Antibiotics

Global Antibiotic Resistance and Its Impact on the Dental Community

Thomas J. Pallasch, DDS, MS

Copyright 2000 Journal of the California Dental Association.

There is significant evidence that the global problems of microbial resistance to antibiotics has reached the dental community both in our practices and our family lives. This paper will present a global overview of microbial resistance, discuss how this problem directly affects the dental community, and show what we can do to change the situation, both as concerned citizens and as dental health care practitioners.

"We screwed up, and we ought to say so and apologize. Doctors were handed the wonderful gift of antibiotics but are destroying them through indiscriminate use. We don’t need another committee. We know what to do, we should use them less. -- Norman Simmons¹

"If you are not part of the solution, you are part of the problem." -- Stokely Carmichael

It is tempting to live in a reverie where outside forces do not affect our daily lives. Cocoons are cozy until it is time to escape mortal danger. The sporadic media reports of a patient death from a microorganism totally resistant to all antibiotics, the death of a 30 (not 90)-year-old from a nosocomial (hospital-acquired) infection, or the demise of several school children from methicillin-resistant staphylococci acquired from a day care center create a moment of panic, but then it is business as usual: This could not happen to us.

Surely what is happening in Southeast Asia -- particularly in Taiwan -- with a rapid and massive increase in antibiotic resistance to the penicillins and macrolides in viridans group streptococci is of little apparent concern to us. However, it should be as these organisms are the most important pathogens in acute oral cellulitis and are on their way to us via the airplane. There is ample evidence that antibiotic-resistant microorganisms have no respect for geographic boundaries and travel easily from country to country and from locale to locale in our communities (long-term care facilities to tertiary-care hospitals and vice versa).

There is significant evidence that the global problems of microbial resistance to antibiotics has reached the dental community both in our practices and our family lives. There are increasing reports of viridans group streptococcal resistance to beta-lactam antibiotics (penicillins and cephalosporins); macrolides and tetracyclines; and beta-lactamase production in the periodontal and cellulitis pathogens, Prevotella intermedia and Porphyromonas gingivalis. Sporadic reports are appearing of significant resistance in Fusobacteria and Veillonella. These resistance patterns have resulted in anecdotal reports of difficulties in the antibiotic management of orofacial infections and even outright antibiotic failures, a problem virtually unheard of in dentistry until recently. Unfortunately, our knowledge of the true scope of this problem is severely hampered by the lack of qualified microbiologists in dentistry and the virtual absence of research funding to support their efforts.

The dental community also includes our staff and immediate families. Children in day care centers and parents in long-term care facilities are part of this community. So too are the practices of the food production industry, pharmaceutical companies, and hospitals, which directly affect the form and extent of microbial resistance to antibiotics in the community. A discussion of the crisis in the resistance of HIV to antiviral agents may dispel the prevalent notion in our children and others that the war on AIDS is won and give some understanding of the lengths to which organisms will go to ensure their survival and why optimism can be short-lived.

The focus of this review is then threefold:

* To present a global overview of microbial resistance so that an appreciation is gained that the microbial revolt against chemicals permeates every aspect of our existence;

* To discuss how this problem directly affects the dental community (our practices, patients, and families); and

* To show how we got into this situation and what we can do to change it both as concerned citizens and as dental health care practitioners.

Before starting on this journey, a word of caution is advised. It is recommended that this paper be reviewed in discrete segments to better digest each aspect. This effort is a distillation of more than 2,000 papers read on microbial resistance with the selection of about one in 10 for referencing. As such, the references give the reader a place to start if he or she should wish to pursue a given segment in detail. This is what good reviews do. However, this is not the end of the story as hundreds of journal papers have been published since this review was completed, none of which require a modification of this saga. The tale of microbial resistance will continue for some time to come but, hopefully, with the good news that it is being taken seriously in all quarters and that redress of the problem is forthcoming.

How We Got Where We Are

In 1967, the U.S. surgeon general concluded that: "The time has come to close the book on infectious diseases." Considering that 17 million people died of infectious disease in 1993 (11.4 million due to bacteria, mostly in children), which was greater than the 15.6 million due to cardiovascular disease and cancer combined, this might seem to be a naïve statement. Yet, the surgeon general was simply echoing the "wisdom" of the medical community at that time that assumed we would always be able to stay ahead of the microbes with new antibiotics. In the late 1950s and early 1960s, introduction of the penicillinase-resistant penicillins, cephalosporins, clindamycin and new aminoglycosides dispelled the concerns about antibiotic-resistant nosocomial microbial pathogens. This assumption that we were smarter and more dedicated than the microbes again has proved that assumptions are the genesis of most mistakes. As Murphy advises: "Optimism indicates that the situation is not clearly understood."

The late 1950s were characterized by significant anxiety regarding the emergence of highly antibiotic-resistant staphylococci in hospitals. Also, some people began to realize that bacteria were capable of transferring between themselves the genetic information for resistance to chemicals intended to destroy their existence. Medicine paid little attention to the warnings of Rene Dubos, Maxwell Finland, and Ernest Jawetz that microbial resistance was here to stay and would not go away. Few read the 1946 Consumers Report prediction that: "The uncritical or promiscuous use of penicillin (may) lead to the persistence of strains of bacteria that will resist its action. Should this happen, it will have serious epidemiological significance."

The first report of microbial resistance to an antimicrobial agent appeared in 1886 with the "acclimatization" of Bacillus subtilis to phenol used as an operating room disinfectant.² Paul Ehrlich in 1907 described parasites resistant to fuchsin,³ and the first report of clinical resistance was in six of 100 isolates of Neisseria gonorrhoeae resistant to sulfanilamide in 1937.⁴ Rene Dubos detected microbial resistance to gramicidin in the early 1940s -- about the same time that Abraham and Chain described penicillinase.³ In the mid 1940s, Dubos warned of staphylococci and other organisms resistant to penicillin, and in the late 1950s he warned of multidrug-resistant tuberculosis. The first general awareness of the real magnitude of the problem came in the late 1950s but was dispelled by the unbridled optimism of the 1960s on to the 1990s.³

In the 1840s in the United States, the average life span was about 40, which has now doubled at the millennium due to the two most significant medical advances: anesthesia and the control of bacteria and viruses. In 1900, infectious disease caused 30.4 percent of all deaths in children younger than 5 while today it accounts for only 1.4 percent of such deaths.⁵ Now heart disease and cancer cause 54.7 percent of all U.S. deaths with only 4.5 percent due to pneumonia, influenza, and HIV.⁵ The public sanitation methods that began in the early 1900s in the United States contributed greatly to the decline in cholera, tuberculosis, typhoid fever, yellow fever, malaria, influenza, and pneumonia.⁵ Vaccination has essentially eliminated tetanus, diphtheria, whooping cough, rubella, and poliomyelitis and completely eliminated smallpox.⁵ Antibiotics have allowed for the control of streptococci, staphylococci, meningococci, pneumococci, gonococci, tuberculosis, and blood-stream infections. The effects of antibiotics were so miraculous that few bothered to study and/or promote proper usage. Most just assumed they would always be there for us.

Now we are faced with methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci; vancomycin-resistant enterococci and vancomycin-intermediate-resistant S. aureus; resistant viridans group streptococci, Prevotella, Porphyromonas, Veillonella and Fusobacteria; and the multiple-antibiotic-resistant Mycobacterium tuberculosis, Shigella dysenteria, Salmonella enteritidis, Pseudomonas aeruginosa, and Streptococcus pneumoniae.

Our hospitals are now filled with immunocompromised patients. Both the young and the old die in hospitals (possibly as many as 300,000 a year in the United States) from infections they did not have when they entered the hospital. Our child day care centers and elderly extended care facilities are major reservoirs of antibiotic-resistant microbes that are transferred to acute care facilities and vice versa. All of this is compounded by the 22 million worldwide refugees, 25 million displaced people, and 500 million people a year crossing geographic borders. Microbes do not respect political distinctions.

Our problems with microbial pathogens have not disappeared but, rather, have taken another direction. We must realize that antibiotics are "societal" drugs as they affect people other than the ones taking the drugs.^6,7 The resistance genes that are created and selected by antibiotics can easily be transferred between people by human contact. Therefore, every antibiotic given to or taken by a single individual can affect other human beings. This may be bad enough when the drugs are used properly, but is intolerable when antibiotics are used improperly. If therapeutic and prophylactic errors are done daily by millions of practitioners, then these millions become billions over the course of a given year and place enormous selective pressure on microbes to resist their effects. As Sen. Everett Dirkson once said about government spending: "A billion here and a billion there, and all of a sudden you’re talking about real money." The most difficult challenge in the control of microbial resistance is to convince all people (health care practitioners and patients alike) that everyone is responsible for the problem and its solution.

This discussion will not describe the mechanisms by which microbes evade the drugs intended to inhibit or kill them, nor will it be a general review of the immense complexity and nuances of microbial resistance to antibiotics. Suffice it to say that microbes have an incredible ability to outwit humans by formulating enzymes that destroy the antibiotic, limiting access of the drug to its microbial target site(s), altering these target sites to reduce antibiotic binding, or actively extruding the antibiotic from the microbial cell. Some antibiotics like metronidazole have essentially only one resistance mechanism (alteration of DNA gyrase binding), while the tetracyclines have them all. Microbes no longer defend themselves from chemicals by single chromosomal mutations every one billion or so cell divisions; but, now, because of their massive exposure to sustained chemical onslaught, they easily and rapidly transfer antimicrobial resistance genes via bacteriophages, plasmids, transposons, and integrons. No longer do they sit idly by when confronted by toxic chemicals but rather manage to express and/or transfer these genes (induced resistance) much more rapidly than if the chemical were not present. Excellent reviews are available on the general aspects of microbial resistance to antibiotics^8-15 and the mechanisms microbes employ to attain this end.^16-20

Resistance to Specific Antibiotics

Vancomycin

The first published report of vancomycin-intermediate-resistant methicillin-resistant S. aureus was in El Salvador in 1996²¹ quickly followed by a report in 1997 from Japan.²² These reports heralded the realization that the worst fears of the infectious disease community may have been realized: that an already highly resistant organism had been rendered resistant to all known antibiotics. Subsequent reports of this resistant organism in the United States (Michigan, New Jersey, New York)^23,24 and France²⁵ have appeared. Vancomycin-intermediate-resistant S. aureus or glycopeptide-intermediate S. aureus has been disseminated throughout various Japanese hospitals,²⁶ caused death in Hong Kong, is a factor in surgical infection treatment failures, and has spread globally.²⁷ The resistance of vancomycin-intermediate-resistant S. aureus may be related to production of abnormal mucopeptides in cell wall synthesis or to an increase in the number of peptidoglycan units in the cell wall.²⁸

All cases to date of vancomycin-intermediate-resistant S. aureus have appeared after prolonged (weeks of) intensive antibiotic (vancomycin) use in the hospital setting, and this presents the possibility that reduced vancomycin use may contain the spread of the organism. Also, vancomycin-intermediate-resistant S. aureus is sometimes sensitive to quinupristin/dalfopristin (Synercid), rifampin, chloramphenicol, penicillin, and beta-lactamase inhibitors combined with aminoglycosides and even sometimes tetracyclines.^29-32 A significant problem with vancomycin-intermediate-resistant S. aureus and glycopeptide-intermediate S. aureus is that they appear to be antibiotic-sensitive with the standard laboratory disc diffusion methods and will only be detected by agar or broth dilution or E test strips.³⁰

The advent of vancomycin-intermediate-resistant S. aureus was not unexpected after the appearance of vancomycin-resistant enterococci in 1988 and glycopeptide resistance in coagulase-negative staphylococci. Vancomycin-resistant enterococci now account for more than 20 percent of all nosocomial enterococci and 14.8 percent of all surgical site infections.³³ In 1994, 61 percent of hospitals surveyed reported vancomycin-resistant enterococci as opposed to 23 percent in 1992.³⁴ Unfortunately, Enterococcus faecium is the major vancomycin-resistant enterococcus and is multiple-antibiotic-resistant rather than Enterococcus faecalis, which remains moderately sensitive to ampicillin and penicillin plus a beta-lactamase inhibitor.³⁴ Vancomycin-resistant enterococci may also be sensitive to erythromycin, tetracycline, chloramphenicol, rifampin, quinolones, quinupristin/dalfopristin, and aminoglycoside combinations with some of these agents.³⁴ Tetracycline has been proven effective against vancomycin-resistant enterococcus.^34-36 Vancomycin-resistant enterococcus appears to be another example of marked resistance development due to intensive selection pressure in U.S. hospitals as has been the case with methicillin-resistant S. aureus, extended beta-lactamase producing Klebsiella pneumoniae, and imipenem resistance in P. aeruginosa.³⁴

Vancomycin-resistant enterococci are endemic in the European population with a 15 percent carrier rate,³⁷ while the carrier rate in the U.S. population is very low. Alternately, the prevalence of vancomycin-resistant enterococci in U.S. hospitals is much higher than in Europe. Possibly the occurrence rate is similar if vancomycin-resistant enterococci are compared in livestock in Europe with hospitals in the United States. Vancomycin-resistant enterococci are very common in food, livestock, and humans in Europe due to the widespread use of avoparcin (an analogue of vancomycin) in animal husbandry prior to its ban in 1997.

In Denmark for example, 24 kg of vancomycin were used in humans in 1994 while 24,000 kg of avoparcin were employed in swine and poultry production (an amount of glycopeptide exceeding all human use in both Europe and the United States in that year).³⁸ While avoparcin was never approved for use in the United States, the use of vancomycin in U.S. hospitals rose from 100 kg orally and 1,900 kg parenterally in 1984 to 888 kg orally and 10,312 kg parenterally in 1996.³⁹

Even more alarming than the appearance of vancomycin-resistant enterococci and vancomycin-intermediate-resistant S. aureus is the recently described vancomycin tolerance in S. pneumoniae, an organism responsible for millions of deaths annually in the world.^40,41 Antibiotic tolerance (conversion of the antibiotic activity from bactericidal to bacteriostatic) is generally considered to be an intermediate step between sensitivity and total resistance and cannot be detected by conventional laboratory testing as the organism appears to be sensitive.^40,41 Between 2 percent and 3 percent of all clinical isolates of the pneumococcus may be tolerant to vancomycin.⁴⁰

The mechanism for tolerance to vancomycin in pneumococci is unique: a mutation in the sensor-response system that controls autolysin activity necessary to kill bacteria.^40,41 With this mutation, the sensor kinase remains inactivated; and autolysis of the bacterial cell is not triggered.⁴⁰ This sensor-response system is also required for the bactericidal activity of the beta-lactams, cephalosporins, aminoglycosides, and quinolones.⁴⁰

S. pneumoniae is a major pathogen in lower respiratory tract infections, sinus and middle ear infections, and meningitis; and it is particularly lethal in the young and old. It is also highly resistant to the penicillins and macrolides. The acquisition of resistance by the enterococcus has demonstrated how a second-rate pathogen can become a first-rate clinical problem.³⁴

The reports of vancomycin intermediate/tolerant resistance in staphylococci and pneumococci possibly herald total antibiotic resistance in these microorganisms. Future difficulties may be even worse. It appears that:

* Streptococci, staphylococci, and enterococci often share the same resistance genes;

* The penicillinase in enterococci is identical to that in staphylococci (shared genes);

* The enterococcus can transfer resistance genes to many other organisms (the vancomycin-resistance gene has been transferred to staphylococci in vitro and in animal models⁴²);

* Staphylococci and enterococci are coinhabiting the skin;⁴³

* The beta-lactamase gene in enterococcus likely came from staphylococcus in this environment; and

* Vancomycin resistance may one day appear in viridans group streptococci.³⁴

It may take years for these transformations to occur, or they may come rapidly as with penicillin resistance in streptococci and pneumococci; but occur they will.

Macrolides

The principal mechanism for resistance to the macrolides (azithromycin, clarithromycin, erythromycin) is via an erm gene that codes for enzymatic methylation of the adenine residue in the 23SrRNA, resulting in decreased macrolide binding to its receptor site.^44,45 Other mechanisms include enzymatic destruction, bacterial efflux, and altered bacterial membrane permeability. This altered ribosomal binding site can confer resistance simultaneously to macrolides, lincosamides, and streptogramin B (MLS_B resistance).^44,45 The macrolides are over-the-counter-drugs in Taiwan and have resulted in resistance rates of 80 percent in methicillin-resistant S. aureus, 30 percent in non-methicillin-resistant S. aureus, 58 percent in S. pneumoniae, 37 percent to 42 percent in Streptococcus pyogenes (Group A streptococci), and significant resistance in enterococci, peptostreptococci and Bacteroides fragilis.⁴⁶ Epidemics of macrolide resistance in S. pyogenes occurred in Finland in 1988 and Italy in 1993 with 40 percent to 42 percent of isolates having MLS_B resistance.⁴⁷ A 1993-1994 outpatient study at 12 major U.S. medical centers indicated a 16 percent incidence of macrolide resistance in penicillin-intermediate resistant S. pneumoniae and 57 percent macrolide resistance in penicillin-resistant S. pneumoniae while penicillin-sensitive strains were only 1.1 percent to 3.1 percent resistant to the macrolides.⁴⁸

Metronidazole

Microbial resistance to metronidazole (Flagyl) is relatively low except in Helicobacter pylori probably because of its limited clinical use. Intracellular reduction of the nitro group of metronidazole leads to DNA strand breakage, helix destabilization, and eventual cell death.⁴⁹

Resistance to metronidazole occurs in Trichomonas vaginalis, H. pylori, Bacteroides, Clostridia, Gardnerella vaginalis, Campylobacter fetus, Leptotrichia buccalis, and Treponema pallidum.^49-52 Mechanisms include decreased microbial production of hydrogen peroxide, superoxide radicals or oxygen tolerance, reduced cellular uptake, or decreased reduction of the nitro group.⁵¹ Resistance of H. pylori (a causative agent of peptic ulcer and gastric cancer) to metronidazole ranges from 10 percent to 50 percent in developed countries and 100 percent in developing countries because of its widespread use in treating parasitic diseases.⁵³ Treatment failures with clarithromycin occur more commonly in regions with high resistance rates of H. pylori to metronidazole; metronidazole resistance may increase macrolide resistance in H. pylori.⁵⁴

New Antibiotic Agents

Quinupristin/dalfopristin (Synercid) is a streptogramin antibiotic recently approved in the United States for skin and soft tissue infections and part of combination regimens against vancomycin-resistant enterococci.⁵⁵ The new drug combination (a 30:70 ratio of quinupristin and dalfopristin) has a remarkable spectrum of activity: S. aureus including methicillin-resistant S. aureus, streptococci including peptostreptococci, E. faecium, N. gonorrhoeae, Haemophilus influenzae, Moraxella catarrhalis, Legionella, Listeria monocytogenes, mycoplasma, Bacteroides, Prevotella, Fusobacterium, Clostridia, Actinomyces, and Lactobacilli.^55,56 E. faecalis is totally resistant by an unknown mechanism. The primary targets of quinupristin/dalfopristin are S. pneumoniae, S. aureus and E. faecium.⁵⁶

The streptogramin group also includes pristinamycin and virginiamycin used in humans (pristinamycin) in France and in agricultural animals (virginiamycin) throughout the world (including the United States) as growth promoters and to treat infections.⁵⁵ Streptogramin-resistant E. faecium was detected in animals before the drugs were used in humans, and virginiamycin is now banned in Denmark.⁵⁵ It is likely that streptogramin resistance can be transferred from animals to humans in food.⁵⁵

Resistance to the streptogramins is through enzymatic modification, active efflux and altered ribosomal binding.^55,56 Quinupristin/dalfopristin bind sequentially to different sites of the 50S subunit of the 70S ribosome to prevent newly synthesized peptide chains from extruding from the ribosome and resulting in cell death.^55,56 Resistance via dimethylation of an adenine residue ^57,58 is commonly coded on the erm gene, which also confers resistance to the macrolides and lincosamides (MLS_B resistance).⁵⁶

Enthusiasm for this new streptogramin antibiotic must be tempered by the following observations:

* Intermediate resistance in S. aureus has been detected;⁵⁹

* Resistant E. faecium has been isolated in animals and humans outside the hospital;⁶⁰

* The vancomycin-resistance gene and the streptogramin-resistance gene have been detected linked together on the same plasmid;⁶¹

* Resistance in E. faecium may develop during treatment with the streptogramins;⁶² and

* Quinupristin/dalfopristin may select for superinfection with resistant E. faecalis during treatment.⁶³

These tarnish the prospects for streptogramins unless they are used with great caution in hospitals and removed from animal husbandry.

Linezolid is an oxazolidinone antibiotic with bacteriostatic activity against staphylococci and enterococci including most gram-positive cocci, vancomycin-resistant enterococci, penicillin-resistant pneumococci, Legionella, and H. influenzae.⁶⁴ It was developed as a plant antibiotic in the 1970s, and resistance has appeared due to decreased ribosomal binding.⁶⁴

Tetracyclines

Microbial resistance to the tetracyclines is widespread, inducible, easily acquired, often associated with multiple drug resistance, and possibly permanent (remains when the microbe is no longer exposed to the drug). The current tetracyclines probably act by binding to the 30S subunit of the bacterial ribosome thereby interfering with aminoacyl-tRNA binding and leading to inhibition of protein synthesis.⁶⁵ The major tetracycline resistance mechanisms are:

* Active drug efflux from the cell;

* Altered ribosomal binding sites (ribosomal protection); and

* Enzymatic destruction.

Altered cell wall permeability to tetracycline influx is of some significance under certain circumstances.⁶⁶

High level tetracycline resistance is achieved by active energy-dependent drug efflux from the bacterial cell either by multidrug resistance pumps or tetracycline specific transporters.⁶⁶ Eleven classes of tetracycline resistance determinants encoding tetracycline-specific efflux proteins are known to date in both gram-positive and gram-negative bacteria.⁶⁶ Ribosomal protection is encoded by six tet genes (M, O, P, Q, S, T) and three oxytetracycline genes.^65,67,68 Tetracycline can be inactivated by a cytoplasmic protein encoded by a tet gene that chemically modifies tetracycline.⁶⁷

The long-term use of conventional doses of tetracyclines results in high levels of resistant organisms in the oral cavity ranging from an 11 percent to 85 percent occurrence rate.^69,70 Short-term (two weeks or less) conventional doses can select for resistance in viridans group streptococci, Veillonella parvula, Eikenella corrodens, and Fusobacterium nucleatum.⁷¹ Tetracycline-resistant genes are widespread in the oral flora,^72,73 and low-level tetracycline doses promote the spread of tet genes to other bacteria^67,68,74 and better select for resistant bacteria than high levels of antibiotics.^6,15 Prolonged tetracycline use will select for both tetracycline and multiple-resistant bacteria^6,75 since tetracycline-resistance genes are often part of a larger transposon, integron, or plasmid containing other antibiotic resistance genes.⁷³

The ongoing debate about the significance of tetracycline-resistant organisms in the oral cavity obscures two far more serious consequences associated with tetracycline use: 1) selective pressures for multiple-resistant organisms in other areas of the body and 2) the significant ability of the tetracyclines to induce antibiotic resistance by promoting the expression of tet genes and/or fostering the transfer of these genes to other bacteria via transposons or integrons either as a single resistance gene or as part of a complex of multiple-antibiotic-resistance genes.

Tetracyclines in various doses can select for resistant microorganisms in the tonsils,⁷⁶ skin,^77-80 and colon.^6,81-84 There is considerable evidence that conventional oral daily doses,^85,86 as well as intravenous doses,⁸⁷ select for tetracycline-resistant intestinal K. pneumoniae, enterococci, Escherichia coli, yeasts, and multiple-antibiotic-resistant organisms. Such antibiotic resistance increases not only in patients taking the drugs but also close-contact relatives.⁸⁶ The oral microbial flora are generally opportunists that commonly only produce disease when host defenses are impaired. The colonic flora is dominated by highly pathogenic and multiply antibiotic resistant organisms: Bacteroides, Salmonella, Shigella, Serratia, E. coli, Providencia stuartii, Proteus mirabilis, Enterobacter cloacea, P. aeruginosa, and K. pneumoniae.

The issue of the transfer or expression of genes by tetracycline has been explored to some extent⁸⁸ but requires far greater study. Pre-exposure of the colonic flora to tetracycline increases the frequency of transfer of conjugative transposons in B. fragilis at a rate of 100 to 1,000 times greater⁸¹ and the transfer of a transposon (Tn925) in B. subtilis 10 times faster⁸² than if the tetracycline were not present.⁶⁷ Doxycycline at a dose of 100 mg/day for seven days can reduce the colon colonization resistance (the ability of the colon to defend itself against implantation of new pathogens) to K. pneumoniae, P. mirabilis, and E. cloacae.⁸⁹

The advocates of low-dose doxycycline therapy ("subinhibitory concentrations") at 40 mg/day hold that the attained blood levels of 0.2-0.7 micrograms/ml ^90,91are "well below the concentration required to inhibit microorganisms associated with adult periodontitis"⁹² and "too low to affect bacteria."⁹³ It is also claimed that when present in the colon, doxycycline is bound as a stable, non-antibacterial conjugate, but a number of studies contradict this contention.^89,94-98 There is a wealth of evidence from the 1960s to the present that tetracycline and doxycycline in particular are therapeutic antibiotics at minimum inhibitory concentrations as low as 0.015-0.04 micrograms/ml for both periodontal and non-oral microbial pathogens.^{69,70,84,94,95,99-110}

It is generally assumed that the tetracyclines have limited therapeutic uses, and they are the only antibiotic group whose use has declined in the past 20 years.⁶⁸ However, the tetracyclines are presently the drugs of choice for the management of Chlamydia pneumoniae and trachomatis, Vibrio cholerae, Yersinia pestis, H. pylori, Lyme disease, mycoplasma, Brucella, and rickettsial infections, and alternate drugs for S. pneumoniae, Legionella, Campylobacter, and E. corrodens.¹¹¹ Possibly because of their rare use in hospitals over the last many years, it appears that some highly antibiotic-resistant and life-threatening organisms have lost their resistance to the drugs. Doxycycline is presently used for the management of vancomycin-resistant enterococci^34-36 and in at least one case at doses of 0.25 micrograms/ml³⁶ that is well within the blood level range achieved by low dose doxycycline. S. aureus isolates have been detected that are sensitive to very low doses of the tetracyclines, and these drugs may again be useful against these highly resistant and life-threatening pathogens.^31,32

It would be a tragedy to lose the tetracyclines once again through inappropriate use now that they have regained their effectiveness against highly pathogenic microbes.

Resistance in Specific Microorganisms

Oral Microorganisms

A high rate of penicillin resistance in viridans group streptococci was first reported in 1987 in South Africa¹¹² and subsequently confirmed in the United States and Europe.^113,114 This resistance in viridans group streptococci (S. milleri, S. mutans, S. salivarius, S. sanguis, and S. mitis groups) is due to an altered penicillin binding protein (PBP2B) that greatly decreases the binding of penicillin to its receptor.^115,116 Both S. pneumoniae and viridans group streptococci coinhabit the pharynx and share the gene for this altered penicillin binding protein, which may have originated in viridans group streptococci or vice versa.^117-119

Reports of 23 percent to 81 percent of viridans group streptococci resistant to ampicillin or amoxicillin in both hospitalized patients and those in the community are not uncommon.^120-123 In the United States, 40 percent to 50 percent of the viridans group streptococci are resistant at concentrations equal to or greater than 0.25 micrograms/ml.¹²⁴ In 1993-1994, 352 blood cultures of viridans group streptococci taken at 43 U.S. medical centers showed a resistance rate of 13.4% at minimum inhibitory concentrations greater than 4 micrograms/ml (high resistance) and 42.9% at minimum inhibitory concentrations of 0.25-2.0 micrograms/ml (intermediate resistance).¹¹⁴ The same study indicated that 96 percent of viridans group streptococci were resistant to cephalexin at greater than 2.0 micrograms/ml. Japanese children may harbor penicillin resistance in viridans group streptococci at a 62.5 percent to 87.5 percent rate.¹²⁵ A cohort of Japanese children at high risk for endocarditis have a 31.7 percent prevalence of viridans group streptococci resistant to amoxicillin at 4-16 micrograms/ml and 28.3 percent showing minimum inhibitory concentrations of 4-8 micrograms/ml for penicillin G.¹²⁶

The resistance rates to penicillins may vary greatly with the various viridans group streptococci with the least resistance in S. milleri and the greatest in S. mitis with an intermediate level in S. sanguis.^114,127-129 In addition to penicillin resistance, viridans group streptococci may be significantly resistant to the tetracyclines, clindamycin, and the newer macrolides (azithromycin, clarithromycin).¹²⁴ In a Taiwan study, clindamycin resistance in viridans group streptococci was 20 percent to 50 percent and for tetracycline was 30 percent to 70 percent in various viridans group streptococci.¹²⁸

Beta-lactamase production is common in oral Prevotella, Porphyromonas, and Fusobacterium species in both children and adults.^130-134 F. nucleatum has produced a fatal septicemia.¹³⁵ Up to one-third of moderately advanced periodontitis patients may harbor strains of P. intermedia/nigrescens, Fusobacteria and beta-hemolytic streptococci that are resistant to both amoxicillin and doxycycline.¹³⁶ Highly penicillin resistant oral strains of Veillonella, Capnocytophaga, E. cloacea, and K. pneumoniae have also been detected.^137-139 Specific strains of methicillin-resistant S. aureus may colonize the oral cavity for many years in those with natural dentitions and in those with dentures.^140-142 One-step fluoroquinolone-resistant determinants can be transferred from viridans group streptococci to pneumococci in vitro.¹⁴² The oral cavity is now as much a part of the microbial resistance millieu as any other part of the body.

Helicobacter Pylori

Chronic gastritis, peptic ulcer, and gastric cancer have all been linked to causation by H. pylori.¹⁴³ This gram-positive organism colonizing the stomach has become highly resistant to metronidazole in many areas of the world, and as a consequence tetracycline has been added to the drug regimens used to treat this organism.

The classic therapy for H. pylori eradication is a three- or four-drug regimen including bismuth, a proton pump inhibitor (omeprazole), and one or more antibiotics (metronidazole, clarithromycin, amoxicillin, tetracycline).¹⁴⁴ Ranitidine has recently been added to the regimen.¹⁴⁴ Resistance to metronidazole due to a decreased ability to reduce its nitro group ranges from 10 percent to 50 percent in developed countries and approaches 100 percent in developing countries due to its widespread use in the treatment of parasitic diseases.⁵³ Resistance to clarithromycin and tetracycline is presently 5 percent to 10 percent due altered ribosomal binding.¹⁴⁵ Amoxicillin tolerance has also been detected in H. pylori.¹⁴⁶ Some studies detect a 30 percent to 60 percent reduction in eradication rates of H. pylori due to metronidazole resistance while others report little effect.¹⁴⁴ A vaccine will be the only mechanism to eliminate the pathology caused by H. pylori since resistance will likely increase in the future.⁵³ The widespread use of metronidazole in periodontics may be expected to add to the difficulties of the antibiotic control of peptic ulcer and gastric cancer.

Human Immunodeficiency Virus

The current therapy for HIV is highly active antiretroviral therapy employing a combination of drugs to interfere with several steps in viral replication. Difficulties have arisen with this therapy due to the ability of the virus to provide reservoirs of replication competent HIV in resting CD4 T lymphocytes persisting through years of intensive highly active antiretroviral therapy .¹⁴⁷ It is estimated that seven to 60 years of highly active antiretroviral therapy may be necessary to eradicate the virus from these reservoirs.¹⁴⁸

The success of this therapy is critically dependent on two factors: patient compliance with the drug regimens and HIV resistance to the antiretroviral drugs (nonsuppressive antiretroviral therapy).¹⁴⁹ Drug therapy can be very complicated, with an average of 50 percent of affected individuals failing to adhere to the entire medication schedules for the entire duration of viral replicability.¹⁵⁰ Failure to take even one of the three drug regimens will lead to greater resistance to the two remaining drugs.^150,151 These difficulties are further compounded by recent reports that HIV already resistant to one or more antiretroviral drugs is being transferred to newly infected individuals, greatly complicating their treatment and prognosis.^149,152,153

Antiretrovial therapy is greatly compromised by the nature of HIV: the reverse transcriptase enzyme of the virus makes one error on average per 10,000 bases copied in a virus that has a 9,200 base genome. Therefore, virtually every virus is slightly different from its forebearer.¹⁵¹ This high error rate in reverse transcriptase activity coupled with a very high replication rate of the virus promotes an enormously variant virus population. With a viral replication rate of 1 billion per day, every single point mutation may occur at a rate of greater than 10,000 copies per day.¹⁵⁴ These HIV variants may then no longer be recognized by T lymphocytes or neutralizing antibodies.¹⁵¹

The current three drug regimens may greatly decrease the HIV viral burden for six to 24 months to less than detectable viral levels (20 copies/ml).¹⁵¹ Some antiretroviral drugs (lamivudine, nevirapine) only require a single mutation to develop high level drug resistance while other agents (indivanir, zidovudine) need three or more mutations in a single viral genome and persistent viral replication and selective antiretroviral therapy for high level resistance development.¹⁵⁵ Any HIV variant less sensitive to an inhibiting drug will outgrow the "wild type" sensitive virus and be selected out by the drugs, but a high replication suppression rate can reduce the number of these mutants.¹⁵⁶ Significant resistance to indivanir and zidovudine may take six to 24 months to develop, while high-level resistance to nevirapine and lamivudine can take less than one month.¹⁵⁰ The idea that HIV can be readily and easily treated by drugs is folly. Possible solutions to these HIV-resistance problems have been discussed.^{150,151,155,157}

Microbial Resistance in the Community

Worldwide Resistance

Seventy percent to 77 percent of all S. pneumoniae isolates in South Korea are resistant to penicillin, with 34 percent being multidrug-resistant to erythromycin, tetracycline, and chloramphenicol.¹⁵⁸ In Taiwan, 61 percent of hospital S. pneumoniae isolates are resistant to penicillin, with 40 percent of these displaying intermediate to high level resistance to cefotaxime and imipenem and 82 percent to 90 percent with resistance to erythromycin.¹⁵⁹ In Hong Kong, penicillin resistance in S. pneumoniae was detected at a rate of 6.6 percent in 1993 but rose to 55.8 percent in 1995 with multiple resistance to tetracycline, chloramphenicol, and erythromycin.¹⁶⁰

In the United States in 1994, 36.5 percent of N. gonorrhoeae isolates were resistant to tetracyclines and penicillin and ciprofloxacin resistance was increasing.¹⁶¹ In 1975, 18 percent of S. pneumoniae isolates in Hungary were resistant to penicillin, which rose to 58.8 percent in 1989.¹⁶² In Poland, S. pyogenes resistance to tetracycline increased from 14 percent in 1976 to 80 percent in 1993.¹⁶² In the United States, 33.4 percent of H. influenzae and 92.7 percent of Moraxella catarrhalis were beta-lactamase producers during the 1996-1997 respiratory disease season.¹⁶³ A multiresistant "Iberian" clone of methicillin-resistant S. aureus has spread from Spain to Portugal, Italy, and Scotland.¹⁶⁴ A highly chloramphenicol-resistant strain of Neisseria meningitidis has been isolated in Vietnam and France and has demonstrated the ability of an aerobic gram-negative coccus to acquire the resistance genes (Tn4451) from a gram-positive bacillus (Clostridium perfringens).¹⁶⁵

Otitis Media

The use of antibiotics to treat middle ear infections is probably second only to antibiotic therapy for upper respiratory tract infections (most of which are viral) as a major factor in the rise and extent of antibiotic resistant microorganisms in the community. Otitis media takes several forms:

* Acute otitis media;

* Recurrent otitis media;

* Persistent otitis media;

* Otitis media with effusion;

* Chronic otitis media; and

* Chronic suppurative otitis media.¹⁶⁶

Signs and symptoms include erythematous bulging of the tympanic membrane, otalgia, fever, irritability, and middle ear serous or purulent effusions.¹⁶⁶ The most common causative microorganisms are S. pneumonia (20 percent to 50 percent), H. influenzae (10 percent to 30 percent) and M. catarrhalis (5 percent to 20 percent).¹⁶⁶

At least 60 percent of children have an episode of acute otitis media by age 1 and 75 percent by age 3.¹⁶⁶ Antibiotic prescriptions for otitis media in the United States have increased from 11.9 million in 1980 to 23.6 million in 1992, with an efficacy rate of 68 percent to 96 percent.¹⁶⁷ The resistance rates to penicillin are up to 31 percent in S. pneumoniae and greater than 90 percent in M. catarrhalis with 31 percent to 57 percent of H. influenzae producing beta-lactamase.¹⁶⁸ In a study of children with acute otitis media who received antibiotic therapy within the previous year, the resistance rate to penicillin in S. pneumoniae and H. influenzae increased from 38 percent to 58 percent in those who had received prior amoxicillin with or without clavulanate, the macrolides, or cephalosporins.¹⁶⁹ Prior use of the macrolides and cephalosporins also increased the rate of penicillin resistance (resistance increased not only for the prescribed antibiotic but also other antibiotics).¹⁶⁹ The longer the antibiotic treatment for otitis media, the greater the pressure for the selection of antibiotic-resistant S. pneumoniae.¹⁷⁰

Pediatricians are currently the only medical specialty that is aggressively attempting to reduce unnecessary antibiotic use. It appears that acute otitis media is overdiagnosed and often unnecessarily treated with prolonged antibiotic therapy.¹⁷¹ Typical resolution of acute otitis media occurs in two to five days, and it appears that five-day therapy (instead of the usual 10 days, a duration extrapolated from the treatment of streptococcal sore throat with penicillin) is effective for uncomplicated otitis media.¹⁷² This short course may not be optimum therapy for children younger than 6 and particularly those younger than age 2.¹⁷³ Better attention to the diagnosis of otitis media and a reduction in duration of antibiotic treatment may reduce the total amount of antibiotics used in otitis media by one-half.¹⁷¹

Antibiotics in Agriculture

Antibiotic use in agricultural animals (primarily beef and veal cattle, broiler chickens, and hogs) began after World War II to treat bovine mastitis.¹⁷⁴ Streptomycin was added to feed to promote growth in chickens in 1946, and tetracycline was added in 1949.¹⁷⁴ Antimicrobials are used in animal husbandry to treat or prevent infections and to promote growth.¹⁷⁵ It is impossible to selectively treat animals with antibiotics when 120,000 hogs are confined to a single farm barn. The use of antimicrobials in feed adds 4 percent to 5 percent to the body weight of the farm animals.¹⁷⁶

Approximately one-half of the 50 million pounds of antibiotics manufactured in the United States are used in agriculture and aquaculture. Fifty thousand pounds of streptomycin and tetracycline are employed for fruit trees each year.¹⁷⁷ In Denmark in 1994, 24 kg of vancomycin was used in humans and 24,000 kg of avoparcin (a vancomycin analogue) in animal feed ^38,178 From 1992 to 1996, Australia imported an average of 582 kg/year of vancomycin for human medical use and 62,642 kg of avoparcin for animal husbandry.¹⁷⁸

The evidence is unequivocal that agricultural antibiotics have selected for microorganisms with multiple-antibiotic resistance to ampicillin, tetracycline, erythromycin, aminoglycosides, chloramphenicol, sulfonamides, methicillin/oxacillin, vancomycin, everninomycin and streptogramins.^176,179,180 These resistance genes are carried by staphylococci, Salmonella typhimurium, Campylobacter species, enterococci, E. coli, and Yersinia enterocolitica^176,181 with the same gene pattern in both animals and humans, indicating transfer between species.^{175,176,179,181,182}

Human-disease-causing Salmonella enterica have been isolated from poultry, red meat, dairy products, and fresh produce (alfalfa sprouts, cantaloupe, tomatoes).¹⁸³ Campylobacter jejuni causes 2 million cases of gastroenteritis per year in the United States,¹⁸⁴ and the increasing use of fluoroquinolones in food animals has resulted in a steadily increasing incidence of Campylobacter infections in humans.¹⁸⁵ The ribotypes of vancomycin-resistant eterococci in some human clinical isolates are identical to those in non-human animal sources.¹⁸⁶ Fish and shrimp produced by aquaculture may exceed those collected by captive fishing by the year 2007 and are a source of antibiotic-resistant Salmonella, Vibrio, Aeromonas, Listeria, and various parasites (nematodes, cestods, and hematodes).¹⁸⁷

The most widely publicized and studied microorganism transmitted to humans in the food chain is enterohemorrhagic E. coli 0157 which may induce bloody diarrhea and, in 5 percent to 10 percent of cases, the hemolytic-uremic syndrome (microangiopathic hemolytic anemia, thrombocytopenia, renal failure) with a 3.5 percent mortality in children and up to 35 percent in the elderly.^189,190 In Japan in 1986, 9,000 documented cases occurred with 11 deaths;¹⁹¹ and in 1993, 20,000 cases occurred in the United States with 250 deaths.¹⁹⁰ This vero cytotoxin-producing E. coli serotype 0157 was recognized in 1982 as a human pathogen,¹⁹²and the infecting dose can be as low as 50 microorganisms.¹⁹³ The primary source of E. coli157:H7 is undercooked beef as 1.6 percent of feedlot cattle and 1.5 percent to 5.7 percent of calves shed the organism.¹⁹⁴

Since 1986, Sweden has banned antibiotic growth-promoting chemicals and has been able to successfully compete in the European Community marketplace in cattle and hogs.¹⁹⁵ This restriction of antibiotics only to diseased animals has led to a 50 percent decline in the agricultural use of antibiotics in Sweden.¹⁹⁵ Since the ban of avoparcin in Germany in 1995, the percentage of vancomycin-resistant enterococci has fallen from 12 percent to 3 percent in the intestines of human vancomycin-resistant enterococci carriers.¹⁹⁶ In 1969, the Swann Committee in the United Kingdom recommended that no antibiotic be used in farm animals if the same drug is employed in humans and selects for antibiotic resistance.¹⁷⁶ It appears wise some 31 years later to now implement this recommendation before the antibiotic resistant microorganisms in food chain animals and the 1.4 billion tons of animal waste (manure) they annually generate in the United States do any more harm.

Institutional Antibiotic Resistance

Day Care Centers

The transmission of microorganisms at day care centers is endemic via contaminated body fluids (saliva, urine, feces) and fomites (toys, surfaces).¹⁹⁷ The most commonly transmitted diseases are respiratory: rhinitis, sinusitis, pharyngitis, bronchitis, and pneumonia. The offending organisms include adenovirus type II and V, respiratory syncytial virus, parainfluenza virus B, H. influenzae Type B, N. meningitidis, and M. tuberculosis.¹⁹⁷ Diarrhea is the second most common infection and is commonly due to rotavirus, adenovirus, Shigella, Salmonella, E. coli, Y. enterocolitica, Giardia lamblia and Entamoeba histolytica.¹⁹⁷ In day care children younger than 3, 2.6 cases of acute diarrhea occur per year.¹⁶⁷ Other day care center transmitted diseases include otitis media, whooping cough, herpesvirus, and hepatitis A and B.¹⁹⁷

Significantly, 20 percent to 60 percent of children attending day care centers are carriers of antibiotic resistant S. pneumoniae.¹⁶⁷ In a recent Canadian study, 44.3 percent of children attending 59 day care centers were carriers of S. pneumonia with 17 percent of the isolates exhibiting decreased susceptibility to penicillin and 13.7 percent displaying multiple-antibiotic resistance.¹⁹⁸ Antimicrobial use both individually and in the total community is strongly associated with nasopharyngeal carriage of penicillin-resistant pneumococci in children.¹⁹⁹

In a study of two child care centers, 3 percent of children at one center and 24 percent at the other were carriers of methicillin-resistant S. aureus.²⁰⁰ The number of children in the community hospitalized with community-acquired methicillin-resistant S. aureus without identifiable risk has increased from 10 of 100,000 hospital admissions in 1988-1990 to 259 of 100,000 hospital admissions in 1993-1995.²⁰¹

The critical factors for disease transmission in day care centers are the age of the child and the size of the facility.²⁰² Age determines the personal hygiene and immunological maturity of the child while the size of the facility (children attending) and the percent of pre-toilet-trained as opposed to toilet-trained children determines the cleanliness and odds of transmission.²⁰² In the first and second years of day care, 52 percent to 76 percent of children contract an infection as opposed to 27 percent to 36 percent in the third year and 16 percent at home.¹⁶⁷ In an eight-month study of child care centers, the incidence of antibiotic use was 36 percent in child care centers, 7 percent in child care homes and 8 percent in the child’s own home.²⁰³ The annual rate of antibiotic use was 3.6 times greater in child care centers than home and five times longer in duration.¹⁶⁷ A symposium on child day care health is available.²⁰⁴

Long-Term Care Facilities

There are presently 2.5 million United States residents of long-term care facilities; and infections, primarily pneumonia, are a major cause of morbidity and mortality. Approximated 43 percent of the U.S. population that turned age 65 in 1990 will spend time in a nursing home.^205,206 Antibiotics account for 40 percent of all drugs employed in nursing homes with 50 percent to 70 percent of residents getting at least one antibiotic per year.²⁰⁶ Between 35 percent and 75 percent of antibiotic use in such facilities is considered inappropriate.²⁰⁶

The occurrence rate of nursing home infections range from 1.6 percent to 32.7 percent with most studies showing an occurrence rate of less than 10 percent with an incidence rate of 1.8 to 7.1 per 1,000 resident days.²⁰⁶ Risk factors include IV lines, indwelling catheters, malnutrition, polypharmacy, chronic disease (dementia, cardiovascular disorders, urinary and fecal incontinence), and altered immunity (T lymphocyte and cytokine function).^205,206 Another major factor is colonization of the oropharynx, external nares, and skin with highly antibiotic-resistant S. aureus, beta-hemolytic streptococci, P. aeruginosa, Enterobacteriaceae, and particularly K. pneumoniae.^205,206

Antibiotic-resistant pathogens in nursing homes include penicillin-resistant S. pneumoniae, extended-spectrum beta-lactamase-producing gram-negative bacilli resistant to third generation cephalosporins, vancomycin-resistant enterococci, methicillin-resistant S. aureus, coagulase-negative staphylococci, and vancomycin-intermediate-resistant S. aureus.^205-208 Antibiotic resistance is high due to extensive antibiotic use in nursing homes, selection, and transfer of resistance genes and microorganisms from incoming residents.²⁰⁶

In a recent study, 31 of 35 nursing home residents admitted to tertiary care hospitals from eight separate nursing homes were infected with or colonized with ceftazidime resistance in E. coli, K. pneumoniae, or both.²⁰⁹ It appears that nursing home residents pose a significant risk for introducing highly antibiotic-resistant pathogens into acute-care hospitals with the reverse also possibly true.

Hospital-Acquired Infections

The Centers for Disease Control and Prevention has variously estimated that of the 40 million people hospitalized every year in the United States, 2 million to 4 million experience a nosocomial infection^210-212 resulting in 90,000 deaths.²¹³ This is likely to be a considerable underestimate.^214,215 This reported death rate from nosocomial infections is likely to be much smaller than the reality as pathologists commonly list causes of death by the general pathologic diagnosis (lobar pneumonia) rather than the causative microorganism (pneumococcus)²¹⁴ and multiple cause-of-death data do not allow for the extraction of microbial causation information.²¹⁵ If the microbial cause (methicillin-resistant S. aureus septicemia, for example) were listed as the cause of death rather than congestive heart failure, renal failure, and so forth, the nosocomial infection death rate would rise dramatically and would likely make the list of the 10 leading causes of death in the United States.^215,216

The morbidity/mortality rate from nosocomial infections has been estimated to be 5 percent to 25 percent depending on the given country²¹⁷ with a possible 50 percent mortality in surgical intensive care units for nosocomial blood-stream infections.²¹⁸ Approximately 50 percent to 60 percent of nosocomial antibiotic-resistant organisms are resistant to several antibiotics and in some intensive care units there is a 27 percent to 70 percent chance of acquiring a nosocomial infection due to one of these microorganisms.²¹⁰ Many of these infections are related to invasive devices (catheters, ventilators, central lines) with possibly at least 400,000 annual catheter-related blood-stream infections in the United States.²¹⁹

In a review of more than 10,000 blood-stream infections at 49 hospitals, gram-positive organisms accounted for 64 percent of cases, gram-negatives for 27 percent, and fungi for 8 percent.²²⁰ The most common organisms were coagulase negative staphylococci (32 percent), S. aureus (16 percent) and enterococci (11 percent).²²⁰ Intensive care unit infections were more likely to be Enterobacter, Serratia, coagulase negative staphylococci, and Candida infections while in patients with neutropenia, viridans streptococci were most common.²²⁰ Methicillin resistance was seen in 29 percent of S. aureus and 80 percent of coagulase-negative staphylococci while 3 percent of E. faecalis and 50 percent of E. faecium were vancomycin-resistant.²²⁰ Studies in the Western hemisphere show similar numbers, with 33 percent to 48 percent of all viridans group streptococci resistant to penicillin and 20 percent resistant to the macrolides.²²¹ New extended-spectrum beta-lactamases have conferred high resistance to third generation cephalosporins in E. coli and K. pneumoniae and increasing resistance is seen in Acinetobacter baumanii, Stenotrophomonas maltophila and P. aeruginosa.^222,223

The principal infections in pediatric intensive care units are primary bloodstream, pneumonia, and urinary tract infections,²²⁴ while in adult intensive care units, urinary tract infections predominate followed by pneumonia and blood-stream infections.²²³ The principal organisms are S. aureus, coagulase-negative staphylococci, enterococci, E. coli, and Candida for blood-stream infections; E. coli, enterococci, K. pneumoniae, and P. aeruginosa for urinary tract infections; S. aureus, H. influenzae, P. aeruginosa, and E. cloacae for respiratory tract infections; and staphylococci, E. cloacae, and P. aeruginosa for skin/wound infections.^222,225-227 All of these microorganisms are highly lethal and multiple-antibiotic resistant.

Patterns of Antibiotic Use

Antibiotics are often employed as "drugs of fear"²²⁸ used to "cover" for errors of omission or commission and thereby "prevent" claims of negligence. Approximately one-half of all antibiotics employed in hospitals are in patients without signs or symptoms of infection, and in many cases are used to prevent infections or to ensure that "all was done" to prevent later criticism.²²⁹ In hospital antibiotic use, approximately one-third are used empirically, one-third for prophylaxis, and one-third with appropriate culture and sensitivity tests.²³⁰ The increasing use of broader spectrum antibiotics may allow hospitals to save the costs of microbial sensitivity tests. Paul Ehrlich’s "magic bullet" has been replaced by a shotgun.²³¹

Outpatient antibiotic use can be characterized by the 80:80 rule: 80 percent of all antibiotics are used in the community and 80 percent of these are used for respiratory infections.²³² Most of these respiratory infections are viral in nature and are not amenable to antibiotic therapy.²³³ Of the 50 percent of people with acute respiratory illness that seek medical treatment, 50 percent to 80 percent will receive an antibiotic; but pneumonia (the only upper respiratory tract infection requiring antibiotic therapy) will account for only 2 percent of these cases.²³⁴ The prescribing of antibiotics can vary 15-fold among physicians, and those that tend to prescribe many drugs tend to do the same with antibiotics.²³⁵ Antibiotics remain the single most abused privilege that physicians have.²³⁶

The reasons for the inappropriate use of antibiotics are:

* Insufficient training in infectious diseases and proper antibiotic therapy;

* Empirical use;

* Lack of culture and sensitivity tests where appropriate and useful;

* Inadequate diagnostics

* Inappropriate choice of drug, dose, and duration;

* Need of self-assurance;

* Patient demands; and

* Fear of litigation.²³²

A final difficulty with antibiotics comes from a pharmaceutical industry that is beholden to stockholders as well as the health professions: "Clearly it is in the best interests of pharmaceutical companies to promote the wide use of antibiotics to justify research and development costs. This fact, coupled with the willingness of some physicians to prescribe the latest antibacterial, has undoubtedly increased the frequency of resistance."²³⁷ To be fair to the pharmaceutical industry, very significant risks and costs are associated with new drug development, particularly with antimicrobials where: "A single base change (in the nucleotide sequence of a bacterial gene) can render useless a hundred million dollars of pharmaceutical research effort."²³⁸ "Humans should not confuse themselves. This is true biological warfare in which new drugs designed by humans will become obsolete through bacterial mutations, only to be replaced by new drugs and new bacterial mutations in a seesaw battle."²³⁸

The Control of Antibiotic Misuse

It is generally accepted that a direct causal relationship exists between antibiotic use and the appearance of microbial resistance as:

* Antibiotics select for specific resistance traits;

* A reduction in antibiotic use results in a reduction in antibiotic resistance to that agent;

* Hospital changes in antibiotic use leads to altered antibiotic resistance patterns;

* Nosocomial resistance rates are far greater than those in the community due to more intensive antibiotic use;

* Hospital patients with resistant strains are more likely to have taken prior antibiotics;

* Areas of the hospital with the greatest antibiotic use have the highest resistance rates; and

* The longer the duration of antibiotic use, the more likely colonization with resistant organisms will occur.²³⁹

The intensity of antibiotic use in a given populationwhether in a hospital or community is the most important factor in the selection of microorganisms for resistance.²⁴⁰ It follows then that all microbial resistance to antibiotics is local and depends on the patterns of antimicrobial use in the particular geographic locale. What is true in Spain may not be true in England nor in Los Angeles nor New York. It is equally true that any attempts to reduce microbial resistance must begin locally. There are only two ways to prevent the development and spread of resistant microorganisms:

* Reduce antibiotic use to reduce the selection of resistant bacteria or the emergence and/or transfer of resistance genes; and

* Improve hygiene measures in hospitals to prevent the development and spread of resistant microbial strains.²⁴¹

Attempts to restrict the use of antibiotics in specific locations such as intensive care units and even entire countries is showing promise in the control of resistant microbes. In Finland, the reduction in defined daily doses (the amount of antibiotic taken in one day) from 2.40 to 1.38 per 1000 people per day from 1992 to 1996 has resulted in a decrease in group A streptococcal resistance to erythromycin from 16.55 percent in 1992 to 8.6 percent in 1996.²⁴² Alarmed by a rise in penicillin-resistant pneumococci from 2.3 percent in 1989 to almost 20 percent in 1993, Iceland restricted the use of penicillin resulting in a decline of these organisms to 16.9 percent in 1994 and a reduction in penicillin-resistant pneumococci in day care centers from 20 percent to 15 percent.²⁴³ Hungary has also experienced a decline in antibiotic-resistant S. pneumoniae from 50 percent to 34 percent with reduced antibiotic use.

An 80 percent reduction in hospital use of cephalosporins between 1995 and 1996 resulted in a 44 percent decrease in ceftazidime-resistant K. pneumoniae infection, and colonization decreased by 70.9 percent in intensive care units.²⁴⁴ A reduction in the hospital use of cephalosporins, imipenem, clindamycin, and vancomycin resulted in a reduction in patients colonized by methicillin-resistant S. aureus and ceftazidime-resistant K. pneumoniae.²⁴⁵ These changes in antibiotic use must be closely monitored as there is a tendency to then employ other antibiotics, which leads to different resistance problems.^244,245

Professional Responsibility to Control Microbial Resistance

Hospitals

A number of suggestions have been made to reduce either the extent of microbial resistance to antibiotics in hospitals or the transmission of strains from patient to hospital staff or vice versa. These include:

* Educate health professionals and the public about microbial resistance to chemicals;

* Decrease antibiotic use by employing proper indications, dosage, and duration of use;

* Restrict the use of new antibiotics;

* Develop a monitoring system for microbial resistance patterns and in-hospital antibiotic use;

* Isolate patients colonized or infected with resistant organisms;

* Decrease the clonal spread of resistant strains by infection control practices;

* Discourage the use of multiple antibiotics unless dictated by culture and sensitivity tests;

* Optimize antibiotic use for surgical prophylaxis and reduce antibiotic prophylaxis to established uses;

* Encourage culture and sensitivity testing instead of broad spectrum antibiotics (a return to the one bug, one drug rule); and

* Improve socioeconomic conditions (crowding, hand washing, feces disposal, clean water).^246,247

Other measures that can be useful outside the hospital include:

* Decreased antimicrobial use in agriculture and aquaculture;

* Practitioner resistance to patient antibiotic demands;

* Better diagnosis of upper respiratory viral diseases and cessation of antibiotic use for these conditions;

* Washing of fruits and vegetables;

* Restriction of antibiotics to proper durations of use;

* Attention to local antibiotic resistance data; and

* Handwashing.²⁴⁸

Dentistry

Since dentistry prescribes approximately 10 percent of all the common antibiotics (penicillins, cephalosporins, macrolides, tetracyclines), our contributions to the problems of microbial resistance can be substantial.²³³ Antibiotic misuse in dentistry primarily involves the use of antibiotics in inappropriate situations or for too long a period of time. Inappropriate uses include:

* Giving antibiotics after a dental procedure is completed in an otherwise healthy patient to "prevent" an infection, which in all likelihood will not occur anyway (read to "prevent a lawsuit" in many cases);

* Using antibiotics as "analgesics" particularly in endodontics;

* Employing antibiotics for prophylaxis in patients not at risk for metastatic bacteremias;

* Using antimicrobials to treat chronic adult periodontitis, which is almost totally responsive to mechanical treatment;

* Using antimicrobial therapy in lieu of mechanical therapy in periodontitis management;

* Using antibiotics and antimicrobials chronically in periodontitis;

* Using antibiotics instead of surgical incision and drainage of infections; and

* Using antibiotics to "prevent" claims of negligence.

The use of antibiotics to "prevent" post-treatment infections by giving the drugs after the dental procedure is completed violates all the principles of antibiotic prophylaxis (loading dose, drug in the system before surgery begins, only against a single pathogen, only as long as bacteremia persists, proper risk-cost/benefit ratio) and has not been demonstrated to be clinically effective.²⁴⁹ Antibiotic prophylaxis for the prevention of surgical infections is only effective if the drug is in the system before the procedure begins and then only in clean/clean or clean/contaminated surgery where the drug is discontinued shortly after the surgery is completed.²⁴⁹ The mouth is one of the most heavily contaminated areas of the body and may not qualify under this scenario. The pharmacokinetics of antibiotics ensures that an antibiotic begun sometime after the dental procedure and without a loading dose may achieve significant blood levels six to 12 hours after the procedure or sometime the next day when the issue of whether an infection occurs has already been decided (in the vast majority of cases against a postoperative infection).^250,251

The use of antibiotics as "analgesics" to treat postoperative pain is irrational as better drugs are available as analgesics, and most studies indicate that antibiotics do not relieve postoperative edema, pain, and trismus.²⁴⁹ The proper attention to the established guidelines for antibiotic prophylaxis to prevent metastatic infections as advocated by the American Heart Association for infective endocarditis and the American Dental Association/American Academy of Orthopaedic Surgeons for dental patients with orthopedic prosthetic joints will significantly reduce unnecessary antibiotic prophylaxis in dentistry.^252,253

The use of antibiotics in the treatment of periodontal disease is only appropriate in the management of acute periodontal infections, primarily periodontal abscesses, and in the management of refractory or rapidly progressive periodontitis, which has failed to go into remission after standard treatment procedures.^254,255 The use of antimicrobials such as low-dose doxycycline as an "adjunct" to periodontal care for extended periods of time or in lieu of periodontal subgingival instrumentation has been discussed above and in a recent review.²⁵⁶ The risk-benefit ratio for such a practice appears inadequate and, if used instead of competent subgingival instrumentation, violates the cardinal principle of infection control: removal of the source of the infection.

Antibiotics are almost never a substitute for surgical drainage (incision and drainage, extraction, endodontics) of an infected area (the sun should never set on undrained pus) for a number of reasons:

* Antibiotics do not diffuse well into infected areas;

* The blood supply to abscesses is usually compromised;

* Some antibiotics do not work well at the acidic pH of abscesses;

* Microorganisms may be dividing slowly or not at all, particularly in older abscesses thereby negating the effects of penicillins and cephalosporins that act only on dividing organisms; and

* High levels of antibiotic inhibitors (beta-lactamases) may be present in abscesses.^250,251

Occasionally, an infected area is not amenable to incision and drainage (pericornitis, indurated cellulitis) and antibiotics are the only available treatment, but the exception should not become the rule.

The use of antibiotics as " drugs of fear" to "prevent" lawsuits has never been rational but has been somewhat understandable considering the tort climate today. Such a practice has contributed substantially to antibiotic resistance problems; and it is unknown just how many lawsuits, if any, have been prevented since no study of this problem has ever been performed. A case can be made that the legal profession in the United States has had as much a role in microbial resistance to antibiotics as the health care professions and patient misuse.

The second factor in the misuse of antibiotics in dentistry in addition to inappropriate use is employing the drugs for too long a duration and at too low a dose. Antibiotics should be used aggressively and for as short a time as is compatible with patient remission of disease.^251,252 In infectious diseases that do not rebound (return upon cessation of the antibiotic), such as orofacial infections, the proper duration of the antibiotic is determined by the time it takes for the patient host defenses to gain control of the infection.^251,252 With orofacial infections, the antibiotic is terminated when the infection has resolved or is reasonably certain to resolve. ^251,252 The use of antibiotics for too long a duration and particularly at subinhibitory concentrations greatly increases microbial resistance.^{6,15,170,257,258}

The duration for antibiotics can vary significantly due to the following factors:

* The ability to incise and drain the infection;

* Host medical status and response to the infection;

* Growth rate and virulence of the infection;

* Ability of the antibiotic to diffuse to the infection site;

* Presence of resistant bacterial strains; and

* Antibiotic choice and dose.^251,252

Therefore, each infection is unique and a "standard therapy" of the same dose and duration for every infection will lead not only to increased microbial resistance, but also to treatment failures.^251,252

The old adage that antibiotics should be given for x number of days (five, 10, 14, or whatever) to "kill resistant strains" is an oxymoron since bacteria that are resistant are by definition unaffected by the antibiotic. While it is true that some bacteria may occasionally mutate to resistance in a "stepwise" fashion over several generations and that prolonged antibiotic therapy may kill or inhibit these mutants before they gain full resistance, this does not reflect the reality of how resistance operates today. Virtually all microbial resistance occurs by the transfer of resistance genes via bacteriophages, plasmids, transposons, and integrons from microorganisms already resistant to the antibiotic(s). Prolonged antibiotic use over what is necessary will only select for these often highly resistant strains and pose a much greater risk for human health than failing to inhibit a few isolated mutants.

Lastly, patients are often mandated to "finish the course of the antibiotics" no matter what has happened with the infection. This is reasonable with rebound infections. However it is also predicated on an assumption: that the prescribing health practitioner actually knows beforehand precisely how long the infection will last. This is often unlikely due to the patient and drug variables listed above. Even the experts make this mistake by assuming that the course of the infection is predictable from its outset, that the practitioner knows precisely what the clinical course will be or that the 10-day therapy established for the treatment of streptococcal sore throat fits all infections. The wise practitioner follows the progress of the infection until its termination.

Conclusions

When antibiotics are employed, six things may occur, only the first of which is good:

* The antibiotic may aid the immune system to gain control of the infection; or

* Toxicity or allergy may occur;

* Already resistant microbes may be selected for and a superinfection may result;

* The antimicrobial may promote microbial chromosomal mutations;

* Gene transfer may be encouraged from resistant to nonresistant microbes; and

* Latent resistance genes may be expressed.

Antibiotic treatment failures will continue to increase in medicine as well as in head and neck infections. Dentistry should not be surprised that the future will hold increasing difficulties with penicillin and macrolide resistant viridans group streptococci and beta-lactamase producing Prevotella and Porphyromonas. Nature may hold other microbial resistance surprises for us also. The more we look, the more we will find.

The global problem of microbial resistance to antibiotics is serious not only in its extent but also in the rapidity with which microorganisms are attaining and maintaining resistance. It is not time to panic, but it is time for all to realize that the problem cannot be solved without a concerted effort on the part of all concerned: patients, parents, health professionals, veterinarians, food producers, and governments. We must fully appreciate that: "Penicillin brought more curative power to a barefoot, itinerant care provider in the deepest reaches of Africa than the collective powers of all the physicians in New York City." ²⁵⁹ It is time for us all to become part of the solution and not the problem. After all, our lives depend upon it.

Author

Thomas J. Pallasch, DDS, MS, is a professor of pharmacology and periodontics at the University of Southern California School of Dentistry.

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