are more likely the more closely related two molecules are. Within the BLA family, there are 4 subfamilies chemically related by a core structure called the b-lactam nucleus but quite different in their side chains. The BLA subfamilies and the drugs used in CF are as follows:

  1. Penicillins
    • Carboxypenicillins
      Ticarcillin (Ticar, Timentin)
    • Acylaminopenicillins
      Piperacillin (Pipracil, Zosyn)
  2. Carbapenems
    • Imipenem (Primaxin)
    • Meropenem (Merrem)
  3. Monbactams
    • Aztreonam (Azactam)
  4. Cephalosporins
    • Ceftazidime (Fortaz, Tazicef)
    • Cefepime (Maxipime)
It turns out that most BLA allergic reactions occur due to allergic or IgE antibodies being formed against the side chains, so most reactions occur upon re-exposure to the same drug, or to a closely related drug in the same subfamily with a similar side chain structure. The chances of a reaction diminish as the structure becomes more dissimilar.

Allergic reactions to BLA occur in 1-10% of subjects during a given course of treatment, with the variation in incidence dependent upon several factors such as the subject population, drugs involved, and ascertainment methods. The vast majority of these are limited to skin or underlying tissues, with only 2-10% involving life-threatening respiratory or cardiovascular reactions. Up to 9% of the life-threatening reactions may result in death, yielding a final fatality rate estimated at about 1 in 50,000 treatment courses.

Most of the information in the medical literature is based on allergy to penicillin itself, not the many derivatives such as those used against Pseudomonas. Ten to 73% of patients giving a history of penicillin allergy react on allergy skin testing to penicillin-derived chemicals or reagents, depending upon time elapsed since the reaction, nature of the reaction, age of subject, and other factors. Evaluation of penicillin allergy with just two commercially available reagents, penicillin and its major metabolite penicilloyl-polylysine [Pre-Pen®], detects 65-93% of allergic individuals. The remainder of allergic subjects are reactive only to minor penicillin metabolites which are unstable and not commercially available. Unfortunately, those sensitized to these minor metabolites are at higher risk of more serious reactions if re-exposed to penicillin.

For people sensitized to BLAs other than penicillin, skin testing and prediction of subsequent clinical reactivity becomes much more difficult. Major and minor metabolites of these drugs are not commercially available and are not well characterized. Cross-reaction studies between various BLAs yield varying results and clinical responses are not predictable from skin test responses. Thus, the safest course is usually to avoid BLAs and choose an alternate class of drug when possible. However, treatment of Pseudomonas aeruginosa infection rarely offers this choice; usually, a BLA is essential.

Studies of BLA allergy in CF have been reported since 1970, including a number studies from our CF Center over the last 15 years. In general, these show BLA allergy rates of about 15-25% in CF patients and 5-10% of iv BLA treatment courses. These reactions are usually in-hospital, physician-observed, well-characterized and documented. Reactions are usually seen in older patients with multiple prior exposures. Reactions always include the skin (itching, redness, hives, swelling) while respiratory involvement occurs in only a small minority. However these can be quite severe with bronchospasm or largyngeal edema. Cardiovascular problems are very rare.

Unusual cases of patients with reactions to several classes of antibiotics, not just BLA, have been reported also.

Our studies using skin testing and laboratory immunological assays suggest that BLA allergy in CF is mainly drug-specific. This situation differs from other penicillin allergic patients in the literature, whose allergy appears mainly directed to the core BLA nucleus. It is clear that cross-reactivity between various BLA occurs, and that any BLA may cause an allergic reaction. It is not currently possible to predict which CF patients will become sensitized, although multiple courses, high doses, and the intravenous route of drug exposure are key elements in sensitization. Patients may become sensitized during or between any given course of antibiotic therapy.

Treatment

The main treatment strategy in CF is called desensitization. Desensitization is the administration of gradually increasing doses of a drug under close observation for adverse effects. Desensitization has been performed safely in pregnant women, critically ill patients, and patients with serious but not life-threatening infections. How desensitization works is incompletely understood.

Desensitization may be performed orally with oral drugs, but most BLA used in CF are given only by the iv route, so most desensitization procedures are done intravenously. In addition, only the iv route allows control of the dose and rapidity by which the drug enters the bloodstream. During iv desensitization, the earliest signs of a reaction can be at least in part immediately managed by slowing or stopping the infusion. If the reaction history was severe pretreatment with Benadryl and sometimes steroids may be included. We have performed many hundreds of iv desensitization for BLA allergy in CF since 1983. Skin rashes occur in 25-30% of cases, often during or just after the last and highest dose. Mild reactions are treated with slowed infusion rates and iv Benadryl. More serious reactions occur in 1-2% of cases and require immediate management and discontinuation of desensitization. In virtually all of these cases, iv desensitization with another BLA has been successfully performed 1-2 days after the patient has been stabilized. Desensitization relies on staying on the prescribed drug schedule; missed doses increase the possibility of a reaction.

While it is possible to maintain desensitization by indefinitely staying on the drug in question, in most cases this is impractical in CF. Instead, we rely on history (identifying prior drug reactions) and repeat desensitization if a BLA causing a reaction needs to be given again. In many instances, an alternative BLA can be chosen instead. Studies show the likelihood of a cross-reactive allergic reaction is in the range of 2-5% if a different BLA subfamily drug is used (e.g., you reacted to piperacillin and we then use ceftazidime). Often in this situation we will give a test dose (1/10 or 1/100 of the full dose) first, and then the full dose if no symptoms occur.

Delayed reactions. Delayed reactions take days or weeks to occur and are not life-threatening, but can be quite troubling. They usually consist of fever, malaise, muscle aches, non-itchy flat irregular red rashes, and sore sometimes swollen joints. Rarely enlarged glands or internal organs, or more severe skin rashes may occur. Delayed reactions are more common with piperacillin than other BLAs. Besides stopping the drug, steroids are often given. Desensitization does not prevent delayed reactions if the same drug is given again.

What You Can Do

Know your drug allergy history! Record the name of the drug, when the reaction occurred and what happened. Do NOT assume the medical record is foolproof - it is not! YOU should take charge of your medical history and make sure you are not exposed to a BLA you reacted to in the past without proper evaluation and a plan.

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