Evaluation of the efficacy and safety of outpatient parenteral antimicrobial therapy for infections with methicillin-sensitive Staphylococcus aureus.

Objectives: As increasing numbers of patients are being treated with outpatient parenteral antimicrobial therapy (OPAT), it becomes ever more important to ascertain the risks and benefits of such treatment for patients.

Methods: We conducted a retrospective analysis of 1,515 patients with methicillin-sensitive Staphylococcus aureus infections who were treated with outpatient parenteral antimicrobial monotherapy. All patients were included in the adverse drug reaction analysis; 1,252 were evaluable for purposes of evaluating treatment efficacy.

Results: The six antibiotics most frequently used in this study (ceftriaxone, cefazolin, vancomycin, oxacillin, nafcillin, and clindamycin) appeared to be equivalent in achieving the desired efficacy outcome.

Conclusions: Vancomycin was associated with a significantly greater number of side effects than was ceftriaxone, cefazolin, or oxacillin, and nafcillin was associated with a significantly greater number of adverse events than ceftriaxone.

Key Words: ceftriaxone, outpatient parenteral antimicrobial therapy, skin infections, Staphylococcus aureus, vancomycin

**********

More than 250,000 Americans receive intravenous antibacterial agents in an outpatient setting each year, and this number continues to increase. (1) In many parts of the United States, outpatient parenteral antimicrobial therapy (OPAT) has become a standard modality for patients with stable infections requiring long-term intravenous antibiotics, such as osteomyelitis, (2) or even short-term antibiotic administration, as, for example, in the case of less serious skin and soft tissue infections. (3) With growing economic pressure to move the treatment of more infections outside the hospital, (4) it becomes imperative to evaluate both the benefits and limitations that may be associated with intravenously administered antibiotics commonly used on an outpatient basis. Comprehensive guidelines for outpatient intravenous antibiotic therapy have been recently republished by the Infectious Diseases Society of America. (5)

We have reviewed and analyzed information from a multicenter OPAT registry, (4) focusing on patients with infections caused by methicillin-sensitive Staphylococcus aureus (MSSA). This focus was chosen for several reasons. MSSA is the pathogen most frequently treated in the OPAT setting, (6) is susceptible to a number of classes of antimicrobial agents, (7) and is associated with a wide range of divergent infections that can be treated by OPAT. (1,7)

Materials and Methods

Patient information was provided by the OPAT Outcomes Registry based in Tacoma, Washington. Data from 1996 to August 2001 were analyzed. These data were collected from 19 physician-based OPAT programs, five home health organizations, and three hospital-based programs in the United States and included information on 12,765 courses of antibiotics.

Clinical outcomes recorded by the registry were determined by the physician responsible for the patient's care, who determined on the last day of OPAT therapy whether the patient was improved, failed, or had no change. The outcome parameter tracked in this study was the question "Did the clinical outcome meet expectations?" This was considered more relevant than a question of "cure" because in a database of diverse infections, the goal of therapy might be suppression of infection rather than cure (eg, chronic osteomyelitis). Bacterial outcomes were determined on the basis of a repeat culture deemed to be negative or positive for the same or a different pathogen. If a repeat culture was not done, the original pathogen was presumed eradicated, a presumption in keeping with current community practice. Adverse events to the antibiotic administered were included only if they resulted in premature discontinuation of the drug. Events that resulted only in dosage adjustment were not included.

Only patients with infections caused by MSSA, and who were treated with monotherapy, were included in the study. The presence of MSSA was determined by cultures taken from the site of the infection and/or blood cultures. Bone biopsy was not performed to determine the presence or cause of osteomyelitis, in keeping with standard practice of infectious disease specialists in a community setting. From our review of the 12,765 courses of antibiotics, we found 1,515 patients who met the inclusion criteria. All 1,515 patients were included in the analysis for adverse events. Because some disease categories were insufficiently populated to supply adequate power for any usable clinical interpretation of efficacy, only 1,252 patients were included in the efficacy analysis. In the group of 1,252 patients evaluated for efficacy, 817 were male. The age range of patients treated was from 1 year to 92 years, with a mean age of 52.3 years.

The 1,252 patients included in the efficacy analysis were treated with one of six antibiotics. Ceftriaxone was the most commonly used antibiotic, followed by vancomycin. The mean dose and dosage range for these six antibiotics can also be seen in Table 1. Antibiotics used in the remaining 263 patients, which were excluded because they were used too infrequently for meaningful statistical analysis, included ampicillin, ampicillin-sulbactam, cefepime, cefonicid, cefotaxime, ceftazidime, cefuroxime, ciprofloxacin, cloxacillin, daptomycin, imipenem, penicillin, piperacillin-tazobactam, and ticarcillin-clavulanate.

The 1,252 patients included in the efficacy analysis were diagnosed with 1 of 10 infectious conditions (Table 2). As was the case for antibiotics used, diagnoses that were not present in sufficient numbers for statistical analysis were excluded. These diagnoses included abscess, bite wound, bronchitis, central nervous system shunt infection, empyema, eye infection, foreign body infection, lymphangitis, mastitis, mastoiditis, mediastinitis, meningitis, necrotizing fasciitis, otitis, peritonitis, pelvic inflammatory disease, pneumonia, prostatitis, pyelonephritis, septic phlebitis, sinusitis, and urinary tract infection.

Among the 1,252 patients included in the safety review, data were available on vascular access complications for 1,232. Antibiotics were administered using the following vascular access devices: peripherally inserted cervical catheters (n = 587), peripheral catheters (n = 379), central tunneled catheters (n = 83), midline catheters (n = 55), ports (n = 44), and other (n = 84) (Table 3).

The categorical data were analyzed by frequency table methods, including [chi square] analysis. The continuous data were analyzed with Pearson and Spearman correlations and analysis of variance where comparison between grouping (such as antibiotic or disease) was desired.

Results

Table 4 shows the percentage of MSSA infections treated successfully for each diagnosis and antibiotic administered in the 1,252 patients included in the efficacy analysis. Each of the six antibiotics compared in this study appeared to be equivalent in achieving the desired outcome of an improved clinical status as assessed by the treating physician.

The number and percentage of patients who had an adverse reaction to the antibiotic administered were tallied for those antibiotics for which numbers were sufficient to provide adequate statistical power. The percentage of adverse events ranged from a low of 1.6% for ceftriaxone to a high of 8.3% for vancomycin. These results, as well as the specific adverse events associated with each antibiotic, are shown in Table 5. Table 6 shows that there were more statistically significant side effects associated with vancomycin than with ceftriaxone, cefazolin, and oxacillin. Nafcillin also had significantly more adverse events than ceftriaxone.

Access device-related adverse events are shown in Table 3.

Discussion

In the present study, we evaluated the use of OPAT for MSSA infections of varying types, using various antibiotics. For our patients, OPAT was demonstrated to be an efficacious and well-tolerated method for treating these infections.

Although this study was not directly comparative, it appears that the OPAT outcomes for patients with MSSA infections are similar to outcomes observed for all patients reported to the OPAT Outcomes Registry. Registry efficacy data as of July 14, 2000, evaluating a total of 5,666 patients who received 7,779 courses of OPAT, revealed an overall improvement rate of 89.4%. Among 5,249 evaluable patients, 183 patients in "unknown" or "other" categories were eliminated, whereas 5,066 (96.5%) showed improvement. These results are consistent with our results shown in Table 3. Registry data as of July 14, 2000, also were analyzed with regard to tolerability. Of 5,794 courses of evaluable antibiotics, adverse events caused early discontinuation in 255 patients (4.4%), again consistent with our findings. (8)

Newer and more recently reported figures with regard to the tolerability of OPAT, compiled from a Registry database of 9,930 patients receiving 13,401 courses of antibiotics from 1996 to 2002, continued to reveal a similarity of outcomes for patients with MSSA infections and all patients receiving OPAT. For example, comparing figures for the 6 antibiotics used in our study with the same 6 agents in the overall 1996 to 2002 Registry data, the use of ceftriaxone was again associated with the lowest incidence of adverse events leading to discontinuation. However, the highest incidence of such adverse events in the overall 1996 to 2002 series was caused by nafcillin, followed by oxacillin, clindamycin, vancomycin, and cefazolin. (9)

In a published report of compiled data from the OPAT Outcomes Registry from 1997 to 2000, the three most commonly treated diagnoses were the same as for our MSSA patients. However, the order of frequency differed in that in the overall population, the most common diagnosis was skin and soft tissue infections, followed by osteomyelitis and then wound infections. In addition, the most frequently used antibiotic was ceftriaxone, (4) as it was for our MSSA patients.

The OPAT Outcomes Registry provides a valid and valuable source of data regarding the overall benefits and risks associated with the administration of antimicrobial agents on an outpatient basis. (4) Likewise, it provides the opportunity to evaluate the role of OPAT in important subsets of patients, as we have done in analyzing patients with MSSA infections, and allows for a comparison of treatment outcomes and adverse effects of antimicrobials. Although a database registry contains some weaknesses (eg, retrospective observational nature, observer variability, potential for incomplete data collection), one of its strengths is the ability to collect large amounts of observational data in a relatively short time that would be difficult, if not impossible, to collect by other means.

In regard to MSSA infections, the OPAT Outcomes Registry indicates a high level of success reported by the treating physician and with a parameter that includes reasonable expectations rather than postculture results. This outcome indicator can encompass confounding factors such as diabetes, gangrene, and expected death.

Decisions to initiate and to continue antimicrobial therapy are based on the estimated risks and benefits to the patient. These factors can be assessed on nearly a real-time basis with the OPAT Outcomes Registry and with statistically significant results, given the number of cases that can be collected from multiple sites. The finding of a higher adverse drug reaction rate with vancomycin is consistent with prior reports in the treatment of endocarditis, pneumonia, and osteomyelitis. (6)

I daresay one profits more by the mistakes one makes off one's own bat
than by doing the right thing on somebody else's advice.
--W. Somerset Maugham

Table 1. Antibiotics used, dosages used, and number of treatment courses
for the 1,252 evaluable patients with MSSA infection treated with
OPAT (a)

             Dosage        Mean    No. of     % of Patients
             range         dose    treatment  outcome met
Antibiotic   (mg/d)        (mg/d)  courses    expectations

Ceftriaxone  1,000-6,000    1,852  400         95.4
Vancomycin     500-4,000    1,641  383         95.5
Cefazolin    1,500-12,000   2,070  217         95.9
Oxacillin    2,000-48,000   9,875  137         94.1
Nafcillin      800-24,000  10,474   79         97.4
Clindamycin  1,600-2,700    2,594   36        100.0

(a) MSSA, methicillin-sensitive Staphylococcus aureus; OPAT, outpatient
parenteral antibiotic therapy.

Table 2. Infectious diagnoses and the number of treatment courses in
1,252 evaluable patients

                                 No. of
Infection treated                treatment courses

Wound infections                      331
Skin and soft tissue infections       273
Acute osteomyelitis                   165
Septic arthritis/bursitis             153
Bacteremia                            100
Chronic osteomyelitis                  94
Prosthetic joint infections            52
Endocarditis                           30
Diskitis                               30
Intravenous catheter infections        24

Table 3. Access-related adverse events observed in the 1,232 OPAT-
treated patients with MSSA infections who were evaluated for safety (a)

                      Type of      No. of such  Total No.
Vascular    No. of    adverse      adverse      of adverse
access      patients  event        events       events (%)

Midline      55       Phlebitis      5           8 (15)
                      Leakage        1
                      Other          2
                      No reaction   47
PICC        587       Phlebitis     14          57 (10)
                      Leakage        9
                      Thrombosis     6
                      Local          5
                      Other         23
                      No reaction  530
Peripheral  379       Phlebitis      9          25 (7)
                      Leakage        7
                      Thrombosis     2
                      Bacteremia     1
                      Local          1
                      Other          5
                      No reaction  354
Central      83       Bacteremia     2           6 (7)
Tunneled              Leakage        2
                      Phlebitis      1
                      Other          1
                      No reaction   77
Port         44       Local          1           1 (2)
                      No reaction   43
Other        84       Local          2           9 (11)
                      Phlebitis      2
                      Thrombosis     2
                      Bacteremia     1
                      Other          2
                      No reaction   75

(a) OPAT, outpatient parenteral antibiotic therapy; PICC, peripherally
inserted central catheters.

Table 4. Percentage of MSSA infections treated successfully for each
diagnosis and antibiotic used to treat 1,252 evaluable patients (a)

                                          No. of patients
                                No. of    successfully
Diagnosis                       patients  treated (%)

Wound infection                 331       318 (96.1)
  Ceftriaxone                   119       115 (96.6)
  Cefazolin                      37        34 (91.9)
  Vancomycin                    120       116 (96.7)
  Oxacillin                      31        30 (96.8)
  Nafcillin                      14        13 (92.9)
  Clindamycin                    10        10 (100)
Skin and soft tissue infection  273       260 (95.2)
  Ceftriaxone                   138       130 (94.2)
  Cefazolin                      24        23 (95.8)
  Vancomycin                     83        80 (96.4)
  Oxacillin                      11        10 (90.9)
  Nafcillin                      10        10 (100)
  Clindamycin                     7         7 (100)
Acute osteomyelitis             165       158 (95.8)
  Ceftriaxone                    20        20 (100)
  Cefazolin                      64        62 (96.9)
  Vancomycin                     40        38 (95)
  Oxacillin                      22        19 (86.4)
  Nafcillin                      12        12 (100)
  Clindamycin                     7         7 (100)
Septic arthritis/bursitis       153       150 (98)
  Ceftriaxone                    53        52 (98.1)
  Cefazolin                      38        38 (100)
  Vancomycin                     24        24 (100)
  Oxacillin                      21        19 (90.5)
  Nafcillin                      14        14 (100)
  Clindamycin                     3         3 (100)
Bacteremia                      100        94 (94)
  Ceftriaxone                    14        12 (85.7)
  Cefazolin                      17        17 (100)
  Vancomycin                     43        39 (90.7)
  Oxacillin                      12        12 (100)
  Nafcillin                      11        11 (100)
  Clindamycin                     3         3 (100)
Chronic osteomyelitis            94        90 (95.7)
  Ceftriaxone                    30        29 (96.7)
  Cefazolin                      12        11 (91.7)
  Vancomycin                     29        27 (93.1)
  Oxacillin                      17        17 (100)
  Nafcillin                       4         4 (100)
  Clindamycin                     2         2 (100)
Prosthetic joint infection       52        52 (100)
  Ceftriaxone                    12        12 (100)
  Cefazolin                       7         7 (100)
  Vancomycin                     23        23 (100)
  Oxacillin                       6         6 (100)
  Nafcillin                       3         3 (100)
  Clindamycin                     1         1 (100)
Endocarditis                     30        27 (90)
  Ceftriaxone                     3         3 (100)
  Cefazolin                       6         4 (66.7)
  Vancomycin                      7         6 (85.7)
  Oxacillin                       7         7 (100)
  Nafcillin                       7         7 (100)
  Clindamycin                     0         0 (0)
Diskitis                         30        30 (100)
  Ceftriaxone                     5         5 (100)
  Cefazolin                       9         9 (100)
  Vancomycin                      3         3 (100)
  Oxacillin                       8         7 (87.5)
  Nafcillin                       2         1 (50)
  Clindamycin                     3         3 (100)
Intravenous catheter infection   24        23 (95.8)
  Ceftriaxone                     6         6 (100)
  Cefazolin                       3         3 (100)
  Vancomycin                     11        10 (90.9)
  Oxacillin                       2         2 (100)
  Nafcillin                       2         2 (100)
  Clindamycin                     0         0 (0)

(a) MSSA, methicillin-sensitive Staphylococcus aureus.

Table 5. Adverse drug reactions sufficient to cause drug discontinuation
among all 1,515 patients identified with MSSA infection and treated with
antibiotic monotherapy (a)

Antibiotic                             Type of
used         No. of patients           adverse event

Vancomycin   520; No data entered = 5  Anaphylaxis
                                       Rash
                                       Leukopenia
                                       Nausea/vomiting
                                       Renal toxicity
                                       Diarrhea
                                       Rash/fever
                                       Other
                                       No reaction
Nafcillin     94; No data entered = 2  Diarrhea
                                       Rash
                                       Renal toxicity
                                       Nausea/vomiting
                                       No reaction
Clindamycin   45                       Diarrhea
                                       Fever
                                       No reaction
Cefazolin    204; No data entered = 1  Diarrhea
                                       Rash
                                       Leukopenia
                                       No reaction
Oxacillin    157; No data entered = 2  Anaphylaxis
                                       Nausea/vomiting
                                       Rash
                                       No reaction
Ceftriaxone  495; No data entered = 1  Anaphylaxis
                                       Fever
                                       Diarrhea
                                       Rash
                                       Renal toxicity
                                       No reaction

Antibiotic    No. of such     Total No. of
used          adverse events  adverse events (%)

Vancomycin         3              43/515 (8.3)
                  20
                   5
                   3
                   4
                   3
                   1
                   4
                 472
Nafcillin          1               5/92 (5.4)
                   2
                   1
                   1
                  87
Clindamycin        1               2/45 (4.4)
                   1
                  43
Cefazolin          2               5/203 (2.5)
                   2
                   1
                 198
Oxacillin          1               3/155 (1.9)
                   1
                   1
                 152
Ceftriaxone        2               8/494 (1.6)
                   3
                   1
                   1
                   1
                 486

(a) MSSA, methicillin-sensitive Staphylococcus aureus.

Table 6. Statistical comparison between antibiotics (P values) with
regard to adverse events sufficient to cause early discontinuation

Antibiotic   Ceftriaxone  Cefazolin  Nafcillin  Oxacillin  Clindamycin

Vancomycin   0.001 (a)    0.021 (a)  0.610      0.020 (a)  0.531
Ceftriaxone               0.454      0.023 (a)  0.790      0.179
Cefazolin                            0.191      0.738      0.468
Nafcillin                                       0.133      0.805
Oxacillin                                                  0.343

(a) Significant P value comparisons.

This study was supported in part by Roche Laboratories, Inc, Basel, Switzerland, and the Outpatient Parenteral Antimicrobial Therapy Outcomes Registry, Tacoma, WA.

Accepted August 13, 2004.

Presented in part at the 40th Annual Meeting of the Infectious Diseases Society of America, Chicago, IL, October 24 to 27, 2002.

References

1. Williams DN, Rehm SJ, Tice AD, et al. Practice guidelines for community-based parenteral anti-infective therapy: ISDA Practice Guidelines Committee. Clin Infect Dis 1997;25:787-801.

2. Bernard L, El-hajj, Pron B, et al. Outpatient parenteral antimicrobial therapy (OPAT) for the treatment of osteomyelitis: evaluation of efficacy, tolerance and cost. J Clin Pharm Ther 2001;26:445-451.

3. Deery HG II. Outpatient parenteral anti-infective therapy for skin and soft-tissue infections. Infect Dis Clin North Am 1998;12:935-949.

4. Nathwani D, Tice A. Ambulatory antimicrobial use: the value of an outcomes registry. J Antimicrob Chemother 2002;49:149-154.

5. Tice AD, Rehm SJ, Dalovisio JR, et al. Practice guidelines for outpatient parenteral antimicrobial therapy. Clin Infect Dis 2004;38:1651-1672.

6. Tice AD, Schleis TG, Nolet B, et al. Outcomes registry for outpatient IV antimicrobial therapy. Infusion 2000;6:27-35.

7. Parsonnet J, Deresiewicz RL. Staphylococcal infections, in Braunwald E, Fauci AS, Kasper DL, et al (eds): Harrison's Principles of Internal Medicine. 15th ed. New York: McGraw Hill, 2001, pp 889-901.

8. Martinelli LP, Tice A, Hoaglund P. Outpatient parenteral antimicrobial therapy (OPAT): safety, efficacy and outcomes. Presented at the 38th Annual Meeting of the Infectious Diseases Society of America, New Orleans, LA, September 7 to 10, 2000.

9. Tice A, Seibold G, Martinelli L. Adverse effects from intravenous antibiotics with OPAT. Presented at the 40th Annual Meeting of the Infectious Diseases Society of America, Chicago, L, October 24 to 27, 2002. Poster No. 59.

RELATED ARTICLE: Key Points

* Outpatient parenteral antimicrobial therapy is now a common modality for treatment of serious infections with methicillin-sensitive Staphylococcus aureus and overall provides a satisfactory level of treatment efficacy and safety.

* The six most commonly used antibiotics (ceftriaxone, cefazolin, vancomycin, oxacillin, nafcillin, and clindamycin) were all equally effective in achieving a successful clinical outcome.

* Vancomycin had significantly more adverse effects than ceftriaxone, cefazolin, or oxacillin; nafcillin had significantly more adverse effects than ceftriaxone.

Melissa Wynn, MD, Joseph R. Dalovisio, MD, Alan D. Tice, MD, and Xiaozhang Jiang, MS

From the Ochsner Clinic Foundation, Section on Infectious Diseases, New Orleans, LA, and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI.

The authors have no commercial, proprietary, or financial interest to disclose in regard to this manuscript.

Reprint requests to Dr. Joseph R. Dalovisio, Infectious Diseases, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail: [e-mail]