PEDIATRIC ASTHMA, ALLERGY & IMMUNOLOGY

Volume 12, Number 4, 1998

Mary Ann Liebert, Inc.

Antibiotic Resistance Changes in Sinusitis

and Otitis Media Pathogens

MICHAEL E. PICHICHERO, M.D.

ABSTRACT

Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis resistance to

traditional first-line antibiotic choices has risen dramatically over the past 5 years. This trend
necessitates a réévaluation of the standard treatment paradigms, as inappropriate antibiotic
use appears to be at least partially responsible for the selection of resistant strains. A prac¬
tical approach may be to estimate the risk that a patient may harbor a resistant organism
as a guide to antibiotic choices. For those at lower risk, continuing to prescribe traditional

therapy such as amoxicillin or trimethoprim-sulfamethoxazole may be appropriate. For

those at higher risk, a broader spectrum agent may be preferred. Empiric antibiotic ther¬
apy may need to give way to pathogen-directed choices in the near future as the complex¬
ity and prevalence of resistant strains continue to rise. Improved microbiologie diagnostic
tools will be needed to face this challenge. (Pediatr Asthma Allergy Immunol 1998;
12[4]:235-240.)

INTRODUCTION
of the major bacterial respiratory pathogens remain fully susceptible to the
A traditional,
diminishing number
first-line antibiotic selections—amoxicillin and trimethoprim-sulfamethoxazole (TMP-
SMX)/1-5' Rates of antimicrobial resistance have risen steadily during the 1990s, both in the United States
and worldwide/3·6-1 " Resistance rates vary geographically and among patient groups but reduced penicillin
and amoxicillin susceptibility among strains of Streptococcus pneumoniae is now more than 30%;
TMP-SMX resistance generally exceeds 50%. Variability in resistance rates among pneumococci to amox¬
icillin and TMP-SMX have begun to collapse with few centers reporting rates of less than 20% and some
reporting rates in excess of 60%.
The proportion of Haemophilus influenzae strains producing /3-lactamase, rendering the organism amox¬
icillin resistant rose during the 1980s to 30% to 40%, and currently appears to be stable, although a few
centers have reported rates in excess of 50%/2-7·"' Among H. influenzae, a new resistance pattern to
TMP-SMX has been rapidly occurring in sporadic locations, with reports of greater than 40% of strains
demonstrating such resistance in some locations/12' Moraxella catarrhalis gained virulence and showed a
rise in resistance to amoxicillin in the 1970s and 1980s to where now 95% to 100% of strains are no longer
susceptible/11'

University of Rochester Medical Center, Elmwood Pediatrie Group, Rochester, New York 14642.

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 PICHICHERO

Although group A streptococcus (GAS) remains exquisitely susceptible to penicillin and cephalosporins,
resistance to erythromycin, clarithromycin, and azithromycin has risen dramatically in several European
countries in the past 2 to 3 years/13·14' The spread of these resistant clones in the United States seems only
a matter of time. Staphylococcus aureus is an uncommon respiratory pathogen, but it must be kept in mind
because it causes serious disease and is resistant to many of the antibiotics commonly employed for respi¬
ratory infections: treatment is increasingly problematic.

MECHANISMS OF RESISTANCE

Respiratory pathogens have developed a number of strategies to resist antimicrobial agents (Table 1 ) and
the mechanism of resistance determines which drugs are affected. Pneumococcal resistance occurs through
alterations in penicillin-binding proteins (PBPs), cell-wall components that are normally the targets for ß-
lactam antibiotics. The ability of the bacteria to prevent antibiotic binding confers resistance to the peni¬
cillins as well as to cephalosporins (to varying degrees depending on the compound). The addition of clavu-
lanate to a treatment regimen offers no additional activity against such organisms. Alterations in PBPs are
chromosomally mediated, meaning that the trait is passed from one generation of the strain to the next.
Pneumococcal resistance, therefore, is likely to persist and escalate over time; unfortunately, this means lit¬
tle chance is seen that these pathogens will spontaneously revert in their drug sensitivity. Furthermore, the
alteration in the PBPs among pneumococcal strains continues to occur in a stepwise fashion that results in
progressive resistance to even higher concentrations of penicillin, amoxicillin, and the cephalosporins.
A second resistance mechanism is production of /3-lactamase, an enzyme that cleaves specific parts of
antibiotic molecules. Amoxicillin and some cephalosporins are inactivated by /3-lactamase; the addition of
clavulanate to amoxicillin allows the maintenance of activity against these pathogens. H. influenzae, M. ca¬
tarrhalis, and S. aureus are all /3-lactamase producers. Bacteria that produce /3-lactamase can interfere with
treatment even when they are not the primary cause of infection. In patients whose symptoms are caused
by /3-lactamase-negative organisms, coexisting /3-lactamase-positive bacteria may "shield" these otherwise
drug-susceptible pathogens from penicillins/15'
Sensitivity to several classes of antibiotics has been compromised through other mechanisms of resis¬
tance. Certain streptococci produce an enzyme that dimethylates a specific residue in their ribosomal RNA,
which is the binding target for macrolides (erythromycin, clarithromycin, and azithromycin). The di-
methylation confers resistance by preventing the drugs from binding to their target sites. A relatively newly
discovered, rapidly spreading mechanism of resistance involves antibiotic efflux pumps whereby the bac¬
terial strain effectively pumps the antibiotic out of the cell before an antibacterial effect is achieved/16' A

Table 1. Mechanisms of Bacterial Resistance

Alteration in target antibiotic-binding proteins

-Organism: Streptococcus pneumoniae
-Antibiotics affected: Penicillin
Amoxicillin (clavulanate offers no additional activity)
Cephalosporins (variability depending on the drug)
Production of /8-lactamase
-Organism: Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
-Antibiotics affected: Amoxicillin
Cephalosporins (variability depending on the drug)
Transformation of new gentic material
-Organism: S. pneumoniae
-Antibiotics affected: Macrolides
Fluoroquinolones

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 ANTIBIOTIC-RESISTANT PATHOGENS

Table 2. Current Breakpoints for Penicillin Resistance*

Oxacillin screen
Minimum inhibitory concentrations (1-p.g oxacillin disk)
Susceptible <0.06 /ig/mL >20 mm
Relatively resistant 0.12-1.0 /xg/mL <19 mm1'
Resistant >2.0 µg/mL <19 mm+

*National Committee on Clinical Labaoratory Standards.

+Test does not distinguish between resistant and relatively resistant strains.

number of "respiratory" fluoroquinolones have recently become available and they are under study in pe¬
diatrie patients. These new drugs are active against otherwise resistant pneumococci. It remains unclear at
this time whether widespread use will lead to resistance to these agents. The production of DNA gyrase,
which inactivates fluoroquinolones, can occur rapidly, even during a short course of therapy.

Streptococcus pneumoniae
Minimum inhibitory concentration (MIC) breakpoints for pneumococci causing meningitis were estab¬
lished by the National Committee on Clinical Laboratory Standards (NCCLS)(17) (Table 2). The breakpoints
were based on the levels of penicillin achievable in cerebrospinal fluid and on the drug concentrations re¬

quired to eradicate the pneumococcus in vitro. Pneumococci are classified as susceptible to penicillin if the
MIC of penicillin for the bacterial strain is less than 0.06 µg/mL. Relatively or intermediately resistant
strains are those that have a MIC of 0.12 to 1.0 yu,g/mL. Highly resistant strains have a MIC greater than 2
/Lig/mL for penicillin.
The applicability of the NCCLS breakpoints to respiratory infections is debatable. In the case of pneu¬
mococcal pneumonia, for example, penicillin or ampicillin concentrations in lung tissue can reach 4 to 8
/xg/mL, which is well in excess of the level needed to kill a strain labeled "resistant" (>2 ^,g/mL). Bacte¬
rial eradication is somewhat more difficult in closed-space infections such as sinusitis and otitis media, but
strains that are defined as "relatively" resistant in a meningitis model—even some of those defined as fully
resistant—can be successfully treated with amoxicillin and many cephalosporins because these antibiotics
reach much higher bactericidal levels in the sinuses and middle ear than achievable in the cerebrospinal
fluid.
Nevertheless, alterations in PBPs continue to develop in a progressive stepwise fashion, so that strains
continue to change their degree of susceptibility. Thus, resistant strains continue to modify their PBPs,
thereby causing the emergence of even more highly resistant strains. Whereas fully resistant strains repre¬
sented only 5% of all S. pneumoniae isolates in the United States in 1988-89, they accounted for nearly
half of all resistant S. pneumoniae isolates by 1997 (Table 2).(]~3-liJ9) It can be expected that both the per-

Table 3. Recent Trends in Penicillin Resistance Among Streptococcus pneumoniae in the United States

Resistance
(%)
Strains
Reference Years (No.) Intermediate High Total

Jorgensen et al., 1990 (1) 1988-1989 476 3.8 0.2 4.0

Thornsberry et al. (1992 (2) 1990-1991 524 15.2 2.6 17.8
Barry et al., 1994 (3) 1992-1993 799 14.9 7.3 22.2
Doernet al., 1996(18) 1994-1995 1527 14.1 9.5 23.6
Doernet al., 1998 (19) 1997 1047 27.8 16.0 43.8

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 PICHICHERO

centage of resistant strains and the percentage that are fully resistant will continue to increase into the next
decade.
A growing issue in treating pneumococcal infections is the emergence of multiple resistant strains. Iso¬
lates resistant to multiple antibiotics were first described in Europe, South Africa, and Southeast Asia; now
these strains are in the United States/19' Drugs that no longer have activity against some penicillin-resis¬
tant strains of S. pneumoniae include certain cephalosporins, TMP-SMX, and the macrolides. Pneumococ¬
cal resistance to both macrolides and penicillin is particularly troubling. In the 1980s, virtually no resis¬
tance was found to the macrolides, even among strains that displayed some changes in their penicillin
susceptibility. However, data from 1997 indicate that fully 25% of S. pneumoniae isolates with intermedi¬
ate penicillin resistance also show resistance to the macrolides/20'
Resistance to the macrolides does not develop in a stepwise fashion as it does with the penicillins and
cephalosporins in S. pneumoniae. Isolates are either fully resistant or fully susceptible. Also, complete cross-
resistance among the macrolides seems to occur, thereby causing the loss of not only erythromycin but also
clarithromycin and azithromycin/21' The trend of increased macrolide resistance has occurred in a time
frame of increased macrolide consumption; as with the fluoroquinolones, macrolides seem to allow the
emergence of resistant strains if used to excess.
Resistance to TMP-SMX among S. pneumoniae also is a rapidly developing problem. In the late 1980s,
less than 1% of pneumococci in the United States were resistant to TMP-SMX. A Boston hospital group
described a 12% resistance rate in 1991/22' which seemed an isolated problem. However, by 1997, the na¬
tional average was 20% of S. pneumoniae resistant to TMP-SMX/19'

Haemophilus influenzae
Approximately 30% to 40% of H. influenzae strains are /3-lactamase producers. Unfortunately, resistance
to other agents also seems to be on the rise. In 1993, only 1% to 12% of strains were resistant to TMP-SMX,
but just 2 years later, frequencies were in the range of 5% to 30%, and current reports cite rates as high as
30% to 60% Z10·23·24' Despite the attraction of TMP-SMX as an inexpensive, easily dosed treatment for res¬
piratory infections, the rapidly rising rates of resistance now suggest that this drug combination cannot be
considered a viable alternative to amoxicillin in many patients.

Moraxella catarrhalis
Virtually all M. catarrhalis produce /3-lactamase, thereby rendering these organisms resistant to amoxi¬
cillin and relatively to some cephalosporins/5' M. catarrhalis can also play an indirect pathogenic role when
it causes infection with S. pneumoniae/25)

IMPACT OF ANTIBIOTICS ON RESISTANCE PATTERNS

Although antibiotics generally do not cause the genetic changes that produce antimicrobial resistance,
excessive or inappropriate use of these drugs appears to confer a selective advantage for organisms that al¬
ready carry such changes in their genomes (either because they developed spontaneously or were acquired
from other bacteria). Drug-resistant organisms are not at a reproductive advantage compared with normal
types, but elimination of the normal flora by antimicrobials may allow preferential colonization and sub¬
sequent disease by these drug-resistant strains/26'

Table 4. Risk Factors for Infection with Resistant Respiratory Pathogens

Antibiotic use in the preceding month

Infection during late winter or spring months
Infection while on antibiotic prophylaxis
Age <2 years
Day care attendance

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 ANTIBIOTIC-RESISTANT PATHOGENS

HIGHER VERSUS LOWER RISK FOR ANTIBIOTIC RESISTANCE

As resistance frequencies change, it may be necessary to modify established prescribing habits. Clinical de¬
cisions should be based on local drug resistance patterns, as they vary geographically and temporally among
community-acquired pathogens. Changes are occurring rapidly. Rates of resistance have even been shown to
vary with the season/27' More /3-lactamase-producing strains and penicillin-resistant pneumococci are recov¬
ered during the winter than in the summer, a variation which may be the result of exposure to /3-lactam an¬
tibiotics. An increase in the rate of /3-lactamase production among the flora of the upper respiratory tract has
been described to follow the common practice of using amoxicillin for prophylaxis in children susceptible to
otitis media(28)—a strategy that may need to be reconsidered. A pragmatic approach to respiratory infections
may be to estimate the patient's risk of harboring a drug-resistant strain (Table 4). Patients at low risk of hav¬
ing a drug-resistant pathogen should receive traditional first-line therapy such as amoxicillin or TMP-SMX.
Those who are at higher risk should receive empiric therapy with a broader spectrum agent. Patients at high
risk include those who have received recent /3-lactam antibiotic treatment, multiple antibiotic courses, or pro¬
phylactic antibiotics. Patients can also be at risk if they are merely exposed to a high-risk individual, as in a
day care center, because resistant pathogens can be passed easily from person to person in such settings. Pre¬
scribing one of the newer, extended-spectrum agents for treating otitis media or sinusitis should take into ac¬
count not only local resistance patterns, but ease of compliance, toxicity profile, and cost/29·30'

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Address reprint requests to:
Michael E. Pichichero, M.D.
Professor of Microbiology and Immunology, Pediatrics and Medicine
University of Rochester Medical Center
Elmwood Pediatrie Group
601 Elmwood Avenue, Box 672
Rochester, NY 14642

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