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Penicillin-resistant pneumococci—an emerging threat to successful therapy
Journal
of Hospital
Infection
Penicillin-resistant threat
(1995)
30 (Supplement),
472-482
pneumococci-an to successful therapy
J. E. McGowan
emerging
Jr and B. G. Metchock
Department of Pathology and Laboratory School of Medicine and Grady Memorial 30335, USA
Medicine, Hospital,
Emory University Atlanta, Georgia
Summary:
Pneumococci highly resistant to penicillin G [minimum inhibitory concentration (MIC) 2 2 mg L-i] have become prevalent in many parts of the world since their emergence and spread in the late 1970s. In the USA, such organisms are seen primarily in two populations: infants and children, and adults with AIDS. Surveys in both rural and urban areas have revealed presence of these oganisms, as well as an increasing frequency of Streptococcus pneumoniae strains relatively resistant to penicillin (MIC 0.1-1.0 mg L-‘-now defined by some as ‘intermediate’ resistance). Predisposing factors are not yet clear. Prior antimicrobial therapy was given to some of the children and most of the adults who are colonized or infected with resistant strains. Prior or concurrent use of cotrimoxazole prophylaxis for Pneumocystis carinii pneumonia has been frequent in our cases in adults. most of whom had a concurrent diagnosis of AIDS. Children with disease often have a history of long-term prophylaxis with a p-lactam drug (for sickle cell disease, etc). Many strains are also resistant to newer cephalosporins like cefotaxime and ceftriaxone (MIC 2 2 mg L-i). The organisms are frequently multi-resistant, with high MIC values common as well for chloramphenicol and variable for tetracycline, macrolides, cotrimoxazole, and fluoroquinolones. Only to vancomycin are the organisms consistently susceptible. These findings raise alarms about the future of pneumococcal disease in both community and nosocomial disease. Increasing prevalence in otitis and pneumonia in children and in community-acquired pneumonia in adults may lead to use of vancomycin as empirical therapy for these clinical situations. This would increase the selective pressure for emergence of vancomycin-resistant organisms, whether S. pneumoniae or others. Moreover, the pneumococcus was a common cause of hospital infection prior to the introduction of penicillin. The potential now exists for nosocomial pneumococcal infection again to become a feared and ominous occurrence. Keywords:
Pneumococcus;
antimicrobial
resistance;
nosocomial
infection.
Introduction
Emerging infections have been a recent focus of attention in the USA.l A major aspect of these changes has been the increasing frequency of resistant strains of common bacterial pathogens. In particular, the development of Correspondence to: John E. McGowan Jr MD, Hospital, 80 Butler Street, Atlanta, GA 30335, 0195-6701/95/060472+11
Clinical USA.
$08.00/O
Microbiology
(Box
26248),
Grady
Q 1995 The Hospital
472
Memorial
Infection
Society
Penicillin-resistant Table
I.
pneumococci
Patients with pneumococcal bacteraemia by minimum inhibitory concentration
Total isolates tested Resistant by screening MIC (mg L-‘) SO.03
test*
(%)
0.12 0.06 0.25 0.5 1.0 22.0 * Agar disc diffusion test using 1 @g oxacillin + Isolated from culture in November, 1992.
473
at Grady Memorial Hospital, (MIC) of infecting organism
1989-1992,
1989
1990
1991
1992
196 9 (5%)
153 9 (6%)
172 21 (12%)
156 19 (12%)
2
:,
:
1 4 3 0 0
i 0 0
0 1;
1
: 2
22 i
:, 1-t
disc
resistance to penicillin in strains of Streptococcus pneumoniue represents a special threat to successful therapy. Penicillin-resistant strains of S. pneumoniae have been increasing in clinical importance in several countries around the world since initial reports in the 1960s and widespread emergence in the late 1970~.‘,~ Spread to Europe, especially Spain, Hungary, Poland and Romania was a feature of the 1980~.‘,~ In the 1990s it now appears to be the turn of North America to encounter these resistant bacteria.’ In a review of strains submitted to the Centers for Disease Control and Prevention (CDC) in the period 1979-1987, only one of 5459 tested strains fit the definition of highly resistant to penicillin G, defined as a minimum inhibitory concentration (MIC) 22.0 mg L-‘, and about 5% were intermediate in resistance (MIC O*l-1.0 mg L-‘).6 However, by 1991-1992 a survey of hospital laboratories by the CDC showed an increase in frequency of resistance.7 In this study of 544 persons with submitted isolates from normally sterile sites, 1.3% were highly resistant to penicillin G and 5.3% were relatively resistant. A wide variety of serotypes and drug susceptibility profiles were encountered, suggesting regional variations in presence of specific pneumococcal strains. Surveys in both rural and urban areas have revealed presence of these organisms, as well as an increasing frequency of S. pneumoniae strains relatively resistant to penicillin (MIC 0.1-1.0 mg L-’ now defined as intermediate). Resistance was detected in isolates from children earlier than from adults.‘f9 These trends are also illustrated by data from Grady Memorial Hospital, a public hospital primarily serving the indigent of inner-city Atlanta, Georgia (Table I). During the period 1989-1992, a gradual increase was seen in MIC of pneumococcal isolates from blood, with the median MIC moving from the 0.12 to 0.25 mg L-’ susceptible to the intermediate range (Table I). The first highly resistant strain was encountered in late 1992,
474 Table
J. E. McGowan II. Patients
with
Jr and B. G. Metchock
pneumococcal bacteraemia at Grady Memorial 1992-April 1994, by age group and HIV status
Susceptible (M1C10.1 mg L-‘) Age group
No.
O-3 4-15 16-19 20-29 30-39 40-49 so-59 60-69 70+ Male:female
61 10 4 ;:
ratio
52 20 11 15 266 1.25
HIV+ 3 (5%) 2 (20%) 445 (i2%) (63%) 16 (31%) 2 (10%) 1 (9%) 0 73 (27%)
Relatively resistant (MIC 0.1-I mg L-‘) No.
HIV+
4 i 1:
::
8 12 2
1 (to%) 7 (70%) 3 (38%) : 0 11 (35%)
3Y3
Hospital,
November
Highly resistant (MIC 2 2 mg L-‘) No.
HIV+
3
2 (67%)
0
::
13 1
2 (067%) 1 (100%)
:,
:
09 1.94
5 (I:5%)
and cases have continued to be identified since. From 1992 to April 1994, resistant pneumococcal isolates have been recovered primarily from two populations: children
resistance
in pneumococci
Increasing penicillin resistance is not the only disturbing change that the pneumococcus has shown. Many of the penicillin-resistant isolates are also resistant to several other drugs that might be employed for treatment of these organisms. The alterations in penicillin-binding proteins that produce penicillin resistance also can cause increased resistance to other p-lactams.’ Thus, many of these strains are also resistant to newer cephalosporins like cefotaxime and ceftriaxone (MIC 2 2 mg L-‘).11*‘2 While cephalosporin resistance is more common in strains highly resistant to penicillin than in relatively resistant strains, some strains relatively resistant to penicillin may be highly resistant to the newer cephalosporins.‘3 Penicillin-resistant pneumococci are frequently resistant to non-P-lactam
Penicillin-resistant
pneumococci
475
antibiotics. For example, such strains often have elevated MIC values for cotrimoxazole and variable susceptibility for tetracycline, chloramphenicol and fluoroquinolones.2,‘4 The CDC survey in 1991-1992 defined multidrug-resistant (MDR) strains as those resistant to at least three drug groups.7 MDR strains were isolated from 5.9% of their tested patients; all were resistant to cotrimoxazole and two-thirds were resistant to erythromycin. Penicillin and erythromycin resistance seem to evolve separately in response to different antimicrobial pressures, but many strains are now resistant to erythromycin as we11.i4 Only vancomycin is consistently susceptible, although many strains will respond to imipenem/cilistatin as we11.5Thus, most penicillin-resistant strains of pneumococci might well be referred to as MDR-pneumococci. Information about the clinical importance of resistance in laboratory testing of pneumococci to erythromycin and cotrimoxazole is limited.7 However, ample evidence now exists that resistance of pneumococci to cephalosporins correlates with treatment failure in meningitis, even when the newer cephalosporins like cefotaxime and ceftriaxone are used.” Thus, these strains are a clinical as well as laboratory concern. These findings raise alarms about the future of pneumococcal disease in both community and nosocomial disease. Several aspects are important. Laboratory
recognition
of MDR-pneumococci
is difficult
Sinusitis, otitis and bronchitis are common infections that are usually treated empirically. Cultures are not usually obtained as a cost-saving measure, to avoid an invasive procedure or because culture interpretation is not easy.13 Now, however, cultures of infection sites such as the above may become more important to guide therapy in geographic areas where MDR-pneumococci are prevalent. This will place new demands on the microbiology laboratory. To recommend appropriate therapy, laboratory workers must be able to identify penicillin-resistant pneumococci that are also resistant to cephalosporins. Unfortunately, this has been difficult, and new susceptibility test methods are being evaluated as quickly as possible. Recognition of MDR-pneumococci by automated test systems is a particular problem.13 Recently the Food and Drug Administration in the USA has required manufacturers of these test instruments to notify their users that the products are often unreliable in detecting pneumococcal resistance to penicillin. At present it appears that the most practical of the accurate ways to screen for penicillin resistance is an agar disc diffusion method using 1 ltg oxacillin discs and Miiller-Hinton agar with added sheep blood.2 The test is sensitive for resistant strains but non-specific. Therefore, follow-up MIC testing to determine whether the organisms with an oxacillin zone size I 19 mm are relatively or highly resistant will also show a number of
476
J. E. McGowan
Jr and B. G. Metchock
organisms in the susceptible range (Table I).” In addition, the test will falsely indicate resistance for strains that are penicillin susceptible but oxacillin resistant.16 A new gradient test (‘E-test’) has been described which provides MIC results consistently below those of MIC determinations, but results are improved if the test is incubated in an atmosphere with increased carbon dioxide. l7 Detecting resistance to newer cephalosporins is efficiently performed by disc diffusion with 30 pg ceftizoxime discs as a screening test.18 However, isolates identified as resistant by this screening test, as well as isolates resistant to penicillin, must then be tested by a MIC method against cefotaxime or ceftriaxone. This is because cefotaxime or ceftriaxone, rather than ceftizoxime, should be used in therapy of patients with a cephalosporinsusceptible strain. While ceftizoxime is useful for laboratory screening, it is much less active than cefotaxime or ceftriaxone for treatment of patients infected with penicillin-resistant pneumococci.” The ceftizoxime screening test is not universally accepted as the best approach to screening for cephalosporin-resistant pneumococci. A group from Texas favours standard disc susceptibility testing with cefuroxime discs as a sensitive means for detecting cephalosporin resistance in pneumococcal strains that are penicillin resistant.lg Testing for penicillin and cephalosporin resistance in pneumococci by broth microdilution methods remains a problem. Fewer than half of isolates with cephalosporin MIC >0*5 mg L-’ were detected by two commercial MIC broth microdilution assay systems.” Breakpoints for MIC testing of cefotaxime and ceftriaxone ( I 0.25 mg L-’ susceptible; 0.5-l .Omg/L-’ intermediate; 2 2.0 mg L-’ resistant) were recently proposed in the USA.*l These breakpoints are based on clinical observations. Treatment failures have usually involved strains with cefotaxime or ceftriaxone MIC 12mgL-‘, and clinical response to these drugs has varied for strains demonstrating MIC values of 05-l mg L-‘.i3,** Even when the organism appears susceptible to chloramphenicol by laboratory testing, clinical response may be poor in patients with pneumococcal meningitis. Therefore, this drug should be avoided for treatment of pneumococcal meningitis, especially when the chloramphenicol MIC is >4 mg L-‘.23 These observations make it clear that further research is urgently needed to determine the most effective and efficient laboratory testing methods for MDR-pneumococci. MDR-pneumococci
and
community-acquired
infections
Most MDR organisms to date present problems for successful therapy primarily in the hospital setting. In contrast, MDR-pneumococci are a dilemma for community care as well. The pneumococcus remains the most common cause of pneumonia, otitis media and bacteraemia in infants and
Penicillin-resistant
pneumococci
477
children, and is a frequent cause of bacterial meningitis.14 Adults with underlying debilitating illnesses, patients with AIDS and the elderly also experience pneumococcal infection as a major cause of illness and death.’ Thus, it is a major problem when penicillin-resistant strains spread rapidly in communities, as occurred in Iceland after resistant organisms were introduced.24 These organisms demonstrated several patterns of resistance, which varied also by serotype. MDR-pneumococcal infections have occurred in both urban and rural settings.” Most outbreaks of resistant organisms occur in the hospital. By contrast, clustered or epidemic spread of MDR-pneumococci has been a feature of some community settings.8,26 For example, a cluster of MDR-pneumococcal infections occurred in a child-care centre in Kentucky.25 Of 80 pneumococcal isolates obtained from children attending this centre, 61% were at least relatively resistant to penicillin. Many of these were MDR strains, exhibiting resistance to cephalosporins, erythromycin, cotrimoxazole and chloramphenicol. Treatment of suspected pneumococcal infection of community origin has usually been an empirical choice because isolates are seldom available from patients with otitis media or pneumonia.7 What was a straightforward process of drug choice (when strains were uniformly susceptible to plactam drugs) now has become a difficult issue. In addition, the need for new policies for vaccination and guides for eradication of pneumococcal carriage in settings such as day-care centres must also be considered now.8 Prior antimicrobial therapy is a predisposing factor for MDR strains in some of the children and most of the adults who develop communityacquired infection with resistant strains. At Grady Memorial Hospital, prior or concurrent use of cotrimoxazole prophylaxis for Pneumocystis carinii pneumonia has been frequent in our adults with penicillin-resistant organisms. Likewise, many of our children with these organisms have a history of long-term prophylaxis with penicillin (for sickle cell disease, etc). Antibiotic use was also found to be a risk factor, along with child-care, in a cluster of MDR-pneumococcal infections in Kentucky.25
MDR-pneumococci
can
cause
nosocomial
infection
The pneumococcus was a common cause of hospital infection prior to the introduction of penicillin.27’28 Initial reports of MDR-pneumococci from South Africa focused on nosocomial infections as we11.3 Hospital outbreaks of MDR-pneumococci have continued to occur in the modern era.2,29 In Bristol, a pneumococcus resistant to penicillin and cotrimoxazole was recovered from 10 patients with lower respiratory tract infection on three different wards over three weeks.30 Likewise, up to 33% of nosocomial pneumonia cases in Spain were associated with MDRpneumococcal strains.2
478
J. E. McGowan
Jr and B. G. Metchock
The South African children with nosocomial infection due to MDRpneumococci had received extensive prior antimicrobial therapy.3 Recent nosocomial cases of MDR strains reported from the USA have also identified prior /3-lactam therapy as a risk factor.” In Bristol, a change in antibiotic policy as well as closing the wards to new admissions was successful in ending the hospital outbreak described above.30 Thus, antimicrobial use seems to be an important associated factor in nosocomial MDR-pneumococcal infection.
MDR-pneumococci
as selection
agents
for emergence
of resistance
As detailed above, antibiotic therapy has been implicated as a risk factor for penicillin-resistant pneumococci in both community-based and nosocomial infections. Therapeutic regimens containing p-lactam drugs are selecting MDR-pneumococci throughout the world.31 However, more than resistance in pneumococci alone is at issue. The emergence of MDR organisms often exerts additional selective pressure on any antimicrobials that remain effective. For MDR-pneumococci, the additional selective pressure is likely to be profound. Because pneumococci are relatively common pathogens, the emergence of MDR strains will greatly increase use of vancomycin, one of the few remaining drugs effective for their treatment. Increasing prevalence of MDR-pneumococci in pneumonia and meningitis is likely to lead to use of vancomycin as empirical therapy for these clinical situations. This would greatly increase the selective pressure for emergence of vancomycin-resistant organisms, whether 5’. pneumoniae or others. Use of vancomycin has been a prominent factor associated with emergence of vancomycin resistance in enterococci. It is reasonable to fear that greatly increased use of vancomycin for community-acquired pneumonia, meningitis and other frequent syndromes would increase the selective pressure so greatly that more resistant enterococci would emerge. In turn, a grave current concern is the possibility of transfer of resistance determinants from enterococci to Staphylococcus aureus.32 Increased use of vancomycin for community disease due to MDR-pneumococci would dramatically increase the selective pressure for resistance in S. aureus as well. It would be a disaster if vancomycin were no longer effective for therapy of methicillin-resistant strains of S. aureus, because no alternate therapies are readily available.33 Therefore, making sure that vancomycin use is optimal remains an urgent priority throughout the world.
What
can/must
we do?
A number of strategies are needed to deal with this these are proper isolation precautions in hospitalized
new threat. Among or institutionalized
Penicillin-resistant
pneumococci
479
individuals, increased use of the currently available pneumococcal vaccines, and more prudent antibiotic use. Evidence of nosocomial transmission means that patients with pneumococci highly resistant to penicillin or MDR should be isolated and that respiratory precautions should be maintained.8 Recommended procedures for prevention of cross-infection have been disregarded in settings where pneumococcal outbreaks have occurred.30 Proper isolation is a cornerstone of dealing with these new resistant organisms. New methods to provide isolation for this setting in cost-efficient fashion are sorely needed, and are being tested in several hospitals.34 Most of the resistant strains in the USA to date have been of serotypes contained within the 23 -valent pneumococcal capsular polysaccharide vaccine that is available in the USA.7 Use of this vaccine is hampered by its relative lack of effectiveness in adults and its ineffectiveness in children less than two years of age.35 Development of new protein-conjugated polysaccharide vaccines, that may be immunogenic in children less than two years of age, and continued research into new vaccines against the pneumococcus, may be the ultimate solutions to the problem. Likewise, research is needed for development of new antimicrobials that may prove effective against MDR-pneumococci. In the meantime, expanded emphasis must be placed on prudent use of antimicrobial agents. Avoiding unnecessary use of’ p-lactam drugs is an obvious approach. Moreover, it is use of p-lactams in the community setting as well as in the hospital that may select for penicillin-resistant pneumococci, so improving use outside the hospital is important as we11.2 Previous plactam antibiotic usage has been associated with recovery of both penicillinresistant and MDR-pneumococci.’ The very places where MDR-pneumococci may spread-hospitals, nursing homes, child-care centres-are the very places where calls for improved antibiotic use have been heard for decades. Unlike prior problems, however, proper use of antimicrobials in the community could have great impact on the selection pressures for resistant pneumococci.8 Little note has been taken of the use and overuse of antibiotics by community practitioners. This facet must be addressed immediately. The use of parenteral vancomycin for extended periods for prophylaxis or therapy without documentation of a pathogen must also be discouraged. ‘Hospitals cannot wait until their first vancomycin-resistant enterococcus or, worse still, staphylococcus or pneumococcus appears before imposing strict infection control measures and restricting the use of antibiotics. Once these organisms appear, eliminating them is a much more difficult task.‘32 To date, data are lacking to demonstrate that intensive hospital antibiotic control programmes prevent the spread of antibiotic resistance.36 Nevertheless, in a new and forceful change in prevention emphasis, such programmes have now been mandated by the CDC in the USA, in an attempt to reduce the spread of vancomycin resistance.37 This governmental agency
480
J. E. McGowan
Jr and B. G. Metchock
Guidelines for proper and improper use of vancomycin, as published by the Centers for Disease Control and Prevention in the USA*
Table
III.
(A)
Situations in which use of vancomycin is appropriate or acceptable: (1) serious infections due to J3-lactam-resistant Gram-positive organisms; (2) infections due to Gram-positive microorganisms in patients with serious allergy to p-lactam antimicrobials; (3) when antibiotic-associated colitis fails to respond to metronidazole or is severe and potentially life-threatening; (4) prophylaxis for endocarditis following certain procedures in patients at high risk for endocarditis; (5) prophylaxis for surgical procedures involving implant of prosthetic materials or devices at institutions with high rates of methicillin-resistant Staphylococcus aureus (MRSA). Situations in which use of vancomvcin should be discouraged: routine surgical prophylaxis;empirical therapy for febrile neutropenia; treatment for single positive blood culture for coagulase-negative staphylococcus; empirical use for presumed infections in patients with negative (4) continued cultures; for infection or colonization of intravascular catheters/vascular (5) prophylaxis grafts; selective decontamination; It{ eradication of MRSA colonization; treatment of colitis or diarrhoea associated with Clostridium difjkile; (8) first-line prophylaxis for low birth weight infants; (9) routine prophylaxis for continuous ambulatory peritoneal dialysis. (10) routine
(B)
,
(1) I:{
* Adapted from reference 37.
has developed recommendations for situations in which vancomycin use is appropriate and settings in which vancomycin use should be discouraged (Table III). No data are yet available to determine acceptance and compliance with these guidelines. Comment
The potential now exists for pneumococcal infection to again become a feared and ominous occurrence. Both epidemic and endemic disease patterns of occurrence become possible when our current arsenal of antimicrobial agents is exhausted. The turn of events that has brought about the spread of MDR-pneumococci may be the one that changes our approach to antibiotic use to a more rational pattern. If so, it can be a sentinel event in our battle against resistant microbes. If we fail to take this opportunity, the consequences may be disastrous. What will we choose to do? References 1. Hughes
263-264.
JM,
LaMontagne
JR.
Emerging
infectious
diseases.
J Infect Dis 1994; 170:
Penicillin-resistant
pneumococci
481
2. Caputo GM, Applebaum PC, Liu HH. Infections due to penicillin-resistant pneumococci. Clinical, epidemiologic, and microbiologic features. Arch Intern Med 1993; 153: 1301-1310. 3. Jacobs MR, Koornhof HJ, Robins-Browne RM et al. Emergence of multiply resistant pneumococci. N Engl J Med 1978; 299: 735-740. 4. Kingman S. Resistance a European problem, too. Science 1994; 264: 363-365. 5. Simberkoff MS. Drug-resistant pneumococcal infections in the United States. A problem for clinicians, laboratories, and public health. JAMA 1994; 271: 1875-1876. 6. Spika JS, Facklam RR, Plikaytis BD, Oxtoby MJ, Pneumococcal Surveillance Working Group. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987. J Infect Dis 1991; 163: 1273-1278. 7. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklam RR. Emergence of drugresistant pneumococcal infections in the United States. JAMA 1994; 271: 1831-1835. 8. Chesney PJ. The escalating problem of antimicrobial resistance in Streptococcus pneumoniue. AJDC 1992; 146: 912-916. 9. Mason EO, Jr, Kaplan SL, Lamberth LB, Tillman J. Increased rate of isolation of penicillin-resistant Streptococcus pneumoniae in a children’s hospital and in vitro susceptibilities to antibiotics of potential therapeutic use. Antimicrob Agents Chemother 1992; 36: 1703-l 707. 10. Janoff EN, O’Brien J, Thompson P et al. Streptococcus pneumoniae colonization, bacteremia, and immune response among persons with human immunodeficiency virus infection. J Infect Dis 1993; 167: 49-56. 11. Linares J, Alonso T, Perez JL et al. Decreased susceptibility of penicillin-resistant pneumococci to twenty-four J3-lactam antibiotics. J Antimicrob Chemother 1992; 30: 279-288. 12. Klugman KP, Saunders J. Pneumococci resistant to extended-spectrum cephalosporins in South Africa. Lancet 1993; 341: 1164. 13. Jorgensen JH. Detection of antimicrobial resistance in Streptococcus pneumoniue by use of standardized susceptibility testing methods and recently developed interpretative criteria. Clin Microbial Newslet 1994; 16: 97-101. 14. McDougal LK, Facklam R, Reeves M et al. Analysis of multiply antimicrobial-resistant isolates of Streptococcuspneumoniae from the United States. Antimicrob Agents Chemother 1992; 36: 2176-2184. 15. John CC. Treatment failure with use of a third-generation cephalosporin for penicillinresistant pneumococcal meningitis: case report and review. Clin infect Dis 1994; 18: 188-193. 16. Dowson CG, Johnson AP, Cercenado E, George RC. Genetics of oxacillin resistance in clinical isolates of Streptococcus pneumoniae that are oxacillin resistant and penicillin susceptible. J Clin Microbial 1994; 38: 49-53. 17. Jorgensen JH, Ferraro MJ, McElmeel ML, Spargo J, Swenson JM, Tenover FC. Detection of penicillin and extended-spectrum cephalosporin resistance among Streptococcus pneumoniae clinical isolates bv use of the E test. .r Clin Micyobiol 1994; 32: 159-163: 18. Tenover FC, Swenson JM, McDougal LK. Screening for extended-spectrum cenhalosnorin resistance in nneumococci. Lancet 1992: 340: 1420. 19. &Fried&d IR, Shelton ST McCracken GH, Jr. Screening for cephalosporin-resistant Streptococcus pneumoniae with the Kirby-Bauer disk susceptibility test. J Clin Microbial 1993; 31: 1619-1621. 20. Krisher KK, Linscott A. Comparison of three commercial MIC systems, E test, fastidious antimicrobial panel, and FOX fastidious panel, for confirmation of penicillin and cephalosporin resistance in Streptococcus pneumoniae. J Clin Microbial 1994; 32: 2242-2245. 21. Daum RS, Nachman JP, Leitch CD, Tenover FC. Nosocomial epiglottitis associated with penicillinand cephalosporin-resistant Streptococcus pneumoniae. J Clin Microbial 1994; 32: 246-248. 22. Tan TQ, Schutze GE, Mason EO, Jr, Kaplan SL. Antibiotic therapy and acute outcomes of meningitis due to Streptococcus pneumoniae considered intermediately susceptible to broad-spectrum cephalosporins. Antimicrob Agents Chemother 1994; 38: 918-923. 23. Friedland IR, Shelton S, McCracken GH, Jr. Chloramphenicol in penicillin-resistant pneumococcal meningitis. Lancet 1993; 342: 240-241.
J. E. McGowan
482
Jr and B. G. Metchock
24. Kristinsson 25. 26.
KG, Hjalmarsdottir MA, Steingrimsson 0. Increasing penicillin resistance in pneumococci in Iceland. Lancet 1992; 339: 1606-1607. Centers for Disease Control and Prevention. Drug-resistant Steptococcus pneumoniaeKentucky and Tennessee, 1993. JAMA 1994; 271: 421422. Cherian T, Steinhoff MC, Harrison LH, Rohn D, McDougal LK, Dick J. A cluster of invasive pneumococcal disease in young children in child care. JAMA 1994; 271:
695-697. 27. Schroder 28. 29. 30. 31. 32. 33.
MC, Cooper G. An epidemic of cold, bronchitis, and pneumoniae due to type V pneumococci. J Infect Dis 1930; 46: 384-392. Stoneburner LT III, Finland M. Pneumococcic pneumonia complicating operations and trauma. JAMA 1941; 116: 1497-1504. Mehtar S, Drabu YJ, Vijeratnam S, Mayet F. Cross-infection with Streptococcus pneumoniae through a Resuscitaire. BMJ 1986; 292: 25-26. Millar MR, Brown NR, Tobin GW, Murphy PJ, Windsor ACM, Speller DCE. Outbreak of infection with penicillin-resistant Streptococcus pneumoniae in a hospital for the elderly. J Hosp Infect 1994; 27: 99-104. Negri MC, Morosini MI, Loza E, Baquero F. In vitro selective antibiotic concentrations of p-lactams for penicillin-resistant Streptococcus pneumoniae populations. Antimicrob Agents Chemother 1994; 38: 122-125. Murray BE. Can antibiotic resistance be controlled? N EnglJMed 1994; 330: 1229-l 230. Kunin CM. Resistance to antimicrobial drugs-a worldwide calamity. Ann Intern Med
1993; 118: 557-561. 34. Patterson JE, Sanchez 35. 36. 37.
RO, Hernandez J, Grota P, Rose KA. Special organism isolation: attempting to bridge the gap. Infect Control Hasp Epidemiol 1994; 15: 335-338. Hirschmann JV, Lipsky BA. The pneumococcal vaccine after 15 years of use. Arch Intern Med 1994; 154: 373-377. McGowan JE, Jr. Do intensive hospital antibiotic control programs prevent the spread of antibiotic resistance? Infect Control Hasp Epidemiol 1994; 15: 478-483. Centers for Disease Control and Prevention. Preventing the spread of vancomycin resistance-report from the Hospital Infection Control Practices Advisory Committee; comment period and public meeting; notice. Fed Register 1994; 59: 25758-25763.
of Hospital
Infection
Penicillin-resistant threat
(1995)
30 (Supplement),
472-482
pneumococci-an to successful therapy
J. E. McGowan
emerging
Jr and B. G. Metchock
Department of Pathology and Laboratory School of Medicine and Grady Memorial 30335, USA
Medicine, Hospital,
Emory University Atlanta, Georgia
Summary:
Pneumococci highly resistant to penicillin G [minimum inhibitory concentration (MIC) 2 2 mg L-i] have become prevalent in many parts of the world since their emergence and spread in the late 1970s. In the USA, such organisms are seen primarily in two populations: infants and children, and adults with AIDS. Surveys in both rural and urban areas have revealed presence of these oganisms, as well as an increasing frequency of Streptococcus pneumoniae strains relatively resistant to penicillin (MIC 0.1-1.0 mg L-‘-now defined by some as ‘intermediate’ resistance). Predisposing factors are not yet clear. Prior antimicrobial therapy was given to some of the children and most of the adults who are colonized or infected with resistant strains. Prior or concurrent use of cotrimoxazole prophylaxis for Pneumocystis carinii pneumonia has been frequent in our cases in adults. most of whom had a concurrent diagnosis of AIDS. Children with disease often have a history of long-term prophylaxis with a p-lactam drug (for sickle cell disease, etc). Many strains are also resistant to newer cephalosporins like cefotaxime and ceftriaxone (MIC 2 2 mg L-i). The organisms are frequently multi-resistant, with high MIC values common as well for chloramphenicol and variable for tetracycline, macrolides, cotrimoxazole, and fluoroquinolones. Only to vancomycin are the organisms consistently susceptible. These findings raise alarms about the future of pneumococcal disease in both community and nosocomial disease. Increasing prevalence in otitis and pneumonia in children and in community-acquired pneumonia in adults may lead to use of vancomycin as empirical therapy for these clinical situations. This would increase the selective pressure for emergence of vancomycin-resistant organisms, whether S. pneumoniae or others. Moreover, the pneumococcus was a common cause of hospital infection prior to the introduction of penicillin. The potential now exists for nosocomial pneumococcal infection again to become a feared and ominous occurrence. Keywords:
Pneumococcus;
antimicrobial
resistance;
nosocomial
infection.
Introduction
Emerging infections have been a recent focus of attention in the USA.l A major aspect of these changes has been the increasing frequency of resistant strains of common bacterial pathogens. In particular, the development of Correspondence to: John E. McGowan Jr MD, Hospital, 80 Butler Street, Atlanta, GA 30335, 0195-6701/95/060472+11
Clinical USA.
$08.00/O
Microbiology
(Box
26248),
Grady
Q 1995 The Hospital
472
Memorial
Infection
Society
Penicillin-resistant Table
I.
pneumococci
Patients with pneumococcal bacteraemia by minimum inhibitory concentration
Total isolates tested Resistant by screening MIC (mg L-‘) SO.03
test*
(%)
0.12 0.06 0.25 0.5 1.0 22.0 * Agar disc diffusion test using 1 @g oxacillin + Isolated from culture in November, 1992.
473
at Grady Memorial Hospital, (MIC) of infecting organism
1989-1992,
1989
1990
1991
1992
196 9 (5%)
153 9 (6%)
172 21 (12%)
156 19 (12%)
2
:,
:
1 4 3 0 0
i 0 0
0 1;
1
: 2
22 i
:, 1-t
disc
resistance to penicillin in strains of Streptococcus pneumoniue represents a special threat to successful therapy. Penicillin-resistant strains of S. pneumoniae have been increasing in clinical importance in several countries around the world since initial reports in the 1960s and widespread emergence in the late 1970~.‘,~ Spread to Europe, especially Spain, Hungary, Poland and Romania was a feature of the 1980~.‘,~ In the 1990s it now appears to be the turn of North America to encounter these resistant bacteria.’ In a review of strains submitted to the Centers for Disease Control and Prevention (CDC) in the period 1979-1987, only one of 5459 tested strains fit the definition of highly resistant to penicillin G, defined as a minimum inhibitory concentration (MIC) 22.0 mg L-‘, and about 5% were intermediate in resistance (MIC O*l-1.0 mg L-‘).6 However, by 1991-1992 a survey of hospital laboratories by the CDC showed an increase in frequency of resistance.7 In this study of 544 persons with submitted isolates from normally sterile sites, 1.3% were highly resistant to penicillin G and 5.3% were relatively resistant. A wide variety of serotypes and drug susceptibility profiles were encountered, suggesting regional variations in presence of specific pneumococcal strains. Surveys in both rural and urban areas have revealed presence of these organisms, as well as an increasing frequency of S. pneumoniae strains relatively resistant to penicillin (MIC 0.1-1.0 mg L-’ now defined as intermediate). Resistance was detected in isolates from children earlier than from adults.‘f9 These trends are also illustrated by data from Grady Memorial Hospital, a public hospital primarily serving the indigent of inner-city Atlanta, Georgia (Table I). During the period 1989-1992, a gradual increase was seen in MIC of pneumococcal isolates from blood, with the median MIC moving from the 0.12 to 0.25 mg L-’ susceptible to the intermediate range (Table I). The first highly resistant strain was encountered in late 1992,
474 Table
J. E. McGowan II. Patients
with
Jr and B. G. Metchock
pneumococcal bacteraemia at Grady Memorial 1992-April 1994, by age group and HIV status
Susceptible (M1C10.1 mg L-‘) Age group
No.
O-3 4-15 16-19 20-29 30-39 40-49 so-59 60-69 70+ Male:female
61 10 4 ;:
ratio
52 20 11 15 266 1.25
HIV+ 3 (5%) 2 (20%) 445 (i2%) (63%) 16 (31%) 2 (10%) 1 (9%) 0 73 (27%)
Relatively resistant (MIC 0.1-I mg L-‘) No.
HIV+
4 i 1:
::
8 12 2
1 (to%) 7 (70%) 3 (38%) : 0 11 (35%)
3Y3
Hospital,
November
Highly resistant (MIC 2 2 mg L-‘) No.
HIV+
3
2 (67%)
0
::
13 1
2 (067%) 1 (100%)
:,
:
09 1.94
5 (I:5%)
and cases have continued to be identified since. From 1992 to April 1994, resistant pneumococcal isolates have been recovered primarily from two populations: children
resistance
in pneumococci
Increasing penicillin resistance is not the only disturbing change that the pneumococcus has shown. Many of the penicillin-resistant isolates are also resistant to several other drugs that might be employed for treatment of these organisms. The alterations in penicillin-binding proteins that produce penicillin resistance also can cause increased resistance to other p-lactams.’ Thus, many of these strains are also resistant to newer cephalosporins like cefotaxime and ceftriaxone (MIC 2 2 mg L-‘).11*‘2 While cephalosporin resistance is more common in strains highly resistant to penicillin than in relatively resistant strains, some strains relatively resistant to penicillin may be highly resistant to the newer cephalosporins.‘3 Penicillin-resistant pneumococci are frequently resistant to non-P-lactam
Penicillin-resistant
pneumococci
475
antibiotics. For example, such strains often have elevated MIC values for cotrimoxazole and variable susceptibility for tetracycline, chloramphenicol and fluoroquinolones.2,‘4 The CDC survey in 1991-1992 defined multidrug-resistant (MDR) strains as those resistant to at least three drug groups.7 MDR strains were isolated from 5.9% of their tested patients; all were resistant to cotrimoxazole and two-thirds were resistant to erythromycin. Penicillin and erythromycin resistance seem to evolve separately in response to different antimicrobial pressures, but many strains are now resistant to erythromycin as we11.i4 Only vancomycin is consistently susceptible, although many strains will respond to imipenem/cilistatin as we11.5Thus, most penicillin-resistant strains of pneumococci might well be referred to as MDR-pneumococci. Information about the clinical importance of resistance in laboratory testing of pneumococci to erythromycin and cotrimoxazole is limited.7 However, ample evidence now exists that resistance of pneumococci to cephalosporins correlates with treatment failure in meningitis, even when the newer cephalosporins like cefotaxime and ceftriaxone are used.” Thus, these strains are a clinical as well as laboratory concern. These findings raise alarms about the future of pneumococcal disease in both community and nosocomial disease. Several aspects are important. Laboratory
recognition
of MDR-pneumococci
is difficult
Sinusitis, otitis and bronchitis are common infections that are usually treated empirically. Cultures are not usually obtained as a cost-saving measure, to avoid an invasive procedure or because culture interpretation is not easy.13 Now, however, cultures of infection sites such as the above may become more important to guide therapy in geographic areas where MDR-pneumococci are prevalent. This will place new demands on the microbiology laboratory. To recommend appropriate therapy, laboratory workers must be able to identify penicillin-resistant pneumococci that are also resistant to cephalosporins. Unfortunately, this has been difficult, and new susceptibility test methods are being evaluated as quickly as possible. Recognition of MDR-pneumococci by automated test systems is a particular problem.13 Recently the Food and Drug Administration in the USA has required manufacturers of these test instruments to notify their users that the products are often unreliable in detecting pneumococcal resistance to penicillin. At present it appears that the most practical of the accurate ways to screen for penicillin resistance is an agar disc diffusion method using 1 ltg oxacillin discs and Miiller-Hinton agar with added sheep blood.2 The test is sensitive for resistant strains but non-specific. Therefore, follow-up MIC testing to determine whether the organisms with an oxacillin zone size I 19 mm are relatively or highly resistant will also show a number of
476
J. E. McGowan
Jr and B. G. Metchock
organisms in the susceptible range (Table I).” In addition, the test will falsely indicate resistance for strains that are penicillin susceptible but oxacillin resistant.16 A new gradient test (‘E-test’) has been described which provides MIC results consistently below those of MIC determinations, but results are improved if the test is incubated in an atmosphere with increased carbon dioxide. l7 Detecting resistance to newer cephalosporins is efficiently performed by disc diffusion with 30 pg ceftizoxime discs as a screening test.18 However, isolates identified as resistant by this screening test, as well as isolates resistant to penicillin, must then be tested by a MIC method against cefotaxime or ceftriaxone. This is because cefotaxime or ceftriaxone, rather than ceftizoxime, should be used in therapy of patients with a cephalosporinsusceptible strain. While ceftizoxime is useful for laboratory screening, it is much less active than cefotaxime or ceftriaxone for treatment of patients infected with penicillin-resistant pneumococci.” The ceftizoxime screening test is not universally accepted as the best approach to screening for cephalosporin-resistant pneumococci. A group from Texas favours standard disc susceptibility testing with cefuroxime discs as a sensitive means for detecting cephalosporin resistance in pneumococcal strains that are penicillin resistant.lg Testing for penicillin and cephalosporin resistance in pneumococci by broth microdilution methods remains a problem. Fewer than half of isolates with cephalosporin MIC >0*5 mg L-’ were detected by two commercial MIC broth microdilution assay systems.” Breakpoints for MIC testing of cefotaxime and ceftriaxone ( I 0.25 mg L-’ susceptible; 0.5-l .Omg/L-’ intermediate; 2 2.0 mg L-’ resistant) were recently proposed in the USA.*l These breakpoints are based on clinical observations. Treatment failures have usually involved strains with cefotaxime or ceftriaxone MIC 12mgL-‘, and clinical response to these drugs has varied for strains demonstrating MIC values of 05-l mg L-‘.i3,** Even when the organism appears susceptible to chloramphenicol by laboratory testing, clinical response may be poor in patients with pneumococcal meningitis. Therefore, this drug should be avoided for treatment of pneumococcal meningitis, especially when the chloramphenicol MIC is >4 mg L-‘.23 These observations make it clear that further research is urgently needed to determine the most effective and efficient laboratory testing methods for MDR-pneumococci. MDR-pneumococci
and
community-acquired
infections
Most MDR organisms to date present problems for successful therapy primarily in the hospital setting. In contrast, MDR-pneumococci are a dilemma for community care as well. The pneumococcus remains the most common cause of pneumonia, otitis media and bacteraemia in infants and
Penicillin-resistant
pneumococci
477
children, and is a frequent cause of bacterial meningitis.14 Adults with underlying debilitating illnesses, patients with AIDS and the elderly also experience pneumococcal infection as a major cause of illness and death.’ Thus, it is a major problem when penicillin-resistant strains spread rapidly in communities, as occurred in Iceland after resistant organisms were introduced.24 These organisms demonstrated several patterns of resistance, which varied also by serotype. MDR-pneumococcal infections have occurred in both urban and rural settings.” Most outbreaks of resistant organisms occur in the hospital. By contrast, clustered or epidemic spread of MDR-pneumococci has been a feature of some community settings.8,26 For example, a cluster of MDR-pneumococcal infections occurred in a child-care centre in Kentucky.25 Of 80 pneumococcal isolates obtained from children attending this centre, 61% were at least relatively resistant to penicillin. Many of these were MDR strains, exhibiting resistance to cephalosporins, erythromycin, cotrimoxazole and chloramphenicol. Treatment of suspected pneumococcal infection of community origin has usually been an empirical choice because isolates are seldom available from patients with otitis media or pneumonia.7 What was a straightforward process of drug choice (when strains were uniformly susceptible to plactam drugs) now has become a difficult issue. In addition, the need for new policies for vaccination and guides for eradication of pneumococcal carriage in settings such as day-care centres must also be considered now.8 Prior antimicrobial therapy is a predisposing factor for MDR strains in some of the children and most of the adults who develop communityacquired infection with resistant strains. At Grady Memorial Hospital, prior or concurrent use of cotrimoxazole prophylaxis for Pneumocystis carinii pneumonia has been frequent in our adults with penicillin-resistant organisms. Likewise, many of our children with these organisms have a history of long-term prophylaxis with penicillin (for sickle cell disease, etc). Antibiotic use was also found to be a risk factor, along with child-care, in a cluster of MDR-pneumococcal infections in Kentucky.25
MDR-pneumococci
can
cause
nosocomial
infection
The pneumococcus was a common cause of hospital infection prior to the introduction of penicillin.27’28 Initial reports of MDR-pneumococci from South Africa focused on nosocomial infections as we11.3 Hospital outbreaks of MDR-pneumococci have continued to occur in the modern era.2,29 In Bristol, a pneumococcus resistant to penicillin and cotrimoxazole was recovered from 10 patients with lower respiratory tract infection on three different wards over three weeks.30 Likewise, up to 33% of nosocomial pneumonia cases in Spain were associated with MDRpneumococcal strains.2
478
J. E. McGowan
Jr and B. G. Metchock
The South African children with nosocomial infection due to MDRpneumococci had received extensive prior antimicrobial therapy.3 Recent nosocomial cases of MDR strains reported from the USA have also identified prior /3-lactam therapy as a risk factor.” In Bristol, a change in antibiotic policy as well as closing the wards to new admissions was successful in ending the hospital outbreak described above.30 Thus, antimicrobial use seems to be an important associated factor in nosocomial MDR-pneumococcal infection.
MDR-pneumococci
as selection
agents
for emergence
of resistance
As detailed above, antibiotic therapy has been implicated as a risk factor for penicillin-resistant pneumococci in both community-based and nosocomial infections. Therapeutic regimens containing p-lactam drugs are selecting MDR-pneumococci throughout the world.31 However, more than resistance in pneumococci alone is at issue. The emergence of MDR organisms often exerts additional selective pressure on any antimicrobials that remain effective. For MDR-pneumococci, the additional selective pressure is likely to be profound. Because pneumococci are relatively common pathogens, the emergence of MDR strains will greatly increase use of vancomycin, one of the few remaining drugs effective for their treatment. Increasing prevalence of MDR-pneumococci in pneumonia and meningitis is likely to lead to use of vancomycin as empirical therapy for these clinical situations. This would greatly increase the selective pressure for emergence of vancomycin-resistant organisms, whether 5’. pneumoniae or others. Use of vancomycin has been a prominent factor associated with emergence of vancomycin resistance in enterococci. It is reasonable to fear that greatly increased use of vancomycin for community-acquired pneumonia, meningitis and other frequent syndromes would increase the selective pressure so greatly that more resistant enterococci would emerge. In turn, a grave current concern is the possibility of transfer of resistance determinants from enterococci to Staphylococcus aureus.32 Increased use of vancomycin for community disease due to MDR-pneumococci would dramatically increase the selective pressure for resistance in S. aureus as well. It would be a disaster if vancomycin were no longer effective for therapy of methicillin-resistant strains of S. aureus, because no alternate therapies are readily available.33 Therefore, making sure that vancomycin use is optimal remains an urgent priority throughout the world.
What
can/must
we do?
A number of strategies are needed to deal with this these are proper isolation precautions in hospitalized
new threat. Among or institutionalized
Penicillin-resistant
pneumococci
479
individuals, increased use of the currently available pneumococcal vaccines, and more prudent antibiotic use. Evidence of nosocomial transmission means that patients with pneumococci highly resistant to penicillin or MDR should be isolated and that respiratory precautions should be maintained.8 Recommended procedures for prevention of cross-infection have been disregarded in settings where pneumococcal outbreaks have occurred.30 Proper isolation is a cornerstone of dealing with these new resistant organisms. New methods to provide isolation for this setting in cost-efficient fashion are sorely needed, and are being tested in several hospitals.34 Most of the resistant strains in the USA to date have been of serotypes contained within the 23 -valent pneumococcal capsular polysaccharide vaccine that is available in the USA.7 Use of this vaccine is hampered by its relative lack of effectiveness in adults and its ineffectiveness in children less than two years of age.35 Development of new protein-conjugated polysaccharide vaccines, that may be immunogenic in children less than two years of age, and continued research into new vaccines against the pneumococcus, may be the ultimate solutions to the problem. Likewise, research is needed for development of new antimicrobials that may prove effective against MDR-pneumococci. In the meantime, expanded emphasis must be placed on prudent use of antimicrobial agents. Avoiding unnecessary use of’ p-lactam drugs is an obvious approach. Moreover, it is use of p-lactams in the community setting as well as in the hospital that may select for penicillin-resistant pneumococci, so improving use outside the hospital is important as we11.2 Previous plactam antibiotic usage has been associated with recovery of both penicillinresistant and MDR-pneumococci.’ The very places where MDR-pneumococci may spread-hospitals, nursing homes, child-care centres-are the very places where calls for improved antibiotic use have been heard for decades. Unlike prior problems, however, proper use of antimicrobials in the community could have great impact on the selection pressures for resistant pneumococci.8 Little note has been taken of the use and overuse of antibiotics by community practitioners. This facet must be addressed immediately. The use of parenteral vancomycin for extended periods for prophylaxis or therapy without documentation of a pathogen must also be discouraged. ‘Hospitals cannot wait until their first vancomycin-resistant enterococcus or, worse still, staphylococcus or pneumococcus appears before imposing strict infection control measures and restricting the use of antibiotics. Once these organisms appear, eliminating them is a much more difficult task.‘32 To date, data are lacking to demonstrate that intensive hospital antibiotic control programmes prevent the spread of antibiotic resistance.36 Nevertheless, in a new and forceful change in prevention emphasis, such programmes have now been mandated by the CDC in the USA, in an attempt to reduce the spread of vancomycin resistance.37 This governmental agency
480
J. E. McGowan
Jr and B. G. Metchock
Guidelines for proper and improper use of vancomycin, as published by the Centers for Disease Control and Prevention in the USA*
Table
III.
(A)
Situations in which use of vancomycin is appropriate or acceptable: (1) serious infections due to J3-lactam-resistant Gram-positive organisms; (2) infections due to Gram-positive microorganisms in patients with serious allergy to p-lactam antimicrobials; (3) when antibiotic-associated colitis fails to respond to metronidazole or is severe and potentially life-threatening; (4) prophylaxis for endocarditis following certain procedures in patients at high risk for endocarditis; (5) prophylaxis for surgical procedures involving implant of prosthetic materials or devices at institutions with high rates of methicillin-resistant Staphylococcus aureus (MRSA). Situations in which use of vancomvcin should be discouraged: routine surgical prophylaxis;empirical therapy for febrile neutropenia; treatment for single positive blood culture for coagulase-negative staphylococcus; empirical use for presumed infections in patients with negative (4) continued cultures; for infection or colonization of intravascular catheters/vascular (5) prophylaxis grafts; selective decontamination; It{ eradication of MRSA colonization; treatment of colitis or diarrhoea associated with Clostridium difjkile; (8) first-line prophylaxis for low birth weight infants; (9) routine prophylaxis for continuous ambulatory peritoneal dialysis. (10) routine
(B)
,
(1) I:{
* Adapted from reference 37.
has developed recommendations for situations in which vancomycin use is appropriate and settings in which vancomycin use should be discouraged (Table III). No data are yet available to determine acceptance and compliance with these guidelines. Comment
The potential now exists for pneumococcal infection to again become a feared and ominous occurrence. Both epidemic and endemic disease patterns of occurrence become possible when our current arsenal of antimicrobial agents is exhausted. The turn of events that has brought about the spread of MDR-pneumococci may be the one that changes our approach to antibiotic use to a more rational pattern. If so, it can be a sentinel event in our battle against resistant microbes. If we fail to take this opportunity, the consequences may be disastrous. What will we choose to do? References 1. Hughes
263-264.
JM,
LaMontagne
JR.
Emerging
infectious
diseases.
J Infect Dis 1994; 170:
Penicillin-resistant
pneumococci
481
2. Caputo GM, Applebaum PC, Liu HH. Infections due to penicillin-resistant pneumococci. Clinical, epidemiologic, and microbiologic features. Arch Intern Med 1993; 153: 1301-1310. 3. Jacobs MR, Koornhof HJ, Robins-Browne RM et al. Emergence of multiply resistant pneumococci. N Engl J Med 1978; 299: 735-740. 4. Kingman S. Resistance a European problem, too. Science 1994; 264: 363-365. 5. Simberkoff MS. Drug-resistant pneumococcal infections in the United States. A problem for clinicians, laboratories, and public health. JAMA 1994; 271: 1875-1876. 6. Spika JS, Facklam RR, Plikaytis BD, Oxtoby MJ, Pneumococcal Surveillance Working Group. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987. J Infect Dis 1991; 163: 1273-1278. 7. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklam RR. Emergence of drugresistant pneumococcal infections in the United States. JAMA 1994; 271: 1831-1835. 8. Chesney PJ. The escalating problem of antimicrobial resistance in Streptococcus pneumoniue. AJDC 1992; 146: 912-916. 9. Mason EO, Jr, Kaplan SL, Lamberth LB, Tillman J. Increased rate of isolation of penicillin-resistant Streptococcus pneumoniae in a children’s hospital and in vitro susceptibilities to antibiotics of potential therapeutic use. Antimicrob Agents Chemother 1992; 36: 1703-l 707. 10. Janoff EN, O’Brien J, Thompson P et al. Streptococcus pneumoniae colonization, bacteremia, and immune response among persons with human immunodeficiency virus infection. J Infect Dis 1993; 167: 49-56. 11. Linares J, Alonso T, Perez JL et al. Decreased susceptibility of penicillin-resistant pneumococci to twenty-four J3-lactam antibiotics. J Antimicrob Chemother 1992; 30: 279-288. 12. Klugman KP, Saunders J. Pneumococci resistant to extended-spectrum cephalosporins in South Africa. Lancet 1993; 341: 1164. 13. Jorgensen JH. Detection of antimicrobial resistance in Streptococcus pneumoniue by use of standardized susceptibility testing methods and recently developed interpretative criteria. Clin Microbial Newslet 1994; 16: 97-101. 14. McDougal LK, Facklam R, Reeves M et al. Analysis of multiply antimicrobial-resistant isolates of Streptococcuspneumoniae from the United States. Antimicrob Agents Chemother 1992; 36: 2176-2184. 15. John CC. Treatment failure with use of a third-generation cephalosporin for penicillinresistant pneumococcal meningitis: case report and review. Clin infect Dis 1994; 18: 188-193. 16. Dowson CG, Johnson AP, Cercenado E, George RC. Genetics of oxacillin resistance in clinical isolates of Streptococcus pneumoniae that are oxacillin resistant and penicillin susceptible. J Clin Microbial 1994; 38: 49-53. 17. Jorgensen JH, Ferraro MJ, McElmeel ML, Spargo J, Swenson JM, Tenover FC. Detection of penicillin and extended-spectrum cephalosporin resistance among Streptococcus pneumoniae clinical isolates bv use of the E test. .r Clin Micyobiol 1994; 32: 159-163: 18. Tenover FC, Swenson JM, McDougal LK. Screening for extended-spectrum cenhalosnorin resistance in nneumococci. Lancet 1992: 340: 1420. 19. &Fried&d IR, Shelton ST McCracken GH, Jr. Screening for cephalosporin-resistant Streptococcus pneumoniae with the Kirby-Bauer disk susceptibility test. J Clin Microbial 1993; 31: 1619-1621. 20. Krisher KK, Linscott A. Comparison of three commercial MIC systems, E test, fastidious antimicrobial panel, and FOX fastidious panel, for confirmation of penicillin and cephalosporin resistance in Streptococcus pneumoniae. J Clin Microbial 1994; 32: 2242-2245. 21. Daum RS, Nachman JP, Leitch CD, Tenover FC. Nosocomial epiglottitis associated with penicillinand cephalosporin-resistant Streptococcus pneumoniae. J Clin Microbial 1994; 32: 246-248. 22. Tan TQ, Schutze GE, Mason EO, Jr, Kaplan SL. Antibiotic therapy and acute outcomes of meningitis due to Streptococcus pneumoniae considered intermediately susceptible to broad-spectrum cephalosporins. Antimicrob Agents Chemother 1994; 38: 918-923. 23. Friedland IR, Shelton S, McCracken GH, Jr. Chloramphenicol in penicillin-resistant pneumococcal meningitis. Lancet 1993; 342: 240-241.
J. E. McGowan
482
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24. Kristinsson 25. 26.
KG, Hjalmarsdottir MA, Steingrimsson 0. Increasing penicillin resistance in pneumococci in Iceland. Lancet 1992; 339: 1606-1607. Centers for Disease Control and Prevention. Drug-resistant Steptococcus pneumoniaeKentucky and Tennessee, 1993. JAMA 1994; 271: 421422. Cherian T, Steinhoff MC, Harrison LH, Rohn D, McDougal LK, Dick J. A cluster of invasive pneumococcal disease in young children in child care. JAMA 1994; 271:
695-697. 27. Schroder 28. 29. 30. 31. 32. 33.
MC, Cooper G. An epidemic of cold, bronchitis, and pneumoniae due to type V pneumococci. J Infect Dis 1930; 46: 384-392. Stoneburner LT III, Finland M. Pneumococcic pneumonia complicating operations and trauma. JAMA 1941; 116: 1497-1504. Mehtar S, Drabu YJ, Vijeratnam S, Mayet F. Cross-infection with Streptococcus pneumoniae through a Resuscitaire. BMJ 1986; 292: 25-26. Millar MR, Brown NR, Tobin GW, Murphy PJ, Windsor ACM, Speller DCE. Outbreak of infection with penicillin-resistant Streptococcus pneumoniae in a hospital for the elderly. J Hosp Infect 1994; 27: 99-104. Negri MC, Morosini MI, Loza E, Baquero F. In vitro selective antibiotic concentrations of p-lactams for penicillin-resistant Streptococcus pneumoniae populations. Antimicrob Agents Chemother 1994; 38: 122-125. Murray BE. Can antibiotic resistance be controlled? N EnglJMed 1994; 330: 1229-l 230. Kunin CM. Resistance to antimicrobial drugs-a worldwide calamity. Ann Intern Med
1993; 118: 557-561. 34. Patterson JE, Sanchez 35. 36. 37.
RO, Hernandez J, Grota P, Rose KA. Special organism isolation: attempting to bridge the gap. Infect Control Hasp Epidemiol 1994; 15: 335-338. Hirschmann JV, Lipsky BA. The pneumococcal vaccine after 15 years of use. Arch Intern Med 1994; 154: 373-377. McGowan JE, Jr. Do intensive hospital antibiotic control programs prevent the spread of antibiotic resistance? Infect Control Hasp Epidemiol 1994; 15: 478-483. Centers for Disease Control and Prevention. Preventing the spread of vancomycin resistance-report from the Hospital Infection Control Practices Advisory Committee; comment period and public meeting; notice. Fed Register 1994; 59: 25758-25763.