The growing problem of antibiotic resistance:
Are we on the verge of a medical disaster?

TINA Q. TAN, MD

aSpring 1999

"Drug-resistant germ shows up in U. S." | "Staph germ resists potent drug" | "Resistant staph germ found in U. S." | "Hospitals under siege: Emerging drug-resistant pathogens."

News bulletins with headlines like these are showing up frequently in popular magazines, newspapers, and medical journals. The stories also are reported on television, radio, and on the Internet. They all emphasize a rapidly growing problem in medicine today—the development of antibiotic resistance among microorganisms, especially those that commonly cause infections in the pediatric population. And the concern is justifiable.

Until very recently, pharmaceutical companies have been able to produce a succession of new, more potent, broad-spectrum antibiotics that cured infections due to various microorganisms and saved the lives of countless patients—a far cry from the days when penicillin was the only antibiotic available. However, this success is now being seen as coming with a price—the growing number of antibiotic-resistant organisms brought about by the widespread, and sometimes inordinate, use of antibiotics.

Two misconceptions are commonly found in the medical community regarding antibiotic resistance: 1) resistant organisms are found only in certain communities and 2) if a patient develops a resistant infection, there are plenty of other antibiotics available for treatment. Bacterial resistance creates clinical problems and therapeutic dilemmas for all physicians—whether they are hospital- or office-based, or whether they practice in the city, the suburbs or in rural areas. And nosocomial pathogens are not the only culprits; bacteria that cause the common infections seen daily by practicing clinicians are also involved.

THE ORGANISMS CAUSING THE MOST PROBLEMS

To understand the magnitude of this problem, it is important to understand how antibiotic resistance is defined, what the mechanisms are by which various microorganisms develop antibiotic resistance, and the frequency with which antibiotic-resistant infections are seen. The following highlights several of the most problematic organisms.

Streptococcus pneumoniae

With the successful implementation of the conjugated H. influenzae type b vaccine and the virtual disappearance of invasive H. influenzae type b disease, Streptococcus pneumoniae has become the major bacterial pathogen causing otitis media, pneumonia, meningitis, and other serious infections in children. Unfortunately, infections due to antibiotic-resistant strains of pneumococci are becoming more common, and infections caused by highly resistant strains are being seen more frequently.

Clinical isolates of penicillin-resistant pneumococcus were first recognized in the United States in 1974,¹ and since that time resistant isolates of this organism have been found worldwide, with the prevalence of infections due to resistant strains rapidly increasing.^1–4 Pneumococcal resistance is mediated by changes in its penicillin-binding proteins (PBPs). These are a set of six cell-membrane-bound proteins that are found in all pneumococci and function in cell-wall synthesis. Penicillin and other ß-lactam antibiotics destroy bacteria by entering the bacterium and binding to the PBPs leading to inhibition of cell-wall synthesis and death of the bacterium. Resistance develops when the bacterium’s PBPs are structurally altered or when certain PBPs are not present, leading to poor binding of the antibiotic to the bacterial PBPs and decreased effectiveness of the antibiotic (Figure 1). Pneumococci are able to develop resistance by acquiring fragments of DNA from other bacterial species, most commonly the viridans streptococci, which they incorporate into their genetic material. This leads to the alterations in the PBPs and the development of antibiotic resistance.⁵

Susceptibility of S. pneumoniae to penicillin and cephalosporins is based on the guidelines for breakpoints established by the National Committee for Clinical Laboratory Standards (NCCLS).⁶ Pneumococcal isolates that have a minimum inhibitory concentration to penicillin of <0.06 mg/mL are considered susceptible; MIC between 0.1 and 1.0 mg/mL, intermediate; and MIC >2.0 mg/mL, highly resistant. Isolates with an MIC to ceftriaxone of >0.5 mg/mL are susceptible; MIC = 1.0 mg/mL, intermediate; and MIC >2.0 mg/mL, resistant.

Surveillance studies have been performed in the United States in order to obtain a better idea of the prevalence of infection and the degree of resistance of this organism.^3,4,7 In a 1994–1995 surveillance study of 1,527 pneumococcal respiratory isolates from pediatric and adult outpatients obtained from 30 medical centers across the United States, researchers found that 23.6% of the isolates had some degree of resistance to penicillin, with one in three of those strains demonstrating high levels of penicillin resistance. Other investigators with the U.S. Pediatric Multicenter Pneumococcal Surveillance Group⁷ assessed the susceptibility of 1,291 systemic pneumococcal isolates from 1993 to 1996, from eight children’s hospitals nationwide and found that 21% of the isolates were resistant to penicillin, and 9.3% were resistant to ceftriaxone. Over the three-year study period, the percent resistant to penicillin and ceftriaxone increased from 14% to 21% and from 2.6% to 9.3%, respectively.

In a study to assess penicillin resistance and susceptibiltiy of pneumococci throughout diverse geographic sites within the U.S.,⁴ 1,627 pneumococcal isolates were collected by 30 medical centers nationwide over a four-month period in 1994. The overall penicillin resistance ranged from 4% to 48% of isolates, demonstrating the variability that exists nationwide. Underscoring the trend of increasing resistance, a 1997 surveillance study of 1,476 pneumococcal isolates found that 50.4% were either penicillin-intermediate (17.9%) or highly penicillin-resistant (32.5%).⁸

In the Chicago area, the pneumococcal resistance rate for sterile site isolates has been increasing steadily over the last five years. In 1994 the resistance rate was 12%, had increased to 21.5% in 1995, and was up to 24% in 1996. By 1997 the rate had jumped to 32%, and in 1998 the rate dramatically increased to 44%. More than 10% of these isolates have a high level of resistance to penicillin, with MIC values >2.0 mg/mL. We have also experienced an increase in the number of isolates that are resistant to the third-generation cephalosporins. In 1994, no isolates were found to be resistant to ceftriaxone; however, the current ceftriaxone resistance rate among pneumococcal isolates is 12 to 15%.

Clinically, the optimal treatment regimen for infections caused by penicillin-resistant pneumococci is unknown. Current recommendations suggest that for infections caused by intermediately resistant and even for some highly penicillin-resistant pneumococci outside of the central nervous system, the patient can be treated effectively with penicillin and other ß-lactam antibiotics.^9–11 For meningitis or for other serious infections caused by pneumococci that are highly resistant to penicillin and to the third-generation cephalosporins, current recommendations suggest the use of combination therapy with a third-generation cephalosporin plus vancomycin, with or without rifampin, or the use of a carbapenem antibiotic—meropenem or imipenem.¹¹ For otitis media, there are no clear answers. Studies have shown that none of the oral cephalosporins provide consistent activity against penicillin-resistant pneumococci, and these organisms are often resistant to other commonly used antibiotics such as erythromycin and trimethoprim-sulfamethoxazole. Even though high-dose amoxicillin is still recommended as first-line therapy, the optimal second-line agent for these organisms is unclear.

Staphylococcus aureus

Methicillin-resistant strains of S. aureus (MRSA) emerged in the late 1970s, and infections due to these organisms have become increasely prevalent especially in patients with underlying risk factors, such as dialysis, malignancy, chronic liver, lung, or vascular disease, or prolonged exposure to antibiotics. Being in a hospital or a long-term care facility is also a factor. Once thought to be primarily a nosocomial pathogen, with community-acquired disease occurring in patients with predisposing risks factors (or only sporadically occurring in children with no risk factors), MRSA infections in children with no identifiable predisposing risk factors have been recognized as causing a substantial increase in community-acquired infections.

In a study to confirm this, researchers found that the number of children hospitalized with community-acquired MRSA disease increased from eight in 1988–1990 to 35 in 1993–1995, with the prevalence of community-acquired MRSA without identified risk increasing from 10 per 100,000 admissions in 1988–1990 to 259 per 100,000 admissions in 1993–1995, p<0.001. The investigators concluded from these findings that the prevalence of community-acquired MRSA infection among Chicago children without identified risk factors is increasing.¹²

Methicillin-resistant Staphylococcus aureus develops resistance to antibiotics through the production of ß-lactamases, which are enzymes that disrupt the ß-lactam ring structure of the ß-lactam antibiotics, and through the production of a unique pencillin-binding protein that has a low binding affinity for the ß-lactam antibiotics.

The optimal therapeutic regimen for infections caused by MRSA is unknown, but vancomycin is the drug of choice for the therapy of serious infections caused by MRSA. Beyond this, therapeutic options are limited. The increasing prevalence of community-acquired MRSA infections in children without risk factors may lead us to rethink our initial antibiotic options when a patient presents with a presumed S. aureus infection. Clindamycin is a drug to which most community-acquired isolates of MRSA have been susceptible and may be used as an alternative drug to vancomycin for the initial therapy of community-acquired infections caused by S. aureus in areas where MRSA infections are prevalent. Other antibiotic regimens that may be effective in the treatment of minor soft tissue infections (cellulitis, paronychia) due to MRSA include oral rifampin, trimethoprim-sulfamethoxazole, and topical bacitracin; topical mupirocin and oral ciprofloxacin; and oral rifampin and mupirocin.

A disturbing scenario that has emerged in the last two years is the identification of small numbers of patients with infections due to isolates of S. aureus that are resistant to Vancomycin.¹³ These clinical isolates may be increasing, and experts have strongly suggested that vancomycin not be used routinely for the treatment of infections due to methicillin-susceptible staphylococci. Neither should it be used as empiric therapy for presumed S. aureus infection until susceptibilities are known because its unnecessary use increases the chances that more vancomycin-resistant isolates will occur.

Enterococci

These organisms are common inhabitants of the gastrointestinal tract and make up a large part of the normal gut flora; however, they have also become a common nosocomial pathogen. Risk factors for acquiring nosocomial enterococcal infections include serious underlying disease, long hospital stays, prior surgery, renal insufficiency, indwelling urinary or vascular catheters, and prolonged stays in an intensive care unit.

Optimal therapy for serious infections due to these organisms is a synergistic combination of ampicillin, piperacillin or vancomycin plus gentamicin, because these organisms are intrinsically resistant to most other agents. Gentamicin alone is not very active against enterococci; however, if the MIC for gentamicin is <500 mg/mL, it will act synergistically with ampicillin, piperacillin or vancomycin, whereas if the MIC is >2000 mg/mL, it will not be active.

Since the mid 1980s the emergence of vancomycin-resistant enterococci (VRE) has created a significant problem and has caused enormous concern given the limited number of antibiotics that act against this organism. Data obtained from U.S. hospitals indicates that in 1989, VRE accounted for 0.3% of nosocomial enterococcal infections in the U.S. By 1993, VRE strains accounted for 7.9% of nosocomial isolates and almost 14% of enterococcal isolates from ICU patients.¹⁴

Enterococci develop resistance to antibiotics by several different mechanisms. Resistance to ampicillin occurs by through the production of ß-lactamases and/or through changes in its penicillin-binding proteins. Vancomycin resistance develops through changes in the organism's site on which the antibiotic binds, causing a decrease in the affinity of binding, and gentamicin resistance is mediated by aminoglycoside-modifying enzymes that inactivate the antibiotic.¹⁴

The major concern for the practicing pediatrician with regards to VRE is the fear that enterococcal vancomycin-resistant genes will spread to other gram-positive bacteria, most notably S. pneumoniae and S. aureus, through the transfer of genetic material from one species to another. If these common pediatric pathogens are already resistant to other antibiotics and were to become resistant to vancomycin, practicing pediatricians would be left without an effective antibiotic to treat infections due to these common organisms.

Gram-negative organisms

Antibiotic resistance of diarrhea-causing organisms poses an important clinical problem in the pediatric population. Resistance to the antibiotics commonly used to treat Salmonella and Shigella infections—primarily ampicillin, trimethoprim-sulfamethoxazole, and doxycycline—have been reported from many countries, and this has become increasingly important as more and more children travel internationally each year. Thirty-one percent of U.S. Salmonella isolates have some antibiotic resistance; 14% are resistant to ampicillin. Thirty-two percent of U.S. Shigella isolates are ampicillin-resistant; 7% are resistant to TMP-SMX.

Other gram-negative organisms such as Pseudomonas, E. coli, Enterobacter, Klebsiella, and Serratia are nosocomial pathogens that have developed resistance to multiple antibiotics. These organisms have developed ingenious mechanisms of antibiotic resistance. The mechanisms include the production of "extended spectrum" ß-lactamases with the ability to degrade the third-generation cephalosporins and monobactams, the alteration of their outer membrane proteins so that the antibiotic cannot enter the organism, and the production of broad spectrum ß-lactamases that can be induced during a course of therapy with third-generation cephalosporins.¹⁵ Of 129 patients with Enterobacter bacteremia, those who had previously received a third-generation cephalosporin were 3.5 times more likely to have a multiple-resistant organism, and 19% of the patients treated with a third-generation cephalosporin developed resistance during the course of therapy.

Based on data from these and other studies, patients with serious gram-negative infections should be treated with combination therapy rather than with a third-generation cephalosporin alone.

WHAT ROLE CAN YOU PLAY IN THE PREVENTION
OF ANTIBIOTIC RESISTANCE?

Antibiotic resistance is a rapidly growing problem that involves all classes of antibiotics and the multiple microorganims that cause infections seen in children. It has rendered many antibiotics ineffective and threatens our ability to treat common infections. Because of this, multiple organizations on local, state, and national levels have formed task forces involving hospitals, microbiologists, pharmaceutical companies, infectious disease specialists, and practicing primary care physicians. Their major goals are to institute guidelines and recommendations regarding the primary factors influencing the emergence of antibiotic resistance, to develop surveillance strategies for monitoring resistance, to limit the emergence of resistance, and to promote the effective use of antibiotics.

Steps that clinicians can take to help combat and prevent the emergence of resistant infections in your patients are outlined in Table 1. Everyone’s cooperation, including pharmaceutical companies, microbiology laboratories, infection-control practitioners, and practicing clinicians, will be necessary in order to control and stop the continued emergence of antibiotic resistance. Our willingness to work together effectively on this issue will have an enormous impact on our ability to treat countless generations of children in the future.

REFERENCES

1. Appelbaum PC: Antimicrobial resistance in Streptococcus pneumoniae: An overview. Clin Infect Dis. 1992;15:77–83.

2. Tan TQ, Mason Jr EO, Kaplan SL: Systemic infections due to Streptococcus pneumoniae relatively resistant to penicillin in a children’s hospital: Clinical management and outcome. Pediatrics 1992;90:928–933.

3. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklam RR: Emergence of drug-resistant pneumococcal infections in the United States. JAMA 1994; 271:1831–1835.

4. Mason Jr EO, Kaplan SL: Penicillin-resistant pneumococci in the United States. Ped Infect Dis J. 1995;14:1017–1018.

5. Neu HC: The crisis in antibiotic resistance. Science 1992;257: 1064–1073.

6. Minimum Inhibitory Concentration (MIC) Interpretive Standards (mg/mL) for Streptococcus spp. Table 2C. M100-S7. Wayne, PA: National Committee for Clinical Laboratory Standards; 1997:17(2).

7. Kaplan SL, Mason Jr EO, Barson WJ, et al.: Three-year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics 1998;102:538–545.

8. Jacobs MR, Bajaksouzian S, Lin G, et al.: Susceptibility of Streptococcus pneumoniae and Haemophilus influenzae to oral agents: Results of a 1997 epidemiologic study. Poster presented at 98th general meeting of the American Society of Microbiology, May 17–21, 1998, Atlanta, GA.

9. Friedland IR, McCracken Jr, GH: Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med. 1994;331:377–382.

10. Tan TQ, Mason Jr EO, Barson WJ, et al.: Clinical characteristics and outcome of children with pneumonia attributable to penicillin-susceptible and penicillin-nonsusceptible Streptococcus pneumoniae. Pediatrics 1998;102: 1369–1375.

11. American Academy of Pediatrics Committee on Infectious Diseases: Therapy for children with invasive pneumococcal infections. Pediatrics 1997;99:289–299.

12. Herold BC, Immergluck LC, Maranan MC, et al.: Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 1998;279:593–598.

13. Sieradzki K, Roberts RB, Haber SW, Tomasz A: The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus Infection. N Engl J Med. 1999;340:517–523.

14. Eliopoulos GM: Vancomycin-resistant enterococci. Infect Dis Clin North Am. 1997;11:851–861.

15. Sanders CC, Sanders Jr WE: b-Lactam resistance in gram-negative bacteria: Global trends and clinical impact. Clin Infect Dis. 1992;15:824–839.

Copyright © 2008 by Children’s Memorial Hospital. All rights reserved.