Comparison of methicillin-resistant and methicillin-sensitive Staphylococcus aureus bacteremia

Comparison of methicilUn-resistant and methicillin.sensitive S t a p h y l o c o c c u s a u r e u s bacteremia Eric Lewis, M.I). Louis D. Saravolatz, M.D. Detroit, Michigan

Methicillin-resistant Staphylococcus aureus (MRSA) has become endemic in Detroit, accounting for 50% of bacteremias in heroin abusers. To identify the salient epidemiologic and clinical features of MRSA bacteremia, case-control studies were performed comparing 28 cases of MRSA bacteremia to 28 cases of methicillinsensitive S. aureus (MSSA) bacteremia in intravenous drug abusers. Infective endocarditis was diagnosed in 46.4% (13 of 28). In endocarditis and nonendocarditis bacteremia alike, the duration of fever, length of hospitalization, need for surgery, and mortality rates were similar. A history of recent antimicrobial therapy, especially cephalosporins, was more common in the MRSA group (p = 0.006). Complications including neurologic, renal, vascular, and musculoskeletal manifestations were more common in the MSSA endocarditis patients than MRSA endocarditis patients, although this difference was not significant. Complications related to antibiotic therapy were similar for both groups. The case-control studies indicate that MRSA and MSSA are similar in their virulence as measured by duration of hospitalization, duration of fever, complications, and mortality. (AMJ INFECTCONTROL13:109-I 14, 1985.) Staphylococcus a u r e u s o r g a n i s m s r e s i s t a n t to m e t h i c i l l i n (MRSA) w e r e i n i t i a l l y d e s c r i b e d in E u r o p e in the e a r l y 1960s, a n d r e p o r t s of noso c o m i a l i n f e c t i o n s w i t h this o r g a n i s m also d a t e f r o m this p e r i o d . " 2 T h e first n o s o c o m i a l outb r e a k of M R S A w a s r e p o r t e d b y B a r r e t t et al. 3 f r o m B o s t o n City H o s p i t a l in 1968. C h a r a c t e r istically, infe, c t i o n s d u e to M R S A w e r e l i m i t e d to hospitaliz,ed p a t i e n t s , u s u a l l y in b u r n or int e n s i v e c a r e units. 4-8 I n 1982, h o w e v e r , c o m m u n i t y - a c q u i r e d M R S A w a s r e p o r t e d as epid e m i c in the D e t r o i t a r e a , a n d c o m m u n i t y -

acquired MRSA endocarditis among parenteral d r u g a b u s e r s w a s also r e p o r t e d in D e t r o i t in the s a m e y e a r . 9' ~0 This r e p o r t d e s c r i b e s M R S A b a c t e r e m i a in both endocarditis and nonendocarditis patients a n d c o m p a r e s 28 c a s e s of c o m m u n i t y - a c q u i r e d M R S A b a c t e r e m i a w i t h 28 cases of c o m m u n i t y a c q u i r e d m e t h i c i l l i n - s e n s i t i v e S . a u r e u s (MSSA) b a c t e r e m i a . T h e s t u d y e x a m i n e s the clinical v i r u l e n c e of the o r g a n i s m as w e l l as a n t i m i c r o b i a l u s a g e as a p r e d i s p o s i n g factor.

MATERIALS AND METHODS From the University of Michigan Medical School and the Division of Infectious Diseases and Hospital Epidemiology, Henry Ford Hospital. Presented at the Twenty-second Interscience Conference on Antimicrobial Age.nts and Chemotherapy, Miami, Fla., October 1982. Reprint requests Louis D, Saravolatz, M.D., Division of Infectious Diseases and Hospital Epidemiology, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202.

We r e v i e w e d the s u r v e i l l a n c e r e c o r d s of the D e p a r t m e n t of H o s p i t a l E p i d e m i o l o g y of H e n r y F o r d H o s p i t a l for c o n s e c u t i v e cases of S . a u r e u s b a c t e r e m i a f r o m M a r c h 1980 to D e c e m b e r 1981. S i n c e m o s t c o m m u n i t y - a c q u i r e d M R S A infections occur a m o n g intravenous drug abusers in D e t r o i t , we s e l e c t e d o n l y those p a t i e n t s w i t h a h i s t o r y of p a r e n t e r a l d r u g use a n d a b u s e 109

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and divided them into two groups: MSSA and MRSA. We identified 28 cases of MRSA and 28 cases of MSSA bacteremia. In both groups, 13 cases were classified as endocarditis and 15 cases as bacteremia without sufficient evidence of endocarditis. The MRSA group consisted of 27 different patients. One patient was counted twice because he had two separate episodes of MRSA endocarditis more than 1 year apart. The MSSA group consisted of 28 different patients. The patients were then m a t c h e d for sex, age, and w h e t h e r they had endocarditis or were simply bacteremic with S. a u r e u s . Four groups of patients were therefore established: 13 MRSA endocarditis patients matched with 13 MSSA endocarditis patients and 15 MRSA bacteremic patients m a t c h e d with 15 MSSA bacteremic patients without sufficient evidence to warrant a diagnosis of endocarditis.

Case.control studies

Case definitions

The antibiotic sensitivities of the organisms were determined by the tube dilution method, the microtiter technique, or the Kirby-Bauer technique. Organisms were classified as MRSA if the minimal inhibitory concentration was >/12.5 ~g/ml to either nafcillin or methicillin in the tube dilution or microtiter assay or if the zone diameter was ~ 9 m m to oxacillin by the Kirby-Bauer technique. 9

In classifying patients as having either endocarditis or bacteremia (nonendocarditis), we considered the criteria of Menda and Gorbach 11 and von Reyn et al. 12 Of the 26 cases of endocarditis, 20 fulfilled criteria similar to those of Menda and Gorbach. All had (1) fever/>38 ~ C during the first 24 hours of admission; (2) at least two of two blood cultures positive during the first 48 hours of admission; (3) a m u r m u r compatible with valvular involvement; and (4) emboli. The remaining six patients were classified as having endocarditis because (1) endocarditis was confirmed at autopsy or at surgery (two cases); (2) they had no evidence of embolization b u t had persistently positive blood cultures (greater than or equal to four of four), fever, and a new m u r m u r compatible with valvular involvement (two cases); and (3) they had at least two of two blood cultures positive, septic p u l m o n a r y emboli, and fever b u t no detectable m u r m u r s (two cases). Thirty patients were classified as having S. a u r e u s b a c t e r e m i a because they had at least one blood culture positive for S. a u r e u s , but there was no evidence to support a diagnosis of infective endocarditis. Twenty-two of 30 had multiple positive blood cultures, and 29 of the patients had coexistent soft tissue infections.

We performed two case-control studies: one compared MRSA with MSSA endocarditis patients and the other c o m p a r e d MRSA with MSSA bacteremic (nonendocarditis) patients. These groups were examined for differences in duration of fever while in the hospital, duration of hospitalization, antimicrobial usage before hospitalization, complications of infection, and complications of antimicrobial therapy. Severity of infection was assessed according to the following criteria: fever for fewer than or equal to 7 days; fever for more then 7 days; bacteremic complications other than septic p u l m o n a r y emboli, such as arthritis, brain abscess, and glomerulonephritis; and death. Statistical analysis was performed with the paired t test for comparing means and Fisher's exact test for comparing proportions. 13 Microbiology

RESULTS Endocarditis

Among the 26 episodes of endocarditis, 23 patients had right-sided endocarditis, three of w h o m had concomitant mitral valve involvement. In all three patients, MSSA was the infecting organism. Eleven of the 23 patients with right-sided disease were infected with MRSA. Left-sided disease alone was present in three of the 26 patients. Its presence was d o c u m e n t e d in two of the MRSA cases, one at surgery and the other at autopsy (mitral valve). The third patient with left-sided disease had a diagnosis of mitral valve disease based on clinical examination and died of an intracerebral hemorrhage. The mean age of the MRSA patients was 32.7 years (range 26 to 42 years). The mean age of the MSSA patients was 30.7 years (range 23 to

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39 years). Twenty-four of these endocarditis patients were m e n and two were women. The admission m e a n white blood cell count (WBC), hemoglobin, and creatinine in the endocarditis patients were WBC 14.9 x 103/mm 3, Hb 13.2 gm, and creatinine 1.2 mg/dl for the MRSA group and WBC 18.8 x 103/mm 3, Hb 12.6 gin, and creatinine 1.3 mg/dl for the MSSA group. There were no significant differences between the MRSA and MSSA endocarditis patients in duration of hospitalization, duration of fever, or those factors examined to assess the severity of infection (Table 1). Six of the 13 MSSA patients had complications of infection other than septic p u l m o n a r y emboli: (1) osteomyelitis of the lumbosacral spine; (2) glomerulonephritis, cerebritis, and epididymitis; (3) pancarditis and glomerulonephritis; and (4) septic arthritis (three cases). Although there were more complications in the MSSA group than in the MRSA group, this difference was not statistically significant (p > 0.1). One patient died in each group; both had fatal mitral valve endocarditis complicated by intracerebral hemorrhage.

cation of the infectious process. This patient bec a m e quadriparetic secondary to a spinal cord compression from a cervical spine abscess. However, when the history of recent antimicrobial use before hospitalization is included, a difference approaching significance is found between the MRSA and MSSA groups (p = 0.06). Among MRSA patients, nine gave a history of antimicrobial usage before hospitalization as compared to only three of the MSSA patients. If cephalosporin and semisynthetic penicillin use is considered separately from other antibiotics, the difference is more striking, with nine in the MRSA group vs. two in the MSSA group (p = 0.02). If one considers the bacteremic patients as a whole, especially for cephalosporin and semisynthetic penicillin usage, 17 of 28 MRSA patients received antimicrobial agents compared with 6 of 28 patients in the MSSA group. This difference is significant (p = 0.006). Regarding complications secondary to antimicrobial therapy among the endocarditis patients with MRSA, all were treated with vancomycin either alone (5 of 13) or in combination with an additional antibiotic (8 of 13). Additional antibiotics were rifampin or an aminoglycoside. All thirteen MSSA patients were treated with a cephalosporin or nafcillin either alone (8 of 13) or in combination (5 of 13) with an aminoglycoside or rifampin. In the nonendocarditis group, 12 of 15 MRSA patients were treated with vancomycin alone or in combination with an additional antibiotic. The remaining three MRSA patients were treated with a beta-lectern antibiotic. In spite of in vitro resistance in these three patients (two treated with nafcillin and one treated with a cephalosporin), all improved, possibly from the surgical drainage of abscesses. All MSSA patients were treated with nafcillin or a cephalosporin either alone (13 of 15) or with an additional antibiotic (2 of 15). There was no significant difference between the MRSA and MSSA groups with regard to complications of antibiotic therapy. Four of the MRSA endocarditis patients had complications from antibiotic therapy, including mild azotemia in two patients treated with vancomycin plus an aminoglycoside and one case each of a

Nonendocarditis bacteremic patients

Among 30 patients with S. a u r e u s bacteremia and insufficient evidence of endocarditis, 16 were m e n and 14 were women. The m e a n age of the MRSA patients was 31.2 years (range 20 to 41 years). The m e a n age of the MSSA patients was 30.9 years (range 20 to 50 years). Twenty-nine of the 30 patients had clinical evidence of a soft tissue infection at the time of admission. In general, these infections were located at the site of drug injection (neck or groin areas). The admission m e a n WBC count, hemoglobin, and creatinine in these bacteremic patients were: WBC 1.4 x 103/mm a, Hb 11.3 gm, and creatinine 1 mg/dl for the MRSA group and WBC 14.5 • 103/ram 3, Hb 11.9 gm, and a creatinine of 1 mg/dl for the MSSA group. No significant difference was found between the MRSA and MSSA bacteremic patients in duration of hospitalization, duration of fever, or those factors used to assess the severity of infection (Table 2). None of the bacteremic patients died; only one had a significant compli-

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Table

1. Infective endocarditis patients Factors

Duration of hospitalization Duration of fever Duration of fever with appropriate antibiotic therapy Fever for ~<7 days Fever for >7 days Systemic complications Mortality Antibiotic usage before hospitalization Cephalosporin or penicillinase-resistant penicillin usage before hospitalization

Table

MRSA (13 patients)

MSSA (13 patients)

p Value

40.9 • 16.8 days 11.6 +_ 10,1 days 9.7 • 10.3 days

43.1 -.- 11.8 days 11.8 +_ 7,0 days 11.6 • 7.0 days

>0.I >0.1 >0,1

6/13 7/13 3/13 1/13 8/13 8/13

5/13 8/13 6/13 1/13 6/13 4/13

>0.1 >0.1 >0.1 >0.1 >0.1 >0.1

MRSA (15 patients)

MSSA (15 patients)

p Value

20,3 - 11.6 days 7.5 • 3.4 days 5.5 • 2.6 days

19,4 • 11,1 days 5.1 • 4.9 days 4.5 • 4.7 days

NS NS NS

11/15 4/15 0/15 0/15 9/15 9/15

13/15 2/15 1/15 0/15 3/15 2/15

NS NS NS NS 0.06 0.02

2. Bacteremic nonendocarditis patients Factors

Duration of hospitalization Duration of fever Duration of fever with appropriate antibiotic therapy Fever for ~<7 clays Fever for >7 days Systemic complications Mortality Antibiotic usage before hospitalization Cephalosporin or penicillinase-resistant penicillin usage before hospitalization NS = not significant, p > 0.1.

rash and urticaria. Four of the MSSA patients had complications associated with antibiotic therapy. One developed nafcillin-induced granulocytopenia, and the other three had allergic manifestations (rash, pruritus, and eosinophilia). Only one of the nonendocarditis patients developed complications of antibiotic therapy, a MSSA patient who developed neutropenia while being treated with nafcillin. DISCUSSION

The pathogenic potential of methicillin-resistant S. a u r e u s has been recognized for more than 20 years. Following its description in a small fraction of S. a u r e u s isolates, MRSA became a recognized nosocomial pathogen in Europe. Its potential as a community pathogen was also recognized during that period. In 1965 Colley et al. 14 reported 73 patients with MRSA

infections. Although most of these infections were nosocomial, six patients were admitted to the hospital for MRSA infections, five of whom had no recent history of hospitalization. Although methicillin-resistant S. a u r e u s has been a well-recognized nosocomial pathogen in the United States for the past 15 years, it was not until recently that its significance as a community pathogen was fully recognized? MRSA has become a significant community-acquired pathogen among intravenous drug abusers in the Detroit area. Over a 19-month period from March 1980 to September 1981, the percentage of community-acquired S. a u r e u s infections due to MRSA increased from 3% to 38% at Henry Ford Hospital. 15 The reasons for the emergence of MRSA as a community pathogen in this area have not been definitely established. However, as in nosoco-

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Methicillin-resistant and -sensitive bacteremias

mial outbreaks, a significant association m a y exist between prior use of antimicrobial agents (especially beta-lactams) and the presence of MRSA as an infecting organism. A strong arg u m e n t can be m a d e that the presence of MRSA among the parenteral drug abusers is correlated with the practice of self-administration of antibiotics either as therapy for infectious complications or as prophylaxis. It is well recognized that self-administration of antimicrobial agents is c o m m o n among parenteral drug abusers. Forty-six percent (26 of 56) of our patients gave a history of antibiotic consumption before their admission to the hospital. Oral antimicrobial agents are readily available for self-administration by the parenteral d r u g - a b u s i n g population of Detroit and some patients even used antimicrobials prophylactically. Initially, the occurrence of MRSA infection among drug addicts was thought to be linked to a particular b r a n d of heroin sold in the Detroit area. However, this does not appear to be the case. 15 It seems likely that the source of the S . a u r e u s is not the heroin and injection apparatus but r a t h e r the drug abuser's endogenous

sites were a problem when vancomycin was administered. Thus vancomycin-treated patients compared favorably with b e t a - l a c t a m - t r e a t e d patients with regard to adverse reactions. Another possible side effect of vancomycin is ototoxicity, but since serial audiograms were not performed, cochlear damage could not be evaluated. In this case-control study it is difficult to evaluate fully the therapeutic response of the MRSA and MSSA groups. It is well known that these patients often leave the hospital against medical advice, and, once discharged, do not return for follow-up. Except for the two deaths of the endocarditis patients, all subjects in this study had no evidence of infection when they were discharged. No difference in therapeutic efficacy was noted in the MRSA patients treated with vancomycin and the MSSA patients treated with beta-lactam antibiotics as demonstrated by the comparable durations of fever, hospitalization, and mortality of the two groups. Recent articles in the literature support the use Of vancomycin as an effective alternate therapy to beta-lactam antibiotics to treat staphylococcal infections. 2~

flora.16, 17

The case-control studies reported in this article indicate that MRSA and MSSA are similar in their virulence as measured by duration of hospitalization, duration of fever, infectious complications, and mortality. While this evidence contradicts some of the earlier views by Lacey/8 it agrees with earlier European literature and more recent studies in this c o u n t r y J 4' ,9 It is also i m p o r t a n t to note the comparison of antibiotic-associated complications between the MRSA and MSSA patients. With three exceptions in the MRSA nonendocarditis group, all MRSA patients were treated with vancomycin either alone or in combination with an additional antibiotic. No major complications of vancomycin therapy occurred among our patients. Mild azotemia, possibly antibiotic related, occurred in two of the MRSA endocarditis patients; however, both of these patients were treated with an aminoglycoside in addition to vancomycin. Thrombophlebitis did not increase at the sites of administration, although these patient,~ were usually treated with central lines. In anot]her study ~9peripheral intravenous

113

The authors t h a n k B. Belian, P. Cornett, a n d E. Stassen.

References

1. Kallings LO: The susceptibility of staphylococcalhospital strains to methyl-isoxazolyl-penicillin.Acta Pathol Microbiol Scand 54:127-128, 1962. 2. Benner EJ, KayserFH: Growingclinical significanceof methicillin-resistant Staphylococcus aureus. Lancet 2:741-744, 1968. 3. Barrett FF, McGehee RF Jr, Finland M: Methicillinresistant S. aureus at Boston City Hospital. N Engl J Med 279:441-447, 1968. 4. CrosselyK, LoeschD, LandesmanB, et al: An outbreak of infectionscaused by strains of Staphylococcus aureus resistant to methicillin and aminoglycosides.I. Clinical studies. J Infect Dis 139:273-279, 1979. 5. CrosselyK, Landesman B, Zaske D: An outbreak of infections caused by strains of Staphylococcus aureus resistant to methicillin and aminoglycosides.II. Epidemiologic studies. J Infect Dis 139:280-287, 1979. 6. DunkleLM, Naqui SH, McCallumR, et al: Eradication of epidemic methicillin-gentamicin-resistant Staphylococcus aureus in an intensive care nursery. Am J Med 70:455-458, 1981. 7. O'TooleRD, Drew WL, Dahlgren BJ, et al: An outbreak of methicillin-resistant Staphylococcus aureus infections: Observations in hospital and nursing home. JAMA213:257-263, 1970. 8. Peacock JE Jr, Marsik FJ, Wenzel RP: Methicillin-re-

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sistant Staphylococcus aureus: Introduction and spread within a hospital. Ann Intern Med 93:523-532, 1980. Saravolatz LD, Markowitz N, Arking L, et al: Methicillin-resistant Staphylococcus aureus epidemiologic observations during a community-acquired outbreak. Ann Intern Med 96:11-16, 1982. Levine DP, Cushing RD, Jui J, et al: Community-acquired methicillin-resistant Staphylococcus aureus endocarditis in the Detroit Medical Center. Ann Intern Med 97:330-338, 1982. Menda KB, Gorbach SL: Favourable experience with bacterial endocarditis in heroin addicts. Ann Intern Med 78:25-32, 1973. von Reyn CF, Levy BS, Arbeit RD, et al: Infective endocarditis: An analysis based on strict case definitions. Ann Intern Med 94:505-518, t98t. Ostle B: Statistics in research: Basic concepts and techniques for research workers, ed 3. Ames, 1974, Iowa State University Press. Colley EW, McNicol MW, Bracken PM: Methicillin-re-

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sistant staphylococci in a general hospital. Lancet 1:595-597, 1965. Saravolatz LD, Pohlod DJ, Arking LM: Community-acquired methici]lin-resistant Staphylococcus aureus infections: A new source for nosocomial outbreaks. Ann Intern Med 97:325-329, 1982. Tuazon CU, Sheagren JN: Increased rate of carriage of Staphylococcus aureus among heroin addicts. J Infect Dis 129:725-727, 1974. Tuazon CU, Sheagren JN: Staphylococcal endocarditis in parenteral drug abusers: Source of the organism. Ann Intern Med 82:788-790, 1975. Lacey RW: Antibiotic resistance plasmids of Staphylococcus aureus and their clinicalimportance. Bacteriol Rev 39:1-32, 1975. Sorrell TC, Packham DR, Shanker S, et al: Vancomycin therapy of methicillin-resistantStaphylococcus aureus. Ann Intern Med 97:344-350, 1982. Hook EW, Johnson WD: Vancomycin therapy of bacterial endocarditis. Am J Med 65:411-415, 1978.

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