Penicillin resistance in pneumococcal pneumonia

Antibiotics with low resistance potential are effective and pose less risk

Burke A. Cunha, MD

VOL 113 / NO 1 / JANUARY 2003 / POSTGRADUATE MEDICINE

CME learning objectives

• To become familiar with respiratory pathogens that have antibiotic resistance and are likely to be encountered in clinical practice
• To recognize which antibiotics used in the treatment of respiratory tract infections or community-acquired pneumonia (CAP) have been linked to resistance problems
• To review the clinical significance of penicillin resistance in pneumococci that cause CAP

The author discloses no financial interests in this article.

This is the first of three articles on community-acquired pneumonia.

Preview: Antibiotic resistance is a potential problem around the world. Among the bacteria that cause community-acquired pneumonia (CAP), resistance in Streptococcus pneumoniae is a primary concern. Resistance can occur through genetic mutations in the bacterial strain itself or can be acquired through use of some antibiotics that have a high resistance potential. In this article, Dr Cunha explores the misperceptions about antibiotic resistance and its occurrence, as well as the most appropriate therapy for CAP in the clinical setting.
Cunha BA. Penicillin resistance in pneumococcal pneumonia. Postgrad Med 2003;113(1):42-54

Antimicrobial resistance among the pulmonary microbes that cause CAP is confined to the typical bacterial pathogens--Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. It does not occur with atypical pulmonary pathogens. The mechanisms and factors involved in antibiotic resistance are varied. Strains of M catarrhalis began to produce beta-lactamase decades ago and continue to do so today. H influenzae strains resistant to ampicillin (Omnipen, Principen, Totacillin) differ in geographic distribution but are now common. Penicillin resistance in S pneumoniae strains is a potential concern, but it has limited clinical relevance. Isolates of penicillin-resistant S pneumoniae are caused by the spread of clonally resistant strains that developed from point mutations and from overuse of antibiotics with a high resistance potential.

Widespread increases in the minimum inhibitory concentrations (MICs) or decreases in penicillin sensitivity are related to the use of a few, but not most, antibiotics. Antimicrobial agents with high resistance potential, such as the macrolides, trimethoprim-sulfamethoxazole (TMP-SMZ) (Bactrim, Cotrim, Septra), and ciprofloxacin (Cipro), have been associated with penicillin resistance. However, despite widespread use, antibiotics with a low resistance potential (eg, amoxicillin and potassium clavulanate extended release [Augmentin XR], clindamycin [Cleocin], doxycycline, meropenem [Merrem], cefepime hydrochloride [Maxipime], linezolid [Zyvox], levofloxacin [Levoquin], gatifloxacin [Tequin], moxifloxacin hydrochloride [Avelox], vancomycin [Vancocin, Vancoled]) and most beta-lactams remain effective against S pneumoniae.

Common misconceptions

Antibiotic resistance has become a concern worldwide. Although the exact mechanism of antibiotic resistance remains obscure, it clearly has a genetic basis. Certain antibiotic agents induce genetic changes in bacteria, and the resulting resistant strains may proliferate and cause widespread, or clonal, resistance. Point mutations occur randomly, but such mutations are not linked to antibiotic use.

In fact, resistance is not related to antibiotic volume or "tonnage" per se. Nor is it linked to duration of treatment, which is a popular misconception. Such myths about antibiotic resistance persist in the mind of many physicians, making the control of antimicrobial resistance difficult. Mechanistic approaches do not explain differences in resistance potential among antibiotics of the same class. Instead, physicians need to approach antibiotic resistance from a historical perspective, which best explains its differences.

For reasons that are not clear, antibiotics with a low resistance potential do not induce resistance even when used in high volume over decades. Examples of such antibiotics include doxycycline, levofloxacin, and all third-generation cephalosporins (with the exception of ceftazidime). However, antibiotics with high resistance potential (eg, tetracycline, ceftazidime, imipenem-cilastatin [Primaxin], ciprofloxacin) may cause resistance with even limited use. Because resistance does not occur in atypical pulmonary pathogens, this article focuses on the resistance potential of the most common CAP pathogen, S pneumoniae (1-3).

Terminology for resistance

Much of the misunderstanding about resistance relates to imprecise terminology. The original concept of resistance can be termed natural or intrinsic resistance. Natural resistance refers to resistant organisms that intrinsically are beyond the spectrum of an antibiotic. For example, about 20% of S pneumoniae bacteria are resistant to all the macrolides--erythromycin, clarithromycin (Biaxin), and azithromycin (Zithromax). Such resistance is intrinsic; it has a genetic basis and is not related to antibiotic use.

If resistance is not natural, then it is termed acquired resistance. Macrolide use can cause acquired resistance in S pneumoniae, which is discussed later in this article. Acquired resistance refers to resistance in an organism that was previously sensitive to a particular antibiotic but has since become resistant to it. Among the pathogens of CAP, examples include penicillin resistance in M catarrhalis, ampicillin resistance in H influenzae, and resistance to TMP-SMZ, ciprofloxacin, and the macrolides in S pneumoniae. Acquired resistance may be further subdivided into relative or high-level resistance. Bacterial strains also may be described as having intermediate sensitivity or intermediate resistance.

The susceptibility of "relatively" resistant strains is concentration-dependent. If an antibiotic's concentration is above the MIC for such strains, then the relatively resistant organism is sensitive to the agent and will be eliminated by it. In contrast, highly resistant strains are truly resistant and cannot be overcome by increases in drug concentration. Such highly resistant organisms may be treated with different antibiotics.

An increase in MICs (MIC drift) should not be confused with resistance. MIC drift refers to the gradual increase in MICs in a large patient population and may be considered a relative resistance phenomenon. In contrast, the term cross-resistance indicates a strain's resistance to all members of a drug class. It refers to this phenomenon in an individual patient, not a large population.

It is important to understand that the mechanism of bacterial resistance in a member of an antibiotic class does not predict or explain differences in class resistance. For example, among the tetracyclines, only tetracycline is associated with resistance; doxycycline is not. The same is true among fluoroquinolones: if S pneumoniae has a penicillin resistance that was induced by ciprofloxacin, this resistance does not imply a cross-resistance to other quinolones. In fact, ciprofloxacin-resistant S pneumoniae strains are sensitive to levofloxacin, gatifloxacin, and moxifloxacin (1,4).

Mechanisms of resistance

Resistance can develop through beta-lactamase inactivation, alterations in penicillin-binding proteins, or intracellular metabolic or genetic mechanisms. Although the mechanism of resistance does not explain resistance differences within antibiotic classes, an understanding of the basic mechanisms within each class is necessary to appreciate how resistance develops in general.

Beta-lactamase inactivation
The primary mechanism of resistance among strains of M catarrhalis is beta-lactamase inactivation. Unless an antibiotic is resistant to beta-lactamase, the beta-lactamases produced by M catarrhalis inactivate the antibiotic by destroying its beta-lactam structure. This has clear implications for therapy. Since most of the current strains of M catarrhalis are beta-lactamase producers, physicians should consider all M catarrhalis strains to be beta-lactamase producers and treat M catarrhalis infection with an antimicrobial agent resistant to beta-lactamase.

Ampicillin resistance among strains of H influenzae is also mediated by beta-lactamases. In contrast to beta-lactamases among Moraxella strains, the ampicillin-resistant strains of H influenzae are not the predominant variety. Ampicillin resistance in H influenzae is a geographically varied phenomenon. The selection of agents to treat CAP that is likely caused by H influenzae depends on the prevalence of ampicillin resistance in the local community. If most strains in a given locale are ampicillin-resistant, then all patients should receive a drug active against ampicillin-resistant strains. If, on the other hand, ampicillin resistance is relatively uncommon in a community, then ampicillin resistance need not be an important factor in the selection of an antibiotic for CAP treatment.

Alterations in penicillin-binding proteins
Penicillin resistance among pneumococci is mediated by changes in penicillin-binding proteins (PBPs), which exist on the surface of S pneumoniae. Alterations in penicillin-binding sites determine the effectiveness of antibiotics that exert their effect at the cell surface (eg, beta-lactam antibiotics). However, penicillin resistance among pneumococci is not caused by beta-lactamases. If a patient is infected with a strain of penicillin-resistant S pneumoniae, a combination of beta-lactamase inhibitors should not be used. Beta-lactamase inhibitors have no effect on alterations in PBPs and hence are not effective in treating for penicillin resistance. In practical terms, if amoxicillin is ineffective against a penicillin-resistant strain of S pneumoniae, then amoxicillin and potassium clavulanate will be similarly ineffective against these strains (1,5).

Intracellular metabolic or genetic mechanisms
Certain antimicrobial agents (eg, TMP-SMZ, the macrolides) exert their antimicrobial effect intracellularly. TMP-SMZ interferes with folic acid synthesis; the macrolides interfere with ribosomal transcription and disrupt bacterial cell functions. Quinolones interfere with intracellular gyrases or tropoisomerases, which disrupt cell functions and result in bacterial death. Ciprofloxacin has a relationship to penicillin resistance: penicillin resistance predicts ciprofloxacin resistance in S pneumoniae. However, pneumococcal resistance to ciprofloxacin or penicillin does not predict resistance to other quinolones.

Because penicillin resistance has been linked to ciprofloxacin use, some physicians have assumed that the same phenomenon applies to the widespread use of fluoroquinolones for CAP. Such a relationship has not been the case, and time and experience are sufficient to support this conclusion. Despite more than 200 million courses of levofloxacin administered during the past 5 years, the prevalence of levofloxacin-resistant S pneumoniae remains at less than 1% worldwide.

Antibiotic resistance has a genetic basis, but it is not entirely clear how this works. Do the macrolides or ciprofloxacin induce genetic changes in bacteria, or are genetic mutations expressed after exposure to these agents? What is clear is that certain antibiotics cause or amplify genetic changes. For example, antibiotics with a high resistance potential have this effect; those with a low resistance potential do not.

Widespread use of antibiotics that have a low resistance potential does not increase resistance over time. This outcome has been shown with many agents, including doxycycline, amikacin, all third-generation cephalosporins (with the exception of ceftazidime), meropenem, cefepime, ofloxacin (Floxin), levofloxacin, sparfloxacin (Zagan), grepafloxacin, trovafloxacin mesylate-alatrofloxacin mesylate (Trovan), gatifloxacin, and moxifloxacin. (These quinolones have been used extensively worldwide, but some of them have been introduced into the United States only recently.) This concept is critical to limiting further resistance by limiting the use of antimicrobial agents with high resistance potential. Antibiotics with low resistance potential and the appropriate spectrum of coverage for CAP should be used preferentially to halt or reverse this process (1,5).

In vitro susceptibility testing

In vitro susceptibility testing is the basis for classifying bacterial strains as either penicillin-resistant or penicillin-sensitive. Most organisms tested in the microbiology laboratory are reported to be either sensitive or resistant on the basis of breakpoints determined by the National Committee for Clinical Laboratory Standards. However, susceptibility of strains is reported as sensitive, intermediately sensitive/resistant, or resistant for penicillins against S pneumoniae.

This system creates difficulty in assessing penicillin resistance among pneumococci. Currently, penicillin resistance is defined as an isolate of S pneumoniae with a MIC of 2 micrograms/mL or more. Strains with a MIC of less than 1 microgram/mL are termed sensitive; those with a MIC of 1 to 2 micrograms/mL are termed intermediately sensitive/resistant. Most "penicillin resistance" reported in the medical literature represents the large number of strains with increased MICs, which puts them into the intermediate category. But are these strains truly resistant? If these intermediate strains are lumped for reporting purposes with the highly resistant strains, then it appears that penicillin resistance is a major problem. However, since these strains are relatively resistant at best--which means they also are relatively sensitive--their eradication is dependent on antibiotic concentration.

Most antibiotics used to treat S pneumoniae achieve concentrations far above those in the intermediately sensitive/resistant category. Therefore, these strains are easily treated with conventional doses of antibiotics for respiratory tract infections and should be grouped properly with the sensitive strains. When this is done, the statistics for penicillin resistance change radically, and penicillin resistance is properly described as a relatively uncommon phenomenon. (Grouping strains in the sensitive category places the incidence of penicillin resistance in the United States at less than 5%, versus about 20% if strains are grouped in the resistant category (2,5).)

Concentration-dependent susceptibility

In vitro determinations of antimicrobial susceptibility and resistance must be translated into the clinical context. For example, the clinical significance of penicillin-resistant pneumococci depends on the degree of pneumococcal resistance and the site of infection. Treating an isolate of S pneumoniae in the lung is very different from treating it in bronchial fluid, middle ear fluid, sinus fluid, or cerebrospinal fluid (CSF).

Because penicillin resistance is defined as an isolate of S pneumoniae with a MIC of 2 micrograms/mL or more--a level determined without precise additional information--the definition is of little use clinically. It makes a great difference whether a "resistant pneumococcus" has a MIC of 2.2, 4, 8, or 20 micrograms/mL and where the infection is located.

Penicillin resistance has its least clinical importance in the treatment of CAP, because the lung is so well vascularized that antibiotic levels in serum and lung parenchyma are essentially equivalent. Virtually all antibiotics used to treat CAP easily exceed therapeutic concentrations in lung parenchyma and therefore can eradicate the sensitive and intermediately sensitive/resistant strains, as well as the majority of highly resistant strains.

In patients with pneumococcal pneumonia and associated pneumococcal meningitis that seeds to CSF, care must be taken to ensure that the antibiotic used can gain a sufficient concentration in the CSF to eradicate the organism. Elimination of the organism from the blood and lung is easy. However, the antibiotic's concentration in CSF is the determining factor in selecting an appropriate agent for associated pneumococcal meningitis (1,6,7).

The therapeutic approach to CAP

Patients with CAP should be treated for infection by both typical and atypical pathogens. This is done most efficiently and cost-effectively using monotherapy with doxycycline or a "respiratory quinolone"--one with a high degree of activity against S pneumoniae (ie, levofloxacin, gatifloxacin, or moxifloxacin). These antibiotics are active against the typical CAP pathogens: S pneumoniae, H influenzae, and M catarrhalis. Furthermore, they are highly effective against the atypical pathogens that cause CAP.

Such antimicrobial agents have the advantage of relatively few side effects, modest cost and, most important, a low resistance potential. In addition, they are effective against most strains of penicillin-resistant pneumococci, and they will not exacerbate existing resistance problems with S pneumoniae.

Other therapeutic approaches may also be used. Combination therapy with a third-generation cephalosporin, such as ceftriaxone, plus a macrolide has been used by some physicians. Although the outcome of using ceftriaxone plus azithromycin, for example, would be the same as with doxycycline or a respiratory quinolone, there are major differences in side effects, resistance potential, cost, and the ease of switching from intravenous (IV) to oral (PO) therapy. Parenteral ceftriaxone plus azithromycin costs 2 to 3 times more than monotherapy with a respiratory quinolone and 5 to 10 times more than doxycycline monotherapy.

The gastrointestinal side effects of doxycycline are minimal if the agent is taken with food, and it has been shown to be active against penicillin-resistant S pneumoniae, in contrast to tetracycline. Unfortunately, laboratories that assess the efficacy of tetracyclines do not use doxycycline but instead extrapolate their tetracycline sensitivity data to doxycycline. This technique has no direct application, because doxycycline is reliably effective against all but the very highly resistant strains of S pneumoniae. In fact, tetracycline should not be used because of resistance problems.

Compared with combination therapy with ceftriaxone and azithromycin, treatment with a respiratory quinolone permits an easy transition from IV to PO therapy. Ceftriaxone has no oral equivalent, and an expensive oral cephalosporin often is used in such a regimen with an oral macrolide (eg, clarithromycin, azithromycin). This constitutes both polypharmacy and double drug therapy, with all the attendant problems of compliance, side effects, and potential drug interactions. As important, ceftriaxone's resistance potential is low, but the resistance potential of the macrolide component is moderate, if not high. When an antibiotic with a low resistance potential is used in combination with a drug that has a high resistance potential, the former does not protect the latter from exerting its resistance-inducing effect on the bacterial strain. Macrolides pose a dual problem: in addition to natural resistance (about 20% in S pneumoniae strains), they also cause acquired resistance, further increasing penicillin-resistant pneumococci.

Given these considerations, there should be little doubt that monotherapy with an agent that has a low resistance potential is preferred. Such monotherapy is possible if the antibiotic has a sufficient spectrum of effectiveness. For example, if a patient has typical CAP, then monotherapy with ceftriaxone is perfectly acceptable. Ceftriaxone achieves high serum and lung levels, has a low resistance potential, and is effective against the typical respiratory pathogens that cause CAP. However, it also has some gastrointestinal side effects and has no oral equivalent in an IV-to-PO switch program.

In contrast, monotherapy with a macrolide, such as azithromycin, is problematic because of pharmacokinetic and resistance issues. The great pharmacokinetic advantage of azithromycin is its prolonged low serum concentrations over many days; high serum concentrations are not part of its pharmacokinetic profile. However, high levels of antibiotic in serum and lung are needed in acutely ill patients. If azithromycin monotherapy is given intravenously to treat patients being admitted to the hospital with CAP, they are, by definition, moderately to severely ill. The serum and lung levels needed to eradicate CAP are not possible, even with parenterally administered azithromycin. Breakthrough bacteremia caused by S pneumoniae has been reported in patients with pneumococcal CAP. Therefore, azithromycin should not be used as monotherapy in CAP treatment. Although it has been combined with ceftriaxone to provide coverage against atypical pathogens, there are problems with using a macrolide in this combination, as previously described (1,7,8).

Fluoroquinolone resistance in S pneumoniae

The term fluoroquinolone-resistant S pneumoniae is a misnomer. Since the inducement of penicillin resistance is not a phenomenon among the fluoroquinolones and is not due to a class effect, the specific agent that causes resistance should be used in the appellation. A review of the literature reveals that essentially all quinolone resistance in S pneumoniae is caused by ciprofloxacin and not other agents in this drug class. For this reason, the proper term for penicillin resistance among the fluoroquinolones is ciprofloxacin-resistant S pneumoniae. Although isolated strains of highly penicillin-resistant S pneumoniae may occur as point mutations with use of any of the respiratory quinolones, this phenomenon is not related to antibiotic use.

Hence, physicians should not assume that widespread use of respiratory quinolones will lead to the same resistance problems as have occurred with ciprofloxacin use. Episodic point mutations may occur with any organism in response to any antibiotic, but this should be recognized as the sporadic and rare phenomenon that it is. Such resistant strains should be contained by infection control measures to prevent clonal dissemination.

Antibiotic use per se is not responsible for these unusual isolates, which are periodically reported in the literature. For example, the volume of ceftriaxone use over the past several decades has been tremendous worldwide, and there have been occasional reports of various strains of organisms resistant to ceftriaxone. However, given the decades of high-volume ceftriaxone use, this demonstrates that resistance against an antibiotic that has a low resistance potential is vanishingly small. The various strains of ceftriaxone-resistant bacteria that have been reported over the past two decades have not been the harbinger of resistance to ceftriaxone or other third-generation cephalosporins (with the exception of ceftazidime) (8-10).

Therapy for resistant S pneumoniae

To optimally plan therapy against highly penicillin-resistant S pneumoniae (MIC, >2 micrograms/mL), the strain must be further defined and its resistance level determined. As previously discussed, initial monotherapy with doxycycline or a respiratory quinolone will handle nearly all situations. In the rare event that a pneumococcal strain resistant to these antibiotics is isolated, the approach to therapy should be based on specific susceptibility testing. Antibiotics that usually are effective against strains with high penicillin resistance include clindamycin, the third-generation cephalosporins (except ceftazidime), cefepime (a fourth-generation cephalosporin), meropenem, linezolid, and vancomycin.

Vancomycin use should be discouraged, because other agents are available to effectively treat highly penicillin-resistant pneumococci and their use is not associated with an increase in the prevalence of vancomycin-resistant enterococci. For patients with simultaneous pneumococcal pneumonia and meningitis caused by highly penicillin-resistant strains, a meningeal dose of cefepime or meropenem or the usual dose of linezolid provides predictable CSF concentrations to eradicate the organisms (1,2,7).

Conclusion

Treatment of CAP should provide coverage against both typical and atypical organisms. Monotherapy with an agent that has few side effects can be effective against all of the typical respiratory pathogens. In addition, the preferred approach to treating CAP is use of an antimicrobial agent whose cost is moderate and whose resistance potential is low. The ideal antibiotic is either a respiratory quinolone that has a high degree of efficacy against S pneumoniae (eg, levofloxacin, gatifloxacin, moxifloxacin) or, alternately, doxycycline. Combination therapy--with its attendant problems of polypharmacy, high cost, compliance issues, drug-drug interactions, increased potential for side effects, and resistance potential--is always more complicated and expensive than the equivalent monotherapy and should be used in situations in which monotherapy with one of the recommended agents is not possible.

Although the severity and progress of S pneumoniae infection are not related to penicillin resistance, physicians should preferentially select antibiotics with a low resistance potential. Antibiotics for CAP, as well as other indications, should be viewed as having a high or low resistance potential. To prevent further resistance in respiratory pathogens, low-resistance antibiotics should be used in preference to those with a high resistance potential. Antibiotic resistance is not related to drug volume or therapy duration per se, but is agent-specific. It is not a class phenomenon.

Knowledge about the resistance potential of antibiotics commonly used for CAP should guide physicians in their selection of CAP therapy. By being familiar with the details of in vitro susceptibility testing and with resistance terminology, they can better evaluate the literature and treat CAP more confidently with antibiotics that have a low resistance potential, knowing that preferential use of these antibiotics can halt or reverse current trends (1,8,11).

References

1. Cunha BA. Clinical relevance of penicillin-resistant Streptococcus pneumoniae. Semin Respir Infect 2002;17(3):204-14
2. Harwell JI, Brown RB. The drug-resistant pneumococcus: clinical relevance, therapy, and prevention. Chest 2000;117(2):530-41
3. Pihlajamski M, Kotilainen P, Kaurila T, et al. Macrolide-resistant Streptococcus pneumoniae and use of antimicrobial agents. Clin Infect Dis 2001;33(4):483-8
4. Shea KW, Cunha BA, Ueno Y, et al. Doxycycline activity against Streptococcus pneumoniae. (Letter) Chest 1995;108(6):1775-6
5. Musher DM, Bartlett JG, Doern GV. A fresh look at the definition of susceptibility of Streptococcus pneumoniae to beta-lactam antibiotics. Arch Intern Med 2001;161(21):2538-44
6. Brueggemann AB, Pfaller MA, Doern GV. Use of penicillin MICs to predict in vitro activity of other beta-lactam antimicrobial agents against Streptococcus pneumoniae. J Clin Microbiol 2001;39(1):367-9
7. Quintiliani R, Nicolau DP, Nightingale CH. Clinical relevance of penicillin-resistant Streptococcus pneumoniae, with particular attention to therapy with ceftizoxime, cefotaxime, and ceftriaxone. Infect Dis Clin Pract 1996;5(1 Suppl):S37-41
8. Cunha BA. Community-acquired pneumonia: diagnostic and therapeutic approach. Med Clin North Am 2001;85(1):43-77
9. Cunha BA. Ciprofloxacin resistant Streptococcus pneumoniae, not fluoroquinolone resistant Streptococcus pneumoniae. Infect Dis Pract 2000;24:30-1
10. Garcia-Rey C, Aguilar L, Baquero F, et al. Influences of different factors on prevalence of ciprofloxacin resistance in Streptococcus pneumoniae in Spain. (Letter) Antimicrob Agents Chemother 2000;44(12):3481-2
11. Cunha BA. Effective antibiotic-resistance control strategies. (Editorial) Lancet 2001;357:1307-8

Dr Cunha is professor of medicine, State University of New York School of Medicine at Stony Brook, and chief, infectious disease division, Winthrop-University Hospital, Mineola, New York. Correspondence: Burke A. Cunha, MD, Infectious Disease Division, Winthrop-University Hospital, 222 Station Plaza N, Suite 432, Mineola, NY 11501.

Symposium Index

• INTRODUCTION TO THE SYMPOSIUM. By Burke A. Cunha, MD
• PENICILLIN RESISTANCE IN PNEUMOCOCCAL PNEUMONIA: Antibiotics with low resistance potential are effective and pose less risk. By Burke A. Cunha, MD
• COMMUNITY-ACQUIRED PNEUMONIA IN IMMUNOCOMPROMISED PATIENTS: Opportunistic infections to consider in differential diagnosis. By Sanda Cebular, MD, Susan Lee, MD, Pooja Tolaney, MD, Larry Lutwick, MD
• THE CHALLENGE OF NONRESOLVING PNEUMONIA: Knowing the norms of radiographic resolution is key. By Andreas Kyprianou, MD, Charles Scott Hall, MD, Rakesh Shah, MD, Alan M. Fein, MD

Copyright (C) 2003. The McGraw-Hill Companies. All Rights Reserved.
Terms of Use.     Privacy Policy.     E-mail Privacy Notice.

Please send technical questions related to the Web site to Ann Harste