Journal of Chemotherapy
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Prophylactic Mezlocillin-Netilmicin Combination in Permanent Transvenous Cardiac Pacemaker Implantation: a Single-Center, Prospective, Randomized Study F. De Lalla, W. Bonini, T. Broffoni, G. Ferrari & G. Alegente To cite this article: F. De Lalla, W. Bonini, T. Broffoni, G. Ferrari & G. Alegente (1990) Prophylactic Mezlocillin-Netilmicin Combination in Permanent Transvenous Cardiac Pacemaker Implantation: a Single-Center, Prospective, Randomized Study, Journal of Chemotherapy, 2:4, 252-256, DOI: 10.1080/1120009X.1990.11739026 To link to this article: http://dx.doi.org/10.1080/1120009X.1990.11739026
Published online: 14 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yjoc20 Download by: [Australian Catholic University]
Date: 14 August 2017, At: 13:06
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
Journal of Chemotherapy
Prophylactic MezlocillinN etilmicin Combination in Permanent Transvenous Cardiac Pacemaker Implantation: a Single-Center, Prospective, Randomized Study F. DE LALLA'~' - W . BONINI H T. BROFFONI *"' - G. FERRARI '""' G. ALEGENTE '~ Summary ------------------------ --------A prospective, randomized study was carried out in order to assess the efficacy and safety of the mezlocillin-netilmicin combination in the prophylaxis of first permanent tran s venous cardiac pacemaker implantation. Five hundred and fifty-two consecutive patients were randomly administered either 2 g mezlocillin and 200 mg netilmicin both as an i.v. bolus before implantation or 2g mezlocillin before and then 6 and 12 hours after surgery and 200 mg netilmicin before and then 12 hours after implantation . No adverse events were seen. Neither pocket nor electrode infections were observed in the 457 subjects still alive (mean follow-up: 29.2 months) or in patients who died after 1 year of follow-up (mean follow-up: 20.1 months) or before this time (mean follow-up: 4. 7 months). The serum and pocket concentrations of mezlocillin and netilmicin at the end of surgery were found to be adequate to cover microorganisms that most often cause infections, including methicillin-resistant staphylococci. Key words: mezlocillin-netilmicin combination, prophylaxis, pacemaker surgery.
* Division of In fectious Disease; ** Division of Cardiology, S.Anna Hospital, Como, Italy. Correspondence: Fausto de Lalla M.D., Divisione Malatrie Infettive, Ospedale S. Bartolo, Via Rodolfi, 36100 Vicenza, Italy. © Edizioni Riviste Scientifiche - Firenze
Vol. 2 - n. 4 (252-256) - 1990
INTRODUCTION
Most of the infections following transvenous cardiac pacemaker implantation are caused by staphylococci 1 ' 3 which are often methicillin-resistant strains 3 • 4 • Other microorganisms which are sometimes isolated from infected pockets or wounds include Propionibacterium acnes, Corynebacterium sp., Escherichia coli and Proteus sp. 1 • 5 , sometimes in mixed culture. Early and even late infections (delayed by months or years) are, indeed, commonly caused by the skin organisms introduced at the time of implantation 6 and, as is well known, these may include Gram-negative bacteria which have colonized the skin, especially in patients hospitalized some days before the operation. Infection remains a serious complication of transvenous pacemaker surgery. The incidence is reported in different studies to vary between 1% and 14% 7 - II; moreover, the infection is very frequently not limited to the surgical pocket, but also involves the electrode and eventually causes endocarditis. 12 ' 13 • In most patients it may, therefore, be resolved only by having recourse to the substitution of the entire system. About six to eight weeks following insertion, on the other hand, the electrode appears to be firmly anchored to the ventricular endocardium and can thus be removed only by cardiopulmonary bypass surgery 12 • Because of this troublesome and sometimes life threatening complication, prophylactic antibiotics are generally recommended 14 • 1 5 • There is, however, no uniformity of practice in the use of antimicrobial agents in pacemaker implantation, or for other kinds of clean surgery in which foreign body or prosthetic devices are implanted. In a recent trial, antibiotics were given for as many as 5 days following pacemaker ISSN 1120-009X
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
PROPHYLACTIC MEZLOCILLIN-NETILMICIN COMBINATION IN PERMAN ENT TRANSVENOUS, ETC .
implantation 11 ; in other studies only short-term regimens (3 doses) were administered 16 • In abdominal surgery, as well as in transurethral, gynecologic and obstetric operations, the efficacy of single-dose prophylaxis has been definitively proven in a large number of published studies 17 • A prospective, randomized study was thus planned to compare the efficacy and the safety of single-dose preoperative prophylaxis with that of a multi-dose perioperative regimen in permanent cardiac pacemaker implantation. Because of the wide range of potential pathogens which may be involved in postoperative infectious complications, an antibiotic combination was chosen, i.e. an antistaphylococcal drug, active also against methicillin-resistant strains (netilmicin), and a broad spectrum penicillin (mezlocillin). PATIENTS AND METHODS
Patients included and prophylactic regimens Patients scheduled for routine cardiac pacemaker surgery (first permanent pacing of both generator and electrode) from January 1986 to December 1988 were included in the study . Pacemakers were inserted for a variety of conditions but mainly for complete heart block, arrhythmias or bradycardia. Patients with signs and/or symptoms of infection at whatever site and those who had received antibiotics in the previous five days, as well as subjects with known allergy to betalactams and/or aminoglycosides, were excluded. Their general condition (good, fair and poor) as well as some concomitant diseases or treatments which are considered potential predisposing factors for infection (such as diabetes mellitus, renal insufficiency, malignancy, corticosteroids or anticoagulant treatment) were evaluated in each subject before surgery. Patients who entered were randomly allocated to group A or to group B. Group A subjects received 2 g mezlocillin (Bayer) and 200 mg netilmicin (Essex) both as an i.v . bolus 15-20 minutes before surgery. Group B patients were given 2 g mezlocillin as an i.v. bolus 15-20 minutes before and then 6 and 12 hours after implantation and netilmicin 200 mg as an i. v. bolus 15-20 minutes before and then 12 hours after surgery .
253
Operative technique When necessary hair was removed with a depilatory cream on the morning of surgery and the whole chest was washed with Hibiscrub; the operating field was disinfected with 0.5% chlorhexidine in 70% ethyl alcohol. Surgery was always performed by one of the two cardiologists responsible for permanent cardiac pacemaker implantation in our hospital. The surgical technique was essentially the same in all patients. The generator was placed in a subcutaneous prepectoral pocket; cephalic or occasionally subclavian veins were used for insertion of the electrode. A light pressure dressing was applied post-operatively to prevent hematoma .
Definition of infection Early infection. Early infection was defined in every case as the evidence of acute inflammation (redness, swelling and/or appearance of a serous-purulent discharge) at the site of implantation, with or without a raised temperature ( > 3 7. 5° C) on at least two separate occasions and laboratory evidence of infection (leukocytosis , increased sedimentation rate) and with or without potential pathogen(s) isolated from pocket discharge . Late infection. Apart from the local signs of infection at the generator site (with or without systemic symptoms) according to the criteria above, fever associated with positive blood culture of inexplicable origin was regarded as the evidence of infection by transvenous electrode catheter itself and/or of the adjacent endothelium (pacemaker-related endocarditis). Antibiotic assays In 20 patients venous blood was drawn immediately before the injection of the first prophylactic dose of antibiotic and then at the beginning and end of implantation. Subcutaneous tissue samples from the generator pocket at the beginning and at the end of operation were also taken. All serum and tissue samples were stored at - 70°C until antibiotic concentrations were determined by high-performance liquid chromatography (HPLC) developed by Knoller et al 18 (mezlocillin) and by Dionisotti et al. 19 • Mezlocillin and netilmicin were separated
254
F. DE LALLA • W. BONINI · T. BROFFONI · G. FERRARI · G. ALEGENTE
on reverse phase columns (Nova-Pak 4C18 3.9x150 mm and Bondapak 10C18 3.9x300 mm, respectively). Detection was by UV spectrophotometry, using a Waters 501 pump, a Lambda-Max 481 variable wavelength detector (Waters) and a Waters 745 Computing Integrator.
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
Follow-up After implantation, patients were examined daily during their stay in hospital (at least 3 days) and on discharge they were instructed to report any signs of infection immediately. Then they were examined monthly for 4-6 months and thereafter every 3-4 months. Routine laboratory examinations (including a complete blood count with differential leukocyte and platelet counts, serum creatinine, serum transaminases, glucose and urinalysis) were made 3-4 days postoperatively and then 8-10 days later .
RESULTS
A total of 552 patients were included in the study. Two hundred and seventy-seven were treated with 1 dose of the mezlocillin-netilmicin combination (group A) and 275 received 3 doses of mezlocillin and 2 doses of netilmicin (group B). During the follow-up 95 patients (45 in group A and 50 in group B) died, with no evidence of infection in any case. Forty-seven of these subjects (22 in group A and 25 in group B) died 2-12 months after implantation. These were evaluated for the safety of the prophylactic regimen but were not assessed for its efficacy, owing to the inadequacy of the follow-up period (4.7 months). Of the other 48 patients who died, 23 belonging to group A and 25 to group B, all had been followed for at least 1 year (average length of follow-up: 20.1 months; range: 12-36 months). They were, therefore, assessed for both prophylactic efficacy and safety. In the 457 patients who are still alive the period of follow-up varied between 12 and 48 months (average length: 29.2 months) . The main demographic and clinical data of 505 patients which could be evaluated for both safety and efficacy (48 dead after at least 1 year after implantation and 457 still alive) are listed in Table 1. There were no sign!ficant differ-
TABLE 1 - Clinical data in 505 patients undergoing pacemaker implantation evaluated for prophylaxis efficacy.
Group B
Group A Patients (M/F) (no.) Mean age (range) (yr)
255 (150/105) 71.4 {19-99)
General co ndition (% ) Good Fair Poor
90 (35.3) 129 (50.6) 36 (14.1)
Hospitalization before surgery (d .) Mean Range
250 (164/86) 70.9 (24-90) 98 (39.2) 122 (48 .8) 30 (12.0)
6.2 0-31
6.4 0-50
Risk factors for infection/no. patients (%) Di abetes mellitus Ren al insufficiency * Cirrhosis H eart failure Corticosteroids therapy Anticoagulant therapy Others
74 37 10 53 3 25 5
Duration of surgery (min.) Mea n Range
57.8 50-160
59.5 45-155
0
0
Pos t-operative infections (no.)
(29 .0) (14.5) (3.9) (20.8) (1.2) (9.8) (1 .9)
75 32 9 56 2 28 7
(30.0) (12.8) (3.6) (22.4) (0.8) (11.2) (2.8)
* creatinine > 1. 8 mg/dl.
ences for any of the variables considered (age, general condition, potential risk factors for infection and duration of surgery) and the two treatment groups (group A, 255 patients and group B, 250 patients) were considered comparable. Neither clinical nor laboratory evidence of adverse reactions to either of the antibiotics used were seen in any of the 552 patients in-
TABLE 2 - Mean serum and pocket wbcutaneous tissue sample concentrations (mgfl or mg/kg) of mezlocillin and netilmicin after prophylaxis with 1 dose of mezlocillin-netilmicin combination in pennanent cardiac pacemaker implantation *
Pocket subcutaneous ti ssue (mgfkg)
Serum (mgfl) Mezlocillin Beginning of surgery
120.5 (75.2 -140. 5)
End of surgery
44 .5 (25.2-66.7)
Netil micin
Mezlocillin
Netilmicin
12 .3 (7.2- 14.0)
10.8 (6 .5- 11 .4)
2.3 (1.0-37)
13.5 (8 .2-15.7)
2.0 (1.0-3. 0)
8.8 (7.2-9 .8)
* 20 patients; mean age: 75 (72-86) years; mean weight: 6 7.5 (50-80) kg; mean duration of surgery: 61.5 (55-85) min.
PROPHYLACTIC MEZLOCILLIN-NETILMICIN COMBINATION IN PERMAN ENT TRAN SVENO US , ETC .
eluded in the study. No early or late onset infectious complications of the pocket and/or pacing system have so far been observed in any patient of either group, during hospitalization or the follow-up period. Mezlocillin and netilmicin serum and subcutaneous tissue sample concentrations are reported in Table 2.
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
DISCUSSION
Infection following implantation of permanent transvenous cardiac pacemaker usually necessitates removal of the whole system and can lead to significant morbidity and mortality rates. Retting et al 20 reported a 25% mortality from infected electrodes in 21 patients from an original group of 1734 implanted patients (overall mortality: 0.3%) and septicemia rates ranging from 0.2% to 6.6% have been published 21 • The most important cause of pacing system infection is wound contamination at surgery . Thus, the rationale of prophylactic administration of antibiotics is that it may reduce the change of wound contamination during implantation. As is the general rule in prosthetic surgery, the most common etiological agents of pacemaker surgery complication are the staphylococci. S. aureus predominates in early onset pocket infection, which, as a rule, begins less than 2 weeks after the operation. S. epidermidis causes predominantly late infections, which appear more than 6 months after surgery 9 . The importance of methicillin-resistant staphylococci (resitant also to first generation cephalosporins) must be emphasized 4 : in Italy methicillin-resistant S. aureus and methicillin-resistant S. epidermidis account for approximately 20% and 30% respectively of all the staphylococci isolated in a hospital environment 22 • Gram-negative bacteria are rarely the cause of infectious complications in prosthetic devices, but these infections tend to be more serious 3 • These microorganisms must therefore be taken into account in choosing the prophylactic agent . As for our study, the absence of side-effects and of infectious complications in over 500 patients lead us to conclude that the mezlocillinnetilmicin combination is a safe and effective prophylactic regimen in pacemaker surgery. In-
255
deed, postoperative infection rates ranging from 3% to 4% have been found in retrospective studies of patients who underwent permanent transvenous pacemaker implantation without any antibiotic coverage in our hospital. The serum and subcutaneous tissue sample concentrations at the end of surgery were found to be adequate to provide cover against the pathogenic organisms that most often cause postoperative infection following pacemaker surgery, including methicillin-resistant staphylococci (netilmicin). The combinations of antibiotics increase the risk of adverse events and are, as a rule, more expensive than the administration of a single drug. However, in our patients, who are generally of advanced years and frequently affected with serious basic illnesses, the mezlocillin-netilmicin combination has not caused any important side effect involving the kidney or other organs or systems. The cost of a single dose of this combination, moreover, is not, at least in Italy, greater than that of 3 doses of any one of the drugs, such as the 1st generation cephalosporins, conventionally used in prophylaxis. The results we obtained indicate that the efficacy of the two prophylactic regimens employed is superimposable. However, since the infection rates after permanent pacemaker implantation are not very high in any case, the number of subjects included in the study is too small to substantiate this conclusion without some caution. The risk of a beta error must, indeed, be taken into account .
REFER E NCES ' Choo MH, H olmes DR, G ersh BJ, et al. Perm anent pacemaker infec tions: ch aracteri za ti on and management. Am H ea rt J 1981; 48: 559-64. 2 Peters G , Saborowski F, Locci R , Pul verer G . In ves ti gati ons on staph ylococcal infec ti on of transvenous end oca rd ial pacemaker electrodes. Am Heart J 1984; 108 : 359-65 . ' Dougherty SH . Pathobiology of infec ti on in pros theti c devi ces . Rev Infec t Dis 1988; 10: 1102- 17. ' Bluhm GL. Pacemaker infecti on. A 2-year follow-up of antibiotic proph ylaxis. Sca nd J Thorac Cardi ovasc Surg 1985; 19: 231-5 . ' Rao G , Ford WB , Zikri a EA, Miller WH , Samadani SR. Incidence and prevention of infec ti on in patients with permanent cardiac pace makers. Intern at Surg 1974; 59: 55961. 6 Stryker DW, Palmer DL. Infec tions assoc iated with pacemakers. In: Suga rm an B, Young EJ , eds. Infec ti ons asso-
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
256
F. DE LALLA • W. BONINI - T. BROFFONI • G. FERRARI • G. ALEGENTE
dated with prosthetic devices. Boca Rato n, Fla: CRC Press, 1984: 113-22 . 7 Bluhm G, Julander I, Levander-Lindgre n M, Olin C. Septicaemia and endocarditis: uncommon but serious complication with permanent cardiac pacing. Scand J Thorac Cardiavase Surg 1982; 16: 65-70. 'Goldman BS , MacGregor DC . Management of infected pacemaker sys tem . Clin Progr Pacing E lectrophysiol 1984; 2: 220-4. • Hartstein AI, Jackson J, Gilbert DN. Prophylactic antibiotics and the insertion of permanent transve nous cardiac pacemakers. J Thorac Cardiovasc Surg 1978; 75: 219-23. 10 Wohl B, Peters RW, Carlina N , eta!. Late unheralded pacemaker pocket infection due to Staphylococcus epidermidis. A new clinical entit y. PACE 1982; 5: 190-5. " Bluhm G, J acobso n B, Ransjo U. Antibiotic prophylaxis in pacemaker surgery: a prospective trial with local or systemic admin istrat ion of ant ibiotics at ge nerator replacements. PACE 1985; 8: 661 -9. "Bryan CS, Sauders DE, Smith CW. Endocarditis related to transvenous pacemakers. Syndromes and surgical im pli cations. J Thorac Cardiovasc Surg 1978; 75: 758-62 . "DeLeon SY, Bojar R , Koster NK, Ilbaw i MN, Munez H, Idriss FS. Recurrent sepsis from retained endocardial electrode in children: successfu l removal with cardiopulmonary bypass . PACE 1984; 7: 166-8. "Hirschmann JV . Systemic proph ylactic ant ibiotics in surgery. In: Kass EH, Platt R eds . Current therapy in infec-
tious di sease-2. Toronto: Decker BC Inc, 1986; 432-6. "Kaiser AB: Antimicrobial prophylaxis in surgery. N Eng! J Med 1986; 315: 1129-38. 16 Muers MF, Arnold AG, Sleight P . Prophylactic ant ibiotics for cardiac implantation: a prospective tri al. Br Heart J 1981; 46: 539-44. 17 Smith JW, Nichols RL. Prophylaxis in the surgical patient. In: Finegold SM, Lance George W, eds. Anaerobic Infections in Humans. San Diego : Academic Press. Inc., 1989: 77 1-7. "Knoller J, Bremm KD, Schonfeld W, Konig W . Determination of mezlocillin and its penicilloate by high-performance liquid chromatography and stability of mezlocillin at different temperatures. Antimicrob Agents Chemother 1986; 29: 527-9. 19 Dioniso tti S, Bamonte F, Gamba M, Ongini E. HPLC determination of netilmicin in guinea pig and human serum by fluorodini tro-benzene derivatization with spec trophotometric detection. J Ch romatogr 1988; 434: 169-76. 20 Retting G, Doenecke P, Sen S, Volkmers A. Complications with retained transvenous pacemaker. Am Heart J 1979; 98: 587-94. " Morgan G, Gink W, Siddons H, Leatham A. Septicemia in pati ents with an endocardial pacemaker. Am J Ca rdi ol 1979; 44: 221 -4. " Schiro GC. Meticillino-resistenza e problemi di terapia. In : Volume dei Riassunt i XIV Congresso Nazionale della Societa Italiana di Chemioterapia. Milano, 1985:220.
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Prophylactic Mezlocillin-Netilmicin Combination in Permanent Transvenous Cardiac Pacemaker Implantation: a Single-Center, Prospective, Randomized Study F. De Lalla, W. Bonini, T. Broffoni, G. Ferrari & G. Alegente To cite this article: F. De Lalla, W. Bonini, T. Broffoni, G. Ferrari & G. Alegente (1990) Prophylactic Mezlocillin-Netilmicin Combination in Permanent Transvenous Cardiac Pacemaker Implantation: a Single-Center, Prospective, Randomized Study, Journal of Chemotherapy, 2:4, 252-256, DOI: 10.1080/1120009X.1990.11739026 To link to this article: http://dx.doi.org/10.1080/1120009X.1990.11739026
Published online: 14 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yjoc20 Download by: [Australian Catholic University]
Date: 14 August 2017, At: 13:06
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
Journal of Chemotherapy
Prophylactic MezlocillinN etilmicin Combination in Permanent Transvenous Cardiac Pacemaker Implantation: a Single-Center, Prospective, Randomized Study F. DE LALLA'~' - W . BONINI H T. BROFFONI *"' - G. FERRARI '""' G. ALEGENTE '~ Summary ------------------------ --------A prospective, randomized study was carried out in order to assess the efficacy and safety of the mezlocillin-netilmicin combination in the prophylaxis of first permanent tran s venous cardiac pacemaker implantation. Five hundred and fifty-two consecutive patients were randomly administered either 2 g mezlocillin and 200 mg netilmicin both as an i.v. bolus before implantation or 2g mezlocillin before and then 6 and 12 hours after surgery and 200 mg netilmicin before and then 12 hours after implantation . No adverse events were seen. Neither pocket nor electrode infections were observed in the 457 subjects still alive (mean follow-up: 29.2 months) or in patients who died after 1 year of follow-up (mean follow-up: 20.1 months) or before this time (mean follow-up: 4. 7 months). The serum and pocket concentrations of mezlocillin and netilmicin at the end of surgery were found to be adequate to cover microorganisms that most often cause infections, including methicillin-resistant staphylococci. Key words: mezlocillin-netilmicin combination, prophylaxis, pacemaker surgery.
* Division of In fectious Disease; ** Division of Cardiology, S.Anna Hospital, Como, Italy. Correspondence: Fausto de Lalla M.D., Divisione Malatrie Infettive, Ospedale S. Bartolo, Via Rodolfi, 36100 Vicenza, Italy. © Edizioni Riviste Scientifiche - Firenze
Vol. 2 - n. 4 (252-256) - 1990
INTRODUCTION
Most of the infections following transvenous cardiac pacemaker implantation are caused by staphylococci 1 ' 3 which are often methicillin-resistant strains 3 • 4 • Other microorganisms which are sometimes isolated from infected pockets or wounds include Propionibacterium acnes, Corynebacterium sp., Escherichia coli and Proteus sp. 1 • 5 , sometimes in mixed culture. Early and even late infections (delayed by months or years) are, indeed, commonly caused by the skin organisms introduced at the time of implantation 6 and, as is well known, these may include Gram-negative bacteria which have colonized the skin, especially in patients hospitalized some days before the operation. Infection remains a serious complication of transvenous pacemaker surgery. The incidence is reported in different studies to vary between 1% and 14% 7 - II; moreover, the infection is very frequently not limited to the surgical pocket, but also involves the electrode and eventually causes endocarditis. 12 ' 13 • In most patients it may, therefore, be resolved only by having recourse to the substitution of the entire system. About six to eight weeks following insertion, on the other hand, the electrode appears to be firmly anchored to the ventricular endocardium and can thus be removed only by cardiopulmonary bypass surgery 12 • Because of this troublesome and sometimes life threatening complication, prophylactic antibiotics are generally recommended 14 • 1 5 • There is, however, no uniformity of practice in the use of antimicrobial agents in pacemaker implantation, or for other kinds of clean surgery in which foreign body or prosthetic devices are implanted. In a recent trial, antibiotics were given for as many as 5 days following pacemaker ISSN 1120-009X
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
PROPHYLACTIC MEZLOCILLIN-NETILMICIN COMBINATION IN PERMAN ENT TRANSVENOUS, ETC .
implantation 11 ; in other studies only short-term regimens (3 doses) were administered 16 • In abdominal surgery, as well as in transurethral, gynecologic and obstetric operations, the efficacy of single-dose prophylaxis has been definitively proven in a large number of published studies 17 • A prospective, randomized study was thus planned to compare the efficacy and the safety of single-dose preoperative prophylaxis with that of a multi-dose perioperative regimen in permanent cardiac pacemaker implantation. Because of the wide range of potential pathogens which may be involved in postoperative infectious complications, an antibiotic combination was chosen, i.e. an antistaphylococcal drug, active also against methicillin-resistant strains (netilmicin), and a broad spectrum penicillin (mezlocillin). PATIENTS AND METHODS
Patients included and prophylactic regimens Patients scheduled for routine cardiac pacemaker surgery (first permanent pacing of both generator and electrode) from January 1986 to December 1988 were included in the study . Pacemakers were inserted for a variety of conditions but mainly for complete heart block, arrhythmias or bradycardia. Patients with signs and/or symptoms of infection at whatever site and those who had received antibiotics in the previous five days, as well as subjects with known allergy to betalactams and/or aminoglycosides, were excluded. Their general condition (good, fair and poor) as well as some concomitant diseases or treatments which are considered potential predisposing factors for infection (such as diabetes mellitus, renal insufficiency, malignancy, corticosteroids or anticoagulant treatment) were evaluated in each subject before surgery. Patients who entered were randomly allocated to group A or to group B. Group A subjects received 2 g mezlocillin (Bayer) and 200 mg netilmicin (Essex) both as an i.v . bolus 15-20 minutes before surgery. Group B patients were given 2 g mezlocillin as an i.v. bolus 15-20 minutes before and then 6 and 12 hours after implantation and netilmicin 200 mg as an i. v. bolus 15-20 minutes before and then 12 hours after surgery .
253
Operative technique When necessary hair was removed with a depilatory cream on the morning of surgery and the whole chest was washed with Hibiscrub; the operating field was disinfected with 0.5% chlorhexidine in 70% ethyl alcohol. Surgery was always performed by one of the two cardiologists responsible for permanent cardiac pacemaker implantation in our hospital. The surgical technique was essentially the same in all patients. The generator was placed in a subcutaneous prepectoral pocket; cephalic or occasionally subclavian veins were used for insertion of the electrode. A light pressure dressing was applied post-operatively to prevent hematoma .
Definition of infection Early infection. Early infection was defined in every case as the evidence of acute inflammation (redness, swelling and/or appearance of a serous-purulent discharge) at the site of implantation, with or without a raised temperature ( > 3 7. 5° C) on at least two separate occasions and laboratory evidence of infection (leukocytosis , increased sedimentation rate) and with or without potential pathogen(s) isolated from pocket discharge . Late infection. Apart from the local signs of infection at the generator site (with or without systemic symptoms) according to the criteria above, fever associated with positive blood culture of inexplicable origin was regarded as the evidence of infection by transvenous electrode catheter itself and/or of the adjacent endothelium (pacemaker-related endocarditis). Antibiotic assays In 20 patients venous blood was drawn immediately before the injection of the first prophylactic dose of antibiotic and then at the beginning and end of implantation. Subcutaneous tissue samples from the generator pocket at the beginning and at the end of operation were also taken. All serum and tissue samples were stored at - 70°C until antibiotic concentrations were determined by high-performance liquid chromatography (HPLC) developed by Knoller et al 18 (mezlocillin) and by Dionisotti et al. 19 • Mezlocillin and netilmicin were separated
254
F. DE LALLA • W. BONINI · T. BROFFONI · G. FERRARI · G. ALEGENTE
on reverse phase columns (Nova-Pak 4C18 3.9x150 mm and Bondapak 10C18 3.9x300 mm, respectively). Detection was by UV spectrophotometry, using a Waters 501 pump, a Lambda-Max 481 variable wavelength detector (Waters) and a Waters 745 Computing Integrator.
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
Follow-up After implantation, patients were examined daily during their stay in hospital (at least 3 days) and on discharge they were instructed to report any signs of infection immediately. Then they were examined monthly for 4-6 months and thereafter every 3-4 months. Routine laboratory examinations (including a complete blood count with differential leukocyte and platelet counts, serum creatinine, serum transaminases, glucose and urinalysis) were made 3-4 days postoperatively and then 8-10 days later .
RESULTS
A total of 552 patients were included in the study. Two hundred and seventy-seven were treated with 1 dose of the mezlocillin-netilmicin combination (group A) and 275 received 3 doses of mezlocillin and 2 doses of netilmicin (group B). During the follow-up 95 patients (45 in group A and 50 in group B) died, with no evidence of infection in any case. Forty-seven of these subjects (22 in group A and 25 in group B) died 2-12 months after implantation. These were evaluated for the safety of the prophylactic regimen but were not assessed for its efficacy, owing to the inadequacy of the follow-up period (4.7 months). Of the other 48 patients who died, 23 belonging to group A and 25 to group B, all had been followed for at least 1 year (average length of follow-up: 20.1 months; range: 12-36 months). They were, therefore, assessed for both prophylactic efficacy and safety. In the 457 patients who are still alive the period of follow-up varied between 12 and 48 months (average length: 29.2 months) . The main demographic and clinical data of 505 patients which could be evaluated for both safety and efficacy (48 dead after at least 1 year after implantation and 457 still alive) are listed in Table 1. There were no sign!ficant differ-
TABLE 1 - Clinical data in 505 patients undergoing pacemaker implantation evaluated for prophylaxis efficacy.
Group B
Group A Patients (M/F) (no.) Mean age (range) (yr)
255 (150/105) 71.4 {19-99)
General co ndition (% ) Good Fair Poor
90 (35.3) 129 (50.6) 36 (14.1)
Hospitalization before surgery (d .) Mean Range
250 (164/86) 70.9 (24-90) 98 (39.2) 122 (48 .8) 30 (12.0)
6.2 0-31
6.4 0-50
Risk factors for infection/no. patients (%) Di abetes mellitus Ren al insufficiency * Cirrhosis H eart failure Corticosteroids therapy Anticoagulant therapy Others
74 37 10 53 3 25 5
Duration of surgery (min.) Mea n Range
57.8 50-160
59.5 45-155
0
0
Pos t-operative infections (no.)
(29 .0) (14.5) (3.9) (20.8) (1.2) (9.8) (1 .9)
75 32 9 56 2 28 7
(30.0) (12.8) (3.6) (22.4) (0.8) (11.2) (2.8)
* creatinine > 1. 8 mg/dl.
ences for any of the variables considered (age, general condition, potential risk factors for infection and duration of surgery) and the two treatment groups (group A, 255 patients and group B, 250 patients) were considered comparable. Neither clinical nor laboratory evidence of adverse reactions to either of the antibiotics used were seen in any of the 552 patients in-
TABLE 2 - Mean serum and pocket wbcutaneous tissue sample concentrations (mgfl or mg/kg) of mezlocillin and netilmicin after prophylaxis with 1 dose of mezlocillin-netilmicin combination in pennanent cardiac pacemaker implantation *
Pocket subcutaneous ti ssue (mgfkg)
Serum (mgfl) Mezlocillin Beginning of surgery
120.5 (75.2 -140. 5)
End of surgery
44 .5 (25.2-66.7)
Netil micin
Mezlocillin
Netilmicin
12 .3 (7.2- 14.0)
10.8 (6 .5- 11 .4)
2.3 (1.0-37)
13.5 (8 .2-15.7)
2.0 (1.0-3. 0)
8.8 (7.2-9 .8)
* 20 patients; mean age: 75 (72-86) years; mean weight: 6 7.5 (50-80) kg; mean duration of surgery: 61.5 (55-85) min.
PROPHYLACTIC MEZLOCILLIN-NETILMICIN COMBINATION IN PERMAN ENT TRAN SVENO US , ETC .
eluded in the study. No early or late onset infectious complications of the pocket and/or pacing system have so far been observed in any patient of either group, during hospitalization or the follow-up period. Mezlocillin and netilmicin serum and subcutaneous tissue sample concentrations are reported in Table 2.
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
DISCUSSION
Infection following implantation of permanent transvenous cardiac pacemaker usually necessitates removal of the whole system and can lead to significant morbidity and mortality rates. Retting et al 20 reported a 25% mortality from infected electrodes in 21 patients from an original group of 1734 implanted patients (overall mortality: 0.3%) and septicemia rates ranging from 0.2% to 6.6% have been published 21 • The most important cause of pacing system infection is wound contamination at surgery . Thus, the rationale of prophylactic administration of antibiotics is that it may reduce the change of wound contamination during implantation. As is the general rule in prosthetic surgery, the most common etiological agents of pacemaker surgery complication are the staphylococci. S. aureus predominates in early onset pocket infection, which, as a rule, begins less than 2 weeks after the operation. S. epidermidis causes predominantly late infections, which appear more than 6 months after surgery 9 . The importance of methicillin-resistant staphylococci (resitant also to first generation cephalosporins) must be emphasized 4 : in Italy methicillin-resistant S. aureus and methicillin-resistant S. epidermidis account for approximately 20% and 30% respectively of all the staphylococci isolated in a hospital environment 22 • Gram-negative bacteria are rarely the cause of infectious complications in prosthetic devices, but these infections tend to be more serious 3 • These microorganisms must therefore be taken into account in choosing the prophylactic agent . As for our study, the absence of side-effects and of infectious complications in over 500 patients lead us to conclude that the mezlocillinnetilmicin combination is a safe and effective prophylactic regimen in pacemaker surgery. In-
255
deed, postoperative infection rates ranging from 3% to 4% have been found in retrospective studies of patients who underwent permanent transvenous pacemaker implantation without any antibiotic coverage in our hospital. The serum and subcutaneous tissue sample concentrations at the end of surgery were found to be adequate to provide cover against the pathogenic organisms that most often cause postoperative infection following pacemaker surgery, including methicillin-resistant staphylococci (netilmicin). The combinations of antibiotics increase the risk of adverse events and are, as a rule, more expensive than the administration of a single drug. However, in our patients, who are generally of advanced years and frequently affected with serious basic illnesses, the mezlocillin-netilmicin combination has not caused any important side effect involving the kidney or other organs or systems. The cost of a single dose of this combination, moreover, is not, at least in Italy, greater than that of 3 doses of any one of the drugs, such as the 1st generation cephalosporins, conventionally used in prophylaxis. The results we obtained indicate that the efficacy of the two prophylactic regimens employed is superimposable. However, since the infection rates after permanent pacemaker implantation are not very high in any case, the number of subjects included in the study is too small to substantiate this conclusion without some caution. The risk of a beta error must, indeed, be taken into account .
REFER E NCES ' Choo MH, H olmes DR, G ersh BJ, et al. Perm anent pacemaker infec tions: ch aracteri za ti on and management. Am H ea rt J 1981; 48: 559-64. 2 Peters G , Saborowski F, Locci R , Pul verer G . In ves ti gati ons on staph ylococcal infec ti on of transvenous end oca rd ial pacemaker electrodes. Am Heart J 1984; 108 : 359-65 . ' Dougherty SH . Pathobiology of infec ti on in pros theti c devi ces . Rev Infec t Dis 1988; 10: 1102- 17. ' Bluhm GL. Pacemaker infecti on. A 2-year follow-up of antibiotic proph ylaxis. Sca nd J Thorac Cardi ovasc Surg 1985; 19: 231-5 . ' Rao G , Ford WB , Zikri a EA, Miller WH , Samadani SR. Incidence and prevention of infec ti on in patients with permanent cardiac pace makers. Intern at Surg 1974; 59: 55961. 6 Stryker DW, Palmer DL. Infec tions assoc iated with pacemakers. In: Suga rm an B, Young EJ , eds. Infec ti ons asso-
Downloaded by [Australian Catholic University] at 13:06 14 August 2017
256
F. DE LALLA • W. BONINI - T. BROFFONI • G. FERRARI • G. ALEGENTE
dated with prosthetic devices. Boca Rato n, Fla: CRC Press, 1984: 113-22 . 7 Bluhm G, Julander I, Levander-Lindgre n M, Olin C. Septicaemia and endocarditis: uncommon but serious complication with permanent cardiac pacing. Scand J Thorac Cardiavase Surg 1982; 16: 65-70. 'Goldman BS , MacGregor DC . Management of infected pacemaker sys tem . Clin Progr Pacing E lectrophysiol 1984; 2: 220-4. • Hartstein AI, Jackson J, Gilbert DN. Prophylactic antibiotics and the insertion of permanent transve nous cardiac pacemakers. J Thorac Cardiovasc Surg 1978; 75: 219-23. 10 Wohl B, Peters RW, Carlina N , eta!. Late unheralded pacemaker pocket infection due to Staphylococcus epidermidis. A new clinical entit y. PACE 1982; 5: 190-5. " Bluhm G, J acobso n B, Ransjo U. Antibiotic prophylaxis in pacemaker surgery: a prospective trial with local or systemic admin istrat ion of ant ibiotics at ge nerator replacements. PACE 1985; 8: 661 -9. "Bryan CS, Sauders DE, Smith CW. Endocarditis related to transvenous pacemakers. Syndromes and surgical im pli cations. J Thorac Cardiovasc Surg 1978; 75: 758-62 . "DeLeon SY, Bojar R , Koster NK, Ilbaw i MN, Munez H, Idriss FS. Recurrent sepsis from retained endocardial electrode in children: successfu l removal with cardiopulmonary bypass . PACE 1984; 7: 166-8. "Hirschmann JV . Systemic proph ylactic ant ibiotics in surgery. In: Kass EH, Platt R eds . Current therapy in infec-
tious di sease-2. Toronto: Decker BC Inc, 1986; 432-6. "Kaiser AB: Antimicrobial prophylaxis in surgery. N Eng! J Med 1986; 315: 1129-38. 16 Muers MF, Arnold AG, Sleight P . Prophylactic ant ibiotics for cardiac implantation: a prospective tri al. Br Heart J 1981; 46: 539-44. 17 Smith JW, Nichols RL. Prophylaxis in the surgical patient. In: Finegold SM, Lance George W, eds. Anaerobic Infections in Humans. San Diego : Academic Press. Inc., 1989: 77 1-7. "Knoller J, Bremm KD, Schonfeld W, Konig W . Determination of mezlocillin and its penicilloate by high-performance liquid chromatography and stability of mezlocillin at different temperatures. Antimicrob Agents Chemother 1986; 29: 527-9. 19 Dioniso tti S, Bamonte F, Gamba M, Ongini E. HPLC determination of netilmicin in guinea pig and human serum by fluorodini tro-benzene derivatization with spec trophotometric detection. J Ch romatogr 1988; 434: 169-76. 20 Retting G, Doenecke P, Sen S, Volkmers A. Complications with retained transvenous pacemaker. Am Heart J 1979; 98: 587-94. " Morgan G, Gink W, Siddons H, Leatham A. Septicemia in pati ents with an endocardial pacemaker. Am J Ca rdi ol 1979; 44: 221 -4. " Schiro GC. Meticillino-resistenza e problemi di terapia. In : Volume dei Riassunt i XIV Congresso Nazionale della Societa Italiana di Chemioterapia. Milano, 1985:220.
