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Resistance Patterns Among Nosocomial Pathogens^*

Trends Over the Past Few Years

^* From the Department of Pathology, University of Iowa College of Medicine, Iowa City, IA.

Correspondence to: Ronald N. Jones, MD, The Jones Group, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317

	Abstract

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 
Multiple surveillance studies have demonstrated that resistance among prevalent pathogens is increasing at an alarming rate, leading to greater patient morbidity and mortality from nosocomial infections. Among Gram-positive organisms, the most important resistant pathogens are methicillin- (oxacillin-)resistant Staphylococcus aureus, ß-lactam-resistant and multidrug-resistant pneumococci, and vancomycin-resistant enterococci. Important causes of Gram-negative resistance include extended-spectrum ß-lactamases (ESBLs) in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis, high-level third-generation cephalosporin (Amp C) ß-lactamase resistance among Enterobacter species and Citrobacter freundii, and multidrug-resistance genes observed in Pseudomonas aeruginosa, Acinetobacter, and Stenotrophomonas maltophilia. In selecting an empiric treatment for a nosocomial infection, one should consider the prevalent resistance patterns. Antimicrobials used for the treatment of nosocomial infections should be effective against any likely resistant pathogens and should not further promote the development of resistance. Recent data suggest that because of ESBLs and high-level amp C ß-lactamase resistances, use of third-generation cephalosporins may be ineffective in many patients with nosocomial infections. In addition, use of these agents may allow overgrowth of inherently resistant enterococci. The role of fluoroquinolones in the empiric treatment of nosocomial infections is also being limited by new resistance patterns and increasing resistance levels. Available antimicrobials with good activity against many resistant pathogens include the carbapenems, piperacillin/tazobactam, and cefepime. In addition, several new agents with good activity against Gram-positive organisms are in development or have been recently released. Appropriate antimicrobial selection, surveillance systems, and effective infection-control procedures are key partners in limiting antimicrobial-resistant pathogen occurrence and spread.

Key Words: antibiotic resistance • antibiotics • cephalosporins • enterococci • fluoroquinolones • methicillin-resistant Staphylococcus aureus • nosocomial infections • penicillins • pneumococci

	Introduction

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 
Over the past several decades, the frequency of antimicrobial resistance and its association with serious infectious diseases have increased at alarming rates. The increasing resistance rate among nosocomial pathogens is particularly disconcerting. Of the > 2 million nosocomial infections occurring each year in the United States, 50 to 60% are caused by antimicrobial-resistant strains of bacteria.¹ This high rate of resistance increases the morbidity, mortality, and costs associated with nosocomial infections.² In the United States, nosocomial infections are thought to contribute to or cause > 77,000 deaths per year and cost approximately $5 to $10 billion annually.^{1 2 3}

Expert panels have concluded that surveillance networks, education of health-care providers and the public, and basic research directed toward development of new methods of infection treatment and prevention are required to address the problem of antimicrobial resistance.⁴ This review will summarize the recent findings of several surveillance networks and discuss the impact of current patterns of antimicrobial resistance on the selection of antimicrobials for the empiric therapy of nosocomial infections, particularly lower-respiratory-tract infections.

	Trends in Nosocomial Infections

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 
Numerous surveillance studies have documented trends in nosocomial infections that might affect resistance patterns. For example, the National Nosocomial Infections Surveillance group¹ found that from 1975 to 1996, the percentage of nosocomial infections that occurred in the lower respiratory tract or bloodstream increased while the percentage that occurred in the urinary tract or in surgical wounds decreased. From 1990 to 1996, the lower respiratory tract and the bloodstream were sites of nosocomial infections 13% and 14% of the time, respectively. This indicates a greater shift toward more severely ill patients, as well as the positive impact of infection control in limiting urinary tract and postoperative infections in those who are hospitalized.

Changes in the types of pathogens isolated in serious infections might also affect resistance patterns because different bacterial species inherently have differing antimicrobial susceptibilities.⁴ The European Organization for Research and Treatment of Cancer trials, which were performed between 1973 and 1994, documented trends in the types of pathogens isolated from oncology patients with febrile morbidities. While Gram-negative pathogens were the dominant bloodstream isolates from 1973 to 1985, Gram-positive isolates were more common in later years.⁵ This change in pathogen dominance coincided with the 1985 introduction of the third-generation cephalosporins ceftazidime and ceftriaxone and was probably driven by the widespread use of these drugs.⁶ The European Organization for Research and Treatment of Cancer trials also documented changes in the species of Gram-positive organisms that were isolated. Over time, a larger percentage of the Gram-positive organisms isolated were Streptococcus, particularly ß-hemolytic streptococci and viridans groups, replacing formerly more commonplace staphylococcal isolates.^{5 6 7}

The international SENTRY Antimicrobial Surveillance Program⁸ is also documenting trends in the occurrence of pathogens that are related to altered resistance patterns. This program, which was initiated in 1997 and has > 70 sites worldwide, is a longitudinal surveillance program designed to track antimicrobial resistance patterns of nosocomial and community-acquired infections. As shown in Table 1 , the program reported that Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae were the most common causes of pneumonia in hospitalized patients in North America in 1997 (R.N. Jones, MD; unpublished data; 2000). Acinetobacter, an organism that has been particularly problematic in Latin America—where it is the third-most-prevalent pathogen—because of the high frequency at which it is isolated and its high rate of resistance,⁹ was ranked as the 10th most common cause of pneumonia in hospitalized patients in the United States and Canada. The SENTRY Antimicrobial Surveillance Program also found that S aureus, Escherichia coli, coagulase-negative staphylococci, Enterococcus, Klebsiella, Streptococcus pneumoniae, P aeruginosa, Enterobacter, ß-hemolytic streptococci, and Acinetobacter were the 10 most common bacterial pathogens responsible for bloodstream infections in the United States and Canada in 1997.

	Gram-Positive Resistance

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

	Enterococcal Resistance

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 
Enterococcal antimicrobial resistance, particularly VRE, is a serious concern. Multiple vancomycin resistance phenotypes have been identified, including van A, van B, and van C. The van A gene, which is often plasmid borne, confers high-level resistance to vancomycin and can be transferred to other micro-organisms.¹² The rate of vancomycin resistance varies among enterococcal species and is most common among Enterococcus faecium.⁴ Studies^{8 11 13} have documented that VRE are most commonly isolated from highly compromised patients, such as those in the ICU.

Other types of enterococcal resistance include ß-lactamase-mediated resistance, ampicillin resistance based on altered penicillin-binding proteins (PBPs), and high-level aminoglycoside resistance. Among enterococcal organisms, ß-lactamase-mediated resistance is currently very rare ( 0.1%). Ampicillin resistance owing to PBP changes is much more common and occurs in > 80% of E faecium clinical isolates and in < 5% of Enterococcus faecalis. While the rate of high-level aminoglycoside resistance varies markedly among institutions, the nationwide prevalence is estimated at 30 to 60%. Some enterococcal species are also highly resistant to macrolides, fluoroquinolones, tetracyclines, and carbapenems.^{4 10}

Table 2 shows the resistance patterns of various enterococcal species as reported by the Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE) program.⁴ E faecalis, which causes approximately 60% of nosocomial bloodstream infections, is associated with low rates of vancomycin, teicoplanin, and penicillin resistance and higher rates of gentamicin resistance. E faecium, which causes approximately 20% of nosocomial enterococcal bloodstream infections, is much more commonly associated with vancomycin, teicoplanin, penicillin, and high-level gentamicin resistance. Greater than 85% of E faecium isolates are resistant to penicillin, and > 50% are resistant to high-level gentamicin. The highest rates of enterococcal resistance were reported with Enterococcus raffinosus, which fortunately is rarely isolated.⁴ While no resistance was noted among some uncommon enterococcal species in the SCOPE study, vancomycin resistance genes from E faecium and E faecalis have been shown to transfer to other rare enterococcal species; however, it is important to note that identification of such rare species may be difficult using commercial identification systems.¹⁴

The rate of VRE occurrence is also influenced by the site of infection. Among US centers that participated in the 1997 SENTRY Antimicrobial Surveillance Program, the rate of VRE was 19.3%, 16.3%, 8.7%, and 6.1% in wound, bloodstream, lung (pneumonia), and urinary tract infections, respectively (R.N. Jones, MD; unpublished data; 1999). Although the rate of resistance in urinary tract infections was low, the greatest absolute number of VRE strains were isolated from the urine because enterococcal urinary tract infections are so common.

Since VRE infections are associated with much higher morbidity and mortality than are vancomycin-sensitive enterococcal infections,¹⁵ and since vancomycin resistance genes may be transmitted to other species,¹⁶ it is important to limit VRE. Recommendations for controlling vancomycin resistance include reducing the use of drugs known to increase the risk of enterococcal infection (eg, third-generation cephalosporins), limiting vancomycin use, applying accurate microbiological identification methods and susceptibility testing methods, conducting epidemiologic surveillance, using barrier precautions, and maintaining strict hand-washing policies.^{4 12} Empiric treatment of nosocomial infections with broad-spectrum agents that provide good enterococcal coverage (eg, a penicillin with a ß-lactamase inhibitor such as piperacillin/tazobactam), may decrease the risk of enterococcal colonization and resistance. It is important to note, however, that the antimicrobial activity of penicillins against enterococcal species varies: penicillin, ampicillin, and piperacillin are much more active than ticarcillin.^{17 18}

	Pneumococcal Resistance

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 
The rate of penicillin resistance among pneumococci has reached crisis proportions. Treatment of pneumococcal infections is further complicated by an increasing rate of resistance to macrolides, cephalosporins, chloramphenicol, tetracyclines, trimethoprim/sulfamethoxazole, and most recently fluoroquinolones.^{19 20} Penicillin and cephalosporin resistance is mediated by multiple alterations in PBPs. Depending on the targeted PBP, penicillin-resistant organisms may or may not be susceptible to other ß-lactams. Table 3 provides the penicillin susceptibility pattern obtained in the SENTRY Antimicrobial Surveillance Program of S pneumoniae isolates to several antimicrobial agents.²¹

	Staphylococcal Resistance

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 
Since staphylococci are commonly responsible for nosocomial infections, particularly pneumonia, resistance among these organisms is also a major concern.¹ Both methicillin (or oxacillin) and glycopeptide (vancomycin and teicoplanin) resistance may occur in staphylococci. A European study demonstrated that 50% of the infectious morbidity in ICUs can be attributed to MRSA or coagulase-negative staphylococci.^{13 24}

Currently, the most prevalent type of resistance among staphylococci is methicillin resistance. This resistance is encoded genetically by mec A, which produces an altered PBP target.⁴ In the 1997 SENTRY program, MRSA was isolated from 26.9%, 49.8%, 29.0%, and 48.0%, of hospitalized patients in the United States with bloodstream, pneumonia, wound, and urinary tract infections, respectively (R.N. Jones, MD; unpublished data; 1999). While the rates of resistance were much lower in Canada, they were substantially higher in Latin America. The relatively low rate of MRSA in Canada is likely the result of formulary controls limiting the choice of available antimicrobials; superior infection control practices also appeared to play a significant role.

Since MRSA is also resistant to many other antimicrobials, both ß-lactams and non-ß-lactams,⁸ vancomycin is generally relied on for the treatment of MRSA infections. However, the expanded use of vancomycin has led to the emergence of other resistance problems.^{4 25} Similarly, when ciprofloxacin was initially introduced to the market, it was highly effective against MRSA. However, almost immediately after release by the US Food and Drug Administration, studies in the United States showed significant increases in the minimum inhibitory concentrations of ciprofloxacin against staphylococci, especially against MRSA.²⁶

The rare reports of glycopeptide-resistant S aureus are also alarming. Teicoplanin-resistant coagulase-negative staphylococci were first reported in 1985; in 1987, vancomycin-resistant coagulase-negative staphylococci were reported.⁷ Since the initial report from Japan in 1997,²⁵ many other groups from around the world have reported strains of S aureus with intermediate resistance to vancomycin. All of the reported cases occurred in patients who had prolonged (> 1 month) exposure to vancomycin.

	Gram-Negative Resistance

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 
Antimicrobial resistance among Gram-negative organisms is also a concern. The most important Gram-negative resistance problems that impact on nosocomial infections are extended-spectrum ß-lactamases (ESBLs) in Klebsiella pneumoniae, E coli, and Proteus mirabilis; high-level third-generation cephalosporin (Amp C) ß-lactamase resistance among Enterobacter and Citrobacter freundii; and multidrug-resistant P aeruginosa, Acinetobacter, and Stenotrophomonas maltophilia.⁴ The treatment of respiratory tract infections is also complicated by ß-lactamase production among H influenzae and Moraxella catarrhalis.⁴ However, over the past 3 to 5 years, the rates of resistance of H influenzae and M catarrhalis have remained stable at approximately 33% and 90%, respectively.²⁴

While the rate of K pneumoniae resistance to third-generation and fourth-generation cephalosporins due to ESBLs is also fairly stable, it remains an important problem in patients with nosocomial infections.⁴ In 1997, the SENTRY Antimicrobial Surveillance Program found that, among K pneumoniae strains isolated in the United States, the resistance rates to ceftazidime (as well as ceftriaxone and cefotaxime) were 6.6%, 9.7%, 5.4%, and 3.6% for bloodstream, pneumonia, wound, and urinary tract infections, respectively (R.N. Jones, MD; unpublished data; 1999). Substantially higher resistance rates were noted in some of the individual hospitals enrolled in the study, and resistance rates of 30 to 50% were observed in the Latin American institutions studied.⁹ Also, resistance of K pneumoniae strains to ceftriaxone has been reported in epidemics.^{27 28}

Alternative antimicrobials that may be considered for use in patients with infections due to ESBL-producing strains of K pneumoniae include ß-lactamase inhibitor combinations, such as piperacillin/tazobactam, and carbapenems.⁴ Cross-resistance may limit the value of aminoglycosides, tetracyclines, and trimethoprim/sulfamethoxazole in these types of infections.⁴ Fluoroquinolone resistance is also increasing among these ESBL strains.

High-level amp C ß-lactamase resistance should also be considered when treating nosocomial infections. In 1997, the SENTRY Antimicrobial Surveillance Program noted that among Enterobacter cloacae bloodstream strains isolated in the United States, the resistance rate to ceftazidime was 21.6%.⁶ These rates reflected a stabilization of the prevalence of high-level amp C ß-lactamase resistance among E cloacae. The corresponding resistance rate for cefepime was only 0.5%, the same as imipenem.⁶ Therefore, these newer ß-lactams may have some utility in the treatment of infections due to amp C enzyme-producing resistant organisms. Other agents with activity against these resistant organisms include meropenem, other carbapenems, aminoglycosides, and fluoroquinolones.^{4 6}

The rate of fluoroquinolone resistance among Gram-negative organisms continues to escalate. In the 1997 SENTRY Antimicrobial Surveillance Program, 2.1% of E coli, 13.3% of P aeruginosa, 24.1% of Acinetobacter, and 48.5% of S maltophilia isolates obtained in the United States were resistant to ciprofloxacin.⁶ Furthermore, in the subgroup of patients with lower-respiratory-tract infections, 1.1% of E coli, 16.3% of P aeruginosa, 37.7% of Acinetobacter, and 42.7% of S maltophilia isolates from the United States and Canada were resistant to ciprofloxacin (R.N. Jones; unpublished data, 1999). The rates of ciprofloxacin resistance are substantially higher in Latin America. In addition, the 1998 SENTRY Antimicrobial Surveillance Program data demonstrate that an even higher percentage of P aeruginosa strains isolated from lower-respiratory-tract infections are resistant to the newer fluoroquinolones (R.N. Jones; unpublished data, 2000).

Table 4 demonstrates the in vitro susceptibility of P aeruginosa to other classes of antimicrobials. Of the various cell wall inhibitors examined, piperacillin/tazobactam had the lowest level of resistance. Ticarcillin/clavulanate was less effective than piperacillin/tazobactam, confirming earlier results.^{17 18} Among the protein synthesis inhibitors, amikacin appeared to be the agent with the lowest level of P aeruginosa resistance.

	New Antimicrobials

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

	Conclusion

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

There are, however, some antimicrobials with good activity against resistant organisms. For example, the carbapenems, piperacillin/tazobactam, and cefepime cover methicillin-susceptible staphylococci, most streptococci, nearly all enterobacteriaceae, and significant numbers of P aeruginosa, S maltophilia, and Acinetobacter, as indicated by data⁸ from North America.

When selecting empiric antimicrobial therapy for nosocomial infections, combinations of drugs that provide effective broad Gram-negative activity and focused Gram-positive activity, as demonstrated by local antimicrobial surveillance, seem preferred. Careful drug selection coupled with surveillance and effective infection control procedures may help control pathogen resistance.

	Appendix 1

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 
Dr. Thomas File: Do you support the use of disease-based breakpoints? For example, using a breakpoint of 2 mg/L for S pneumoniae isolates responsible for pneumonia?

Dr. Ronald Jones:
Yes, I think in the near future the National Committee for Clinical Laboratory Standards will recommend that the current system for pneumonia, which bases all breakpoints on the treatment of a closed-space infection (eg, meningitis), will be replaced by a system that includes multiple disease-based breakpoints. Based on the available data, a breakpoint of 2 mg/L—indicating susceptible ( 0.06 mL for meningitis) for penicillin—does appear appropriate for S pneumoniae isolates responsible for pneumonia.

Dr. Joseph Lynch:
Given the high rate at which MRSA is isolated from patients with pneumonia, do you recommend the empiric use of vancomycin for pneumonia in ICU patients?

Dr. Jones:
I am a pathologist and a microbiologist, but I do think these data will drive clinicians to use more vancomycin or newer alternatives in these patients.

Dr. John Segretti:
How effective are aminoglycosides in the treatment of MRSA?

Dr. Jones:
Approximately 10% of our patients have coresistance to gentamicin. Other hospitals have reported tobramycin resistance in as many as 20% of isolates. Local information is essential to select the best aminoglycoside combination therapy.

Dr. Michael Miller:
I have observed clinically that aminoglycosides do not work in the treatment of many deep-seated staphylococcal infections. I think their lack of clinical efficacy is due to the following: (1) selection of small colony areas that are very unstable, and (2) aminoglycoside uptake being a voltage-gated phenomenon driven by pH and anaerobic conditions.

	Footnotes

 
Abbreviations: ESBL = extended-spectrum ß-lactamase; MRSA = methicillin-resistant Staphylococcus aureus; PBP = penicillin-binding protein; SCOPE = Surveillance and Control of Pathogens of Epidemiological Importance; VRE = vancomycin-resistant enterococci

	References

TOP Abstract Introduction Trends in Nosocomial Infections Gram-Positive Resistance Enterococcal Resistance Pneumococcal Resistance Staphylococcal Resistance Gram-Negative Resistance New Antimicrobials Conclusion Appendix 1 References

 

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5. Klastersky, J (1998) Science and pragmatism in the treatment and prevention of neutropenic infection. J Antimicrob Chemother 41(suppl D),13-24[Abstract/Free Full Text]
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15. Linden, PK, Pasculle, AW, Manez, R, et al (1996) Differences in outcomes for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E faecium. Clin Infect Dis 22,663-670[ISI][Medline]
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18. . for the In Vitro Susceptibility Surveillance GroupMurray, PR, Cantrell, HF, Lankford, RB (1994) Multicenter evaluation of the in vitro activity of piperacillin-tazobactam compared with eleven selected ß-lactam antibiotics and ciprofloxacin against more than 42,000 aerobic Gram-positive and Gram-negative bacteria. Diagn Microbiol Infect Dis 19,111-120[CrossRef][ISI][Medline]
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