Can antimicrobial activity be sustained? an appraisal of orally administered drugs used for respiratory tract infections

ELSEVIER

GLASGOW

SYMPOSIUM

Can Antimicrobial Activity be Sustained? An Appraisal

of Orally Administered

Used for Respiratory Ronald

Drugs

Tract Infections

N. Jones

Respiratory tract infections (RTlsJ represent a major cause of illness worldwide. Therefore, it is of great concetn that common RTI pathogens have become increasingly resistant to many of the antimicrobial agents used for therapy. For example, Haemophilus influenzae and Moraxella catarrhalis have become resistant to beta-lactam drugs by producing eficient beta-lactamases (>35 and 90% of strains, respectively). More recently, pneumococci have become more resistant through the mechanism of altered penicillin-binding proteins (PBPs). The rate of penicillin nonsusceptible isolates has risen to >25% in the United States (1994-1995). It is important to monitor the resistance characteristics of such pathogens and, if possible, to use regionally acquired data to guide empiric selec-

tion of therapeutic agents for RTls. Currently, some antimicrobials remain efiective against the majority of these three bacterial species, as exemplified by amoxicillin/clavulanic acid. Furthermore, amoxicillin alone seems to possess greater inhibition than other orally administered beta-lactams at clinically achievable concentrations against pneumococci with altered PBPs. It is critical that steps are taken to limit resistance problems, particularly through: 1) education of prescribers and the public; 2) initiation of the development of novel drugs with alternative modes of action OY stability to existing resistance mechanisms; and 3) by continuing to generate quality susceptibility testing data to guide empiric chemotherapy against bacterial pathogens causing RTI. 0 1997 Elsevier Science Inc.

INTRODUCTION

mation gleaned from such systems will greatly facilitate the decision-making process when selecting an empiric antimicrobial therapy for hospitalized as well as ambulatory patients. The maintenance of surveillance over a number of years can also reveal whether existing commonly used antimicrobial agents are sustaining their activity and spectrum. Surveillance initiatives such as the Alexander Project, which is an ongoing, international collation of data on antimicrobial resistance patterns, have a significant role in this process. Continuous appraisal of such information by primary care physicians, government agencies, professional societies, and the pharmaceutical industry at large is vital for making intelligent choices about antimicrobial therapy and drug development in the 1990s and into the next millennium. In this presentation, available data from the Alexander Project and several well-performed, complementary studies are summarized for selection

The problem of resistance to antimicrobial agents has now reached global proportions, with the pathogens responsible for respiratory tract infections (RTIs) posing a particular threat. The establishment of worldwide resistance surveillance systems seems to be a key factor in assessing the extent of resistance problems and in characterizing which susceptibility patterns are emerging and where (Jones 1996). lnfor-

From the Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa, USA. Address reprint requests to Professor Ronald N. Jones, Director, Medical Microbiology Division, Department of Pathology, 5232 RCP, University of Iowa College of Medicine, Iowa City, IA 52242, USA. Received 30 June 1996; revised and accepted 10 December 1996.

DIAGN MICROBIOL INFECT DIS 1997;27:21-28 0 1997 Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

0732-8893/97/$17.00 I’11 SO732-8893(97)00018-7

R.N. Jones

22

of optimal therapeutic regimens for respiratory pathogens in ambulatory patients.

PATHOGENS INFECTIONS

tract

IN RESPIRATORY AND OTITIS MEDIA

This paper discusses a particularly significant problem-resistance in pathogens involved in respiratory infection and otitis media. One reason for the seriousness of these infections is their sheer abundance, with RTIs representing the commonest cause of clinic visits (105 million clinic visits in the United States in 1994) at all ages, in all parts of the world. Otitis media accounts for 40% of all outpatient antimicrobial use in children in the United States (Nelson et al. 1987). Furthermore, even mild RTIs have the potential to lead to serious complications; therefore, the use of appropriate antimicrobials is vital. Important RTIs include: l

acute pharyngitis

(caused by Streptococcus

pyqpW; l

acute otitis media;

l

acute exacerbations

l

acute/chronic

l

milder forms of pneumonia.

of chronic bronchitis;

sinusitis;

and

1 Principal Bacterial Causes of Respiratory Outpatient Pathogen

Streptococcus pneumoniae Haemophilus injluenzae Moraxella catarrhalis Staphylococcus aweus (Streptococcus pyOgenes)b

penicillin-resistant streptococci (particularly pneumococci with altered penicillin-binding protein [PBP] targets); and beta-lactamase-producing catarrhalis.

Tract Infection

Treated in

Clinics Overall % of Isolates” 40-60

2.540 Z-10 (Eoo)”

“Consensus from AOM, AECB, and sinusitis. bFor pharyngitis only.

H. influenzae and M.

When common infections are associated with resistant pathogens, the implications for global morbidity and mortality can be immense. A recognition of the seriousness of such problems has led to urgent calls for strategies to address antimicrobial resistance among commonly observed infections. STRATEGIES

Such infections can be treated successfully with outpatient-oriented, orally administered antimicrobial agents. Because they are predominantly treated empirically during the critical initial days of therapy, it is important for physicians to be aware of prevalent resistance patterns, so that they may choose an effective drug. The compounds most commonly considered for therapy are penicillins (penicillin V or amoxicillin), cephalosporins (multiple), macrolides (multiple) alone or with a sulfonamide, fluoroquinolones (multiple but limited use in children), and trimethoprim/sulfamethoxazole. The bacterial pathogens most frequently responsible for such infections are shown in Table 1. Although S. pyogenes is the principal bacterial pathogen

TABLE

in RTIs, it remains largely susceptible to beta-lactams (penicillin); therefore, it is not relevant in this context. The most significant organisms in terms of resistance are Haemophilus influenzae, Moraxella catarrhalis, and more recently, Streptococcus pneumoniae. Resistant strains of these organisms are recognized as a major international problem. Moreover, in the United States, the U.S. Food and Drug Administration contends that any antimicrobial agents claiming to be suitable for the cited respiratory infections must be significantly active against these three bacterial pathogens. The main types of resistance encountered in outpatients with respiratory infections are:

American

TO COMBAT

RESISTANCE

Society of Microbiology

Task Force

The American Society of Microbiology (ASM) has registered grave concern about the increase in resistance to antimicrobial agents and the associated threat to public health. This led to the formation of a Task Force on Antibiotic Resistance, comprising expert scientists from the academic, government, and industrial sectors. A series of recommendations focusing on resisemerged from this “think-tank” education, and research (Jones tance surveillance, 1996). It is recommended that national surveillance systems should be instituted as soon as possible, to monitor the extent of resistance problems and thereby guide choices of antimicrobial therapy. Computerized databases of antimicrobial resistance would be very useful, allowing both analysis of the data and exchange of data between centers for comparative purposes. For example, WHONET is a program developed in collaboration with the World Health Organization for storage and analysis of susceptibility data, both as minimum inhibitory concentration (MIC) values or zone diameters (O’Brien 1992). However, there are significant financial implications associated with comprehensive surveillance systems, and in the current economic climate, many countries may find it impossible to muster the necessary resources.

Antimicrobial

Resistance

23

in RTIs

It is suggested that health care professionals must be more aware (education) of the problem of antimicrobial resistance. Updated information should be disseminated to physicians through teaching establishments and through postgraduate educational programs. In particular, office-based physicians must be aware of issues relating to drug resistance, because the majority of antimicrobial agents are used for real or suspected outpatient infections. For example, in 1992, an estimated 110 million courses of antimicrobial therapy were prescribed by officebased physicians in the United States, a 28% increase over the number in 1980 (McCraig and Hughes 1995). In addition, efforts should be made toward education of the general public about this issue, because increasing pressure from patients can encourage the inappropriate prescription of antimicrobial agents. This component of the ASM program has recently been initiated with help from some professional societies. Finally, the ASM task force has called for an increase in basic research to develop new antimicrobial agents and effective vaccines. Also, research should be directed toward finding better and more rapid methods for testing the susceptibility of pathogens. In addition, efforts should be made to determine the mechanisms of spread of resistance and to evaluate resistance more fully at the genetic level. It is recognized that many pharmaceutical companies have reduced their antimicrobial development programs in the belief that this direction of research is not cost effective. A greater awareness within industry of resistance problems and of the potentially wide market for new compounds should help to stimulate more basic research. Cooperation should be encouraged between national governments and pharmaceutical companies. Industry must see a profit from their investments so they might finance further research, and governments should encourage a favorable market for pharmaceutical products; for example, by extending patent limits or permitting licensing at earlier stages of development for selected products. In return, it is suggested that industry could contribute to this partnership by the following measures (Kunin 1993): contributing appropriate

to education antimicrobial

programs about agent use;

improving the availability effective drugs;

and distribution

helping to monitor the emergence strains; and sponsoring training programs investigators in therapeutics.

of

of resistant

for young

Strategies Using Newer Molecular Combat Resistance

Entities to

One approach toward overcoming microbial resistance is to develop new oral drugs that circumvent existing resistance mechanisms. For example, a major cause of resistance is the production by bacteria of beta-lactamases that destroy beta-lactam drugs. Therefore, two approaches are to use drugs within the class that are stable to beta-lactamases, such as the orally administered “third-generation” cephalosporins; or to use nonbeta-lactam compounds. Alternatively, the problem can be addressed by protecting the active beta-lactam by using a co-drug, as exemplified by clavulanic acid with amoxicillin; i.e., the clavulanic acid component shields amoxicillin from enzyme attack by high-affinity binding. The effectiveness of this latter approach is demonstrated by reviews that have cited study results proving the utility of such drugs maintained over many years of use. For example, a recent comparison of over 400 studies by Neu et al. (1993) highlighted the fact that amoxicillin/clavulanic acid has been used for 14 years with success in almost 40,000 published cases. In this review, it was concluded that amoxicillin/clavulanic acid has a continued role in RTIs and numerous other infections, with cure rates of 88 to 92% (adverse events 13.0%). Another review of over 1500 studies highlighted the ongoing microbiologic efficacy of amoxicillin/ clavulanic acid combination delivered by the oral route (Rolinson 1994). Potency against the key respiratory tract pathogens was not compromised over the 15-year period of monitoring since 1978 (marketed in 1981). In particular, of 59 studies reporting beta-lactamase-producing H. influenzae, only 1 reported a ME greater than 4 kg/ml (nonsusceptible by NCCLS guidelines), with no trend toward greater resistance.

RESISTANCE PATTERNS UNITED STATES

IN THE

The United States is an example of a country where resistance rates are increasing among key respiratory tract pathogens, and where surveillance results are more often recorded. As shown in Figure 1, levels of resistance in the three pathogens under discussion have increased dramatically over the last 20 years. Moruxellu cufurrhalis and Haemophilus influenzae have both gained high-level resistance by the production of beta-lactamases, whereas, the pneumococci utilize the mechanism of altered PBPs. These proteins are the bacterial enzymes that construct bacterial cell walls, and they represent the normal target of beta-

24

R.N. Jones

1975

1980

1985 Year

1990

1995

FIGURE 1 Trends in the antimicrobial resistance to betalactam drugs among M. catarrhalis (beta-lactamase), H. influenzue (beta-lactamase), and S. pneumoniue (altered PBPs).

lactams. They are altered in resistant strains, so they have lower affinity for beta-lactams. Some alterations increase resistance to penicillin only modestly; whereas, others may result in a MIC of 216 kg/mlnearly a 2000-fold increase over that of a susceptible strain. Altered PBPs generally also affect the action of cephalosporins (Dowson et al. 1994).

TABLE

2

Activity

cafarrhalis,

of Selected

Oral Antimicrobial

H. influenzae,

A key difference between these two types of resistance (beta-lactamase versus altered PBP) is that the adverse effect of modified PBPs can be minimized, if drugs reach sufficiently high serum/tissue concentrations. In the following discussion of individual pathogens, reference is made to the Alexander Project-a longitudinal study wherein a large number of bacterial isolates from RTI have been examined for their susceptibilities to many antimicrobials. This industry-sponsored initiative was designed to provide accurate baseline statistics on resistance patterns and to monitor subsequent changes over time (Baquero et al. 1995; Griineberg et al. 1996).

Moraxella

Of the three pathogens under discussion, the first in which significant resistance was noted was M. cafarrhalis, with resistant isolates appearing in the mid1970s (Figure 1). Subsequently, the percentage of M. cafarrhalis isolates producing beta-lactamases has in-

Agents

and S. pneumoniae

1992

1993

Tested

against

M.

(USA, 1992-1994) % Susceptibility

MIC,, Antimicrobial Agent

catarrhalis

1994

1992

1993

1994

M. cafarrhalis (335)b Amoxicillin Amoxicillin/clavulanate Cefaclor Cefuroxime Cefixime Erythromycin Trimethoprim/sulfamethoxazole H. influenzae (1258)b Amoxicillin Amoxicillin/clavulanate Cefaclor Cefuroxime Cefixime Clarithromycin Trimethoprim/sulfamethoxazole S. pneumoniae (457)b Penicillin Amoxicillin Amoxicillin/clavulanate Cefaclor Cefuroxime Cefixime Erythromycin Trimethoprim/sulfamethoxazole

4 0.25 1 2 0.5 0.12 CO.5

8 0.25 2 2 0.5 0.25 0.5

8 0.25 2 2 0.5 0.25 0.25

26 100 100 100 100 100 100

25 100 99 99 100 100 100

26 100 100 100 99 100 100

32 1 16 2 co.12 8 GO.5

32 1 8 2 GO.12 8 GO.5

8 1 16 4 GO.12 8 GO.5

73 100 88 98 100 97 97

71 100 95 98 100 99 98

64 100 87 94 100 95 94

0.5 0.25 0.25 4 1 4 SO.06 2

0.12 0.12 0.12 2 0.5 2 ~0.06 2

2 1 1 32 4 16 GO.06 4

78 92 92 NA’ 90 NA” 94 86

85 95 96 NA’ 91 NA’ 98 85

81 88 88 NAC 86 NA’ 92 69

“Modified from Washington et al. (1996), Alexander Project (USA). bNo. of strains tested. ‘NA = Not applicable because of no interpretive criteria or because the interpretation was based on the penicillin test result.

Antimicrobial

Resistance

in RTIs

creased to over 90% (Wood et al. 1996). However, recent data from the United States between 1992 and 1994 show that there are still a wide variety of orally administered compounds that are effective (>99% susceptible) against M. catarrhalis, including amoxicillin/clavulanic acid, oral cephalosporins, macrolides, and trimethoprim/sulfamethoxazole (Table 2). This contrasts with the performance of older penicillins such as ampicillin and penicillin (data not shown)-approximately three-quarters of M. cutarrhalis isolates in the United States are now capable of hydrolyzing these drugs (Washington et al. 1996) using MIC criteria. Higher rates of resistance have been reported using appropriate beta-lactamase tests (chromogenic cephalosporins) to directly detect the resistance producing enzyme.

Haemophilus

influenzae

Increase in resistance among H. in&enzae isolates was initially less dramatic in the United States, steadily increasing from the first emergence of resistant, beta-lactamase-producing strains in the mid-1970s (Figure 1). However, recent analysis of more than 2000 strains from 187 medical centers in the United States has revealed that the percentage of resistant isolates has now risen to 36% (Jones et al. 1997). Similar resistance rates have also been noted for H. infuenme isolates in numerous other countries; for example, 19% in Japan and Canada; 21% in the United Kingdom, 23% in France; 28% in Australia; 35% in Belgium and Italy; and 37% in Spain (Rolinson 1994). The worldwide incidence of beta-lactamase production in H. influenzae can be estimated at approximately 35%. However, each nation should be monitoring for this resistance mechanism to determine their own level. It is also important to test individual antimicrobials on an ongoing basis to determine changes in overall activity against these beta-lactamaseproducing strains of H. influenzae. For example, as shown in Table 2, the MIC,, varied widely between the tested compounds, notably some of such earlier generation cephalosporins as cefaclor (MI&,, 8 to 16 kg/ml; marginal activity) compared to the MIC,, for amoxicillin/clavuIanic acid, cefuroxime, and cefixime that are more beta-lactamase stable. The MICgO values of the macrolides (erythromycin, clarithromycin, and azithromycin) have demonstrated some variation over time (Washington et al. 1996) and are generally less active against Haemophilus. In addition, a recent study in the United States tested the activity of ten orally administered antimicrobials against H. inf2uenzae (Jones et al. 1997). Over 99% of isolates were susceptible to amoxicillin/ clavulanic acid; this was comparable to the levels of

25

susceptibility of third generation oral cephalosporins (cefixime, cefpodoxime) and superior to the macrolides (clarithromycin, 84% susceptible) and some of the older beta-lactam drugs (cefaclor, 82% susceptible).

Streptococcus

pneumoniae

Penicillin-resistant pneumococci were not seen until the early 80s in the United States, but they have now reached a level of >25% of isolates (Figure 1). It is important to note that the potency of different penicillins may vary in the same isolate. For example, Pankuch et al. (1995) determined that amoxicillin (either alone or in combination with clavulanic acid) is generally twice as active as penicillin or ampicillin against strains with altered PBPs (Table 3). This led to a recommendation in 1995 by the NCCLS that the breakpoint for S. pneumoniae resistance to amoxicillin should be 22 pg/ml. Many strains with intermediate resistance can be successfully treated using higher doses of amoxicillin or amoxicillin/clavulanic acid, because the systemic level of these drugs is high enough to eradicate many of these strains of S. pneumoniae. As with H. infuenzae, data published over a period of 13 years illustrate the extent to which various drugs have maintained their activity against pneumococci. The beta-lactams in general have shown a marked increase in their MIC, values over recent years, although some drugs (amoxicillin + clavulanic acid) have MIC,, values that remain at a treatable level. As shown in Table 2, 92 to 96% of clinical isolates of pneumococci were categorized as susceptible to amoxicillin alone or with clavulanic acid from 1992 through 1994 (Washington et al. 1996), while other agents were less active. A recent study by Doern et al. (1996) analyzed the susceptibility patterns of over 1500 isolates of S. pneumoniae from 30 medical centers in the United States. This revealed that the overall level of resis-

TABLE 3

Comparative Activity of Four Beta-lactams Tested against 189 S. pneumoniae strains” Strain MI&,, (&ml)

for Penicillin

Beta-lactam

Susceptible

Intermediate

Penicillin Ampicillin Amoxicillin Amoxicillin/ clavulanate

0.03 0.03 0.15

0.25 0.25 0.12

0.15

0.12

“Modified from Pankuch et al. (1995).

Resistant

26

R.N. Jones

tance (MIC, 20.12 t&ml) to penicillin was 23.5%, with approximately 10% of the total isolates exhibiting a high level of resistance (MIC, 22 &ml). Only 7% of isolates were resistant to amoxicillin or amoxicillin/clavulanic acid, and these isolates belonged to the subset of isolates that were highly resistant to penicillin and to parenteral “third-generation” cephalosporins. This study also revealed: a remarkable drug classes;

degree of cross resistance

between

0 pathogen

higher degrees of resistance to oral cephalosporins (12 to 25%) than to amoxicillin/clavulanic acid or amoxicillin

alone;

macrolide resistance slightly greater than that of the penicillin high level resistance; and high levels of resistance to trimethoprim/ sulfamethoxazole (18%). These types of resistance may vary in different countries, depending upon the levels of usage of specific classes of oral drugs. For example, in France, there has been long-term widespread use of the macrolides and, as shown in Figure 2, higher and increasing levels of resistance to such drugs among pneumococci have been observed (Geslin et al. 1994). Indeed, approximately one-third of S. pneumoniae strains from France are now resistant to macrolides.

ACTION

FOR THE FUTURE

It is important that physicians take note of these resistance rate statistics, as well as recently available

35

pharmacodynamic data, when making empiric antimicrobial choices for respiratory tract infection therapy. If possible, local susceptibility testing results should be taken into account when selecting these drugs. If local data are not available, then data from quality, longitudinal surveillance studies, published in peer-reviewed journals, should be used to guide choices (Washington et al. 1996). The following factors should be considered in this process:

1

30 1

25 -I

84 85 86 87 88 89 90 91 92 93 Year FIGURE 2 Trends in macrolide resistance in France (1984 through 1993) monitoring 14,786 S. pneumoniae cultures (Geslin et al. 1994).

frequency

(Table 1);

l

likely antimicrobial (Table 2);

susceptibility

l

drugs of equal documented should be considered; and

l

cost, safety, and pharmacodynamic

by species

clinical efficacy only parameters.

Example: A Typical U.S. Clinic Physician Treating Acute Otitis Media Acute otitis media (AOM) can be used as an example of how local susceptibility information should guide therapeutic choices. Table 4 shows the frequency of pathogens causing AOM in a typical U.S. clinical setting. Approximately one-half of such infections are currently caused by the pneumococcus. Also listed in the table are the susceptibility rates of these pathogens to various orally administered drugs likely to be selected to target them (Doern et al. 1996; Jones et al. 1997; Washington et al. 1996). This information can be used to select empiric therapy if local results are limited. For example, when considering all the potential pathogens (Table 5), a rank order can be obtained of the antimicrobial likely to be most effective in this therapeutic setting (AOM). It is evident that amoxicillin/clavulanic acid has the highest empiric spectrum probability, and thus the greatest potential for treatment and cure. Although the absolute values for these percentages may vary between regions or nations, it is unlikely that the rank order will change among the cited oral compounds; i.e., amoxicillin/ clavulanic acid > macrolides 2 oral cephalosporins, etc. At the molecular level, this rank is influenced by altered PBPs and associated cross resistances that remain the greatest threat to the successful treatment of AOM and other significant outpatient RTIs, essentially consigning the beta-lactamases (although still important) to a secondary importance. Furthermore, PBP and macrolide co-resistance is high, particularly among streptococci, so beta-lactams and macrolides would generally decline in unison. Finally, high levels of resistance to fluoroquinolones are emerging in many parts of the world to the three most common pathogens. For example, MICs to ciprofloxacin of 32 mg/ml or greater are no longer a rare occurrence in the western region of the United

Antimicrobial

TABLE

4

Resistance

27

in RTIs

Using the Microbiology and Epidemiology Information to Select an Optimal Oral Regimen Respiratory Tract Infection-I, Example: Typical USA Clinic Treating Acute Otitis Media

for

Proportion Susceptible to

Pathogen (frequency)

Amoxicillin/ Clavulanate

S. pneumoniae(0.50) H. influenzae (0.35)b M. catarrhalis (0.05)’ S. aureus (0.02)

0.93 1.00 1.00 1.00

Other (0.08)

1.00

Cefuroxime

Cefixime

Clarithromycin

Trimethoprim/ Sulfamethoxazole

0.88 0.94 1.00 1.00 1.00

0.77 0.96 0.99 0.00 1.00

0.90 0.90 1.00 0.90 1.00

0.82 0.94 1.00 0.90 1.00

“From Doem et al. (1996). ‘From Jones et al. (1997). ‘From Washington et al. (1996).

TABLE

5

Using the Microbiology and Epidemiology Information To Select an Optimal Oral Regimen for Respiratory Tract Infection-II

Oral Antimicrobial

Combined Probability Calculation

Amoxicillin/clavulanic acid Clarithromycin Cefuroxime Trimethoprim/sulfamethoxazole Cefixime

0.97 0.92 0.92 0.89 0.85”

“Cefaclor has the same calculated probablity.

States and in Europe for H. influenzae and M. catarrhaZis (Gould et al. 1994; Barriere and Hindler 1993; Corkill et al. 1994; Cunliffe et al. 1995). Furthermore, most currently available fluoroquinolones have marginal potency against streptococci, such as the pneumococcus.

CONCLUSIONS The overall list of pathogens responsible for RTIs generally remains unchanged over time, but the emphasis may shift from one species to another. For example, the pneumococcus is currently assuming a greater role, a trend likely to continue throughout

this decade. Resistance patterns among common pathogens causing RTIs have continued to evolve, typically with loss of potency and spectrum over time. A notable exception to this is amoxicillin/ clavulanic acid, which has maintained its potency and spectrum to a greater degree compared to peer beta-lactams over many years of use. The phenomenon of co-resistance between classes of drugs, such as beta-lactams, tetracyclines, sulfonamides, macrolides and lincosamines, suggests that there will be a uniform reduction in spectrum of all commonly used oral antimicrobials. Penicillin-binding protein mediated resistance in S. pneumoniae has decreased the clinical efficacy of beta-lactams in a fixed relationship of altered activity among oral drugs, and will continue to do so. Finally, it is also important to consider other factors in addition to the potency of an antimicrobial such as bioavailability, rapidity of action, and drug stability in body fluids. As the altered PBP mode of resistance becomes more prevalent, pharmacodynamic considerations will increasingly dictate the potential for each drug to sustain its clinical efficacy, some of which may continue as therapeutic entities through safe increases in dosing schedules. As we use and/or abuse potent drugs in the outpatient clinic setting, the selection toward resistance will sadly become as commonplace as that observed in the hospital environment.

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in respiratory tract bacterial pathogens in US and Europe: The third year of the Alexander Project. In Program and Abstracts of the 35th Interscience Conference of Antimicrobial Agents and Chemotherapy (San Francisco, CA). Washington, DC:

American Society for Microbiology, (Abst LB-23).

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Corkill JE, Percival A, McDonald P, Bamber AI (1994) Detection of quinolone resistance in Haemophilus spp. ] Antimicrob Chemother 34~841-844. Cunliffe NA, Emmanuel FXS, Thomson CJ (1995) Lower respiratory tract infection due to ciprofloxacin-resistant Moraxella catarrhalis. J Antimicrob Chemother 36:273-274. Doern GV, Brueggemann A, Holley Jr HP, Rauch AM (1996) Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States

28

R.N. Jones

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of antibiotic resis-

Pankuch GA, Jacobs MR, Appelbaum PC (1995) Comparative activity of ampicillin, amoxicillin, amoxicillin/ clavulanate and cefotaxime against 189 penicillinsusceptible and -resistant pneumococci. I Antimicrob Ckemotker 35~883-888. Rolinson GN (1994) A review of the microbiology of amoxicillin/clavulanic acid over the 15-year period 1978-1993. J Ckemotker 6:283-318. Washington JA and the Alexander Project Group (1996) A multicenter study of the antimicrobial susceptibility of community-acquired lower respiratory tract pathogens in the United States, 1992-1994; The Alexander Project. Diagn Microbial Infect Dis 25:183-190. Wood GM, Johnson BC, McCormack JG (1996) Moraxella catarrkalis: Pathogenic significance in respiratory tract infections treated by community practitioners. Clin Infect Dis 22:632-636.