ANTIBIOTIC TREATMENT OF STREPTOCOCCAL AND STAPHYLOCOCCAL ENDOCARDITIS

815

Therapeutics ANTIBIOTIC TREATMENT OF

STREPTOCOCCAL AND STAPHYLOCOCCAL

Patients with endocarditis may deteriorate rapidly despite apparently appropriate antibiotic treatment. Such patients need expert management by a cardiologist and a cardiac surgeon. Early referral of any patient with endocarditis is strongly recommended. Delay in valve replacement may prove fatal.

ENDOCARDITIS

Report of a Working Party of the British Society for Antimicrobial Chemotherapy* ALTHOUGH endocarditis is a potentially curable disease, it still carries a mortality of about 30% and causes about 200 deaths a year in England and Wales. The disease is uncommon and most physicians in hospitals in the United Kingdom probably see no more than one or two cases a year. Since the heart valves are damaged at an early stage, prompt treatment is essential. Patients with fever and a heart murmur should have blood cultures taken without delay, before any antibiotic treatment is given, even if this necessitates referral to hospital. Patients with prosthetic valves who become feverish should be referred at once to a hospital with cardiological and cardiothoracic surgical facilities, and they too should have blood cultures taken before antibiotics are

given. Personal preference plays a part in the choice of antibiotics for the

of any disease, and endocarditis is no The exception. following recommendations emerged as the choice of this working party after discussions of published work and personal experience. They are confined to management of streptococcal and staphylococcal infections, which between them are responsible for more than 80% of cases of endocarditis. 2,3 treatment

STREPTOCOCCAL

ENDOCARDITIS

Whilst almost any streptococcus can cause endocarditis, those most often responsible are the oral streptococci conventionally, but inaccurately, referred to as "Streptococcus viridans". The oral streptococci are S mitior, S sanguis, S mutans, and S salivarius and of these S mitior and S sanguis are most commonly isolated. Other streptococci responsible for endocarditis are S milleri, which may originate from the mouth or the gut, and the gut-specific streptococci, Sfaecalis, Sfaecium (the enterococci or faecal streptococci), and S bovis. Very occasionally endocarditis may be caused by the pyogenic &bgr;-haemolytic streptococci of Lance field groups B or G or even more rarely A or C. With the exception of the faecal streptococci, which are almost always of low sensitivity to penicillin and impossible to kill in vitro with penicillin alone, the species of streptococcus isolated cannot be equated with a specific susceptibility to penicillin. The oral and other streptococci listed above will vary from highly sensitive to moderately resistant. It is therefore essential to determine the minimum bactericidal concentration (MBC) of penicillin for the streptococcus isolated in every case of endocarditis.

Penicillin-sensitive Streptococci

Streptococci whose MBC of benzylpenicillin is 1 mg/l or are regarded as being fully sensitive to penicillin. Streptococci are seldom very sensitive to gentamicin alone, but this agent usually acts synergistically with penicillin against streptococci and we believe that, even when the infecting organisms are sensitive to penicillin, gentamicin should be administered concurrently for the first two weeks to achieve the maximum bactericidal effect. However, when the infection is caused by penicillin-sensitive organisms, administration of gentamicin for more than two weeks is not justifiable. Patients with endocarditis, particularly those who are elderly or who have impaired renal function, are at risk of gentamicin toxicity. Gentamicin blood levels must therefore be monitored frequently and the dosage adjusted in accordance with the results. In our opinion, patients with endocarditis should be treated only in hospitals where gentamicin assays are available. Netilmicin is claimed to be less toxic than gentamicin. It should be considered as an alternative to gentamicin in elderly patients or when there is impaired renal function. The dosage and blood levels are the same as for gentamicin. We recommend that benzylpenicillin should be given by intravenous bolus injection in a dose of 7.2 g (12 megaunits) daily in six divided doses (4-hourly). The proposed dose of gentamicin is less than that required to treat serious infections caused by gram-negative bacilli since the intention is to enhance the activity of the penicillin, which necessitates only low blood levels of gentamicin. The initial dose for an adult should be 80 mg twice daily, coinciding with a dose of penicillin. Subsequent dosage will depend upon the blood levels, which should be monitored at less

THE EARLY STAGE

In general, treatment is best delayed until the results of cultures are available. Three specimens, taken at intervals of several hours, should be sufficient; if these are negative, further specimens are very unlikely to be positive. However, when there is a firm clinical diagnosis of endocarditis or the patient is very ill, antibiotic treatment should be started as soon as one blood sample has been taken for culture. Since two-thirds of endocarditis cases are streptococcal, the combination-a recommended penicillin and an aimed at aminoglycoside-is primarily streptococci, though it will have activity also against staphylococci. The penicillin should usually be benzylpenicillin and the aminoglycoside gentamicin. (Although other aminoglycosides may be equally effective, most physicians have experience in the administration of gentamicin and most laboratories have experience in monitoring the blood levels.) The dosages and routes of administration should be the same as those recommended below for the treatment of endocarditis caused by penicillin-sensitive streptococci. Where there is a strong possibility of staphylococcal infection-eg, in drug addicts or patients with skin sepsis-flucloxacillin should be added to the regimen. *Dr N. SIMMONS (chairman), Department of Clinical Microbiology, Guy’s Hospital, London SE1 9RT; Prof R. A.CAWSON, Department of Oral Medicine and Pathology, Guy’s Hospital; Dr S. J. EYKYN, Department of Clinical Microbiology, St Thomas’ Hospital Medical School, London; Prof A. M GEDDES, Department of Infectious Diseases, University of Birmingham; Prof W. A.LITTLER, Department of Cardiovascular Medicine, University or Birmingham; Dr C. M. OAKLEY, Department of Medicine (Cardiology), Royal Postgraduate Medical School, London; Dr D. C. SHANSON, Department of Medical Microbiology, Charing Cross and Westminster Medical School, London.

least twice a week. Peak levels in blood taken 20 min after intravenous bolus injections should be 3-5 mg/1 and trough

816

levels in blood taken 20-30 min before the next dose less than 1 mg/1. Rising trough levels, particularly where they exceed 2 mg/1, are a danger signal; if they cannot be rapidly reduced by adjustment of dosage, gentamicin should be stopped. Back-titrations of serum bactericidal activity ’against the infecting organism should be used to monitor antibiotic Serum collected 20-30 min after the treatment. administration of both antibiotics should usually kill the streptococci at a dilution of 1 in 8 or more. After 14 days the gentamicin should be stopped. The benzylpenicillin may then be replaced with oral amoxycillin 0’ 5-1’ 0 g three times a day for another 14 days to complete a total of one month’s treatment. Probenecid may be administered concurrently.

Streptocococci with Reduced Sensitivity to Penicillin Penicillin alone will not be adequate treatment when the MBC is more than 1 mg/1. We recommend benzylpenicillin and gentamicin in the same dose as given for the first two weeks of treatment of endocarditis caused by penicillinsensitive streptococci. However, for these less sensitive organisms, gentamicin must be given with the penicillin for less than four weeks. Again, netilmicin should be considered as an alternative to gentamicin in elderly patients or those with impaired renal function. The treatment should always be reviewed after four weeks, when the following factors will influence decisions on the duration of gentamicin therapy: the sensitivity of the streptococci to the antibiotics; the clinical severity of the infection; the response to treatment; whether a natural or prosthetic valve is involved; the age and renal function of the not

patient. Recurrent Fever The response to penicillin and gentamicin is usually prompt. A persistent or recurrent pyrexia is not necessarily a reason to change the antibiotics. It is, however, a reason for seeking the advice of a cardiologist, cardiac surgeon, and microbiologist. Occasionally a recurrent fever in the second or third week may be due to penicillin allergy, even in the absence of a rash.

Allergy to Penicillins If a patient is genuinely allergic to the penicillins (and the evidence needs close examination in view of the therapeutic difficulties that arise), we advise initial treatment with vancomycin plus gentamicin. Since both are potentially toxic, the treatment should be undertaken only in hospitals with facilities for assaying them. Initially, vancomycin should be given in a dose of 1 g iv over 60 min once or twice a day and blood levels determined daily. The amount given should then be adjusted to achieve peak blood levels of 30 mg/1and trough blood levels of 5-10 mg/1. Gentamicin should be given in the same doses as those recommended for patients not allergic to the penicillins. The minimum inhibitory and bactericidal concentrations of vancomycin alone and of alternative antibiotics, including erythromycin, should be determined and the patient’s condition assessed daily. Depending upon the clinical response to treatment and results of investigations, consideration may be given to employing vancomycin alone, substituting erythromycin for vancomycin and gentamicin, or stopping antibiotic treatment after only two weeks; these decisions can only be made on an individual basis.

Tooth Extraction during Treatment Patients with endocarditis should have a dental consultation as soon as possible after diagnosis. In those with gingival or other sepsis affected teeth should be extracted within 48 h of the beginning of antibiotic treatment. If the teeth are not extracted at that time, extra antibiotic cover should be given for the extractions with a single dose of vancomycin, 1 g iv over 60 min, in addition to the other antibiotics being used to treat the endocarditis. STAPHYLOCOCCAL ENDOCARDITIS

Staphylococcus aureus Although Staph aureus may infect previously damaged valves, it more frequently attacks healthy valves, and in both instances the presenting features are those of septicaemia and severe toxaemia. There may be rigors and meningism. Polymorphonuclear leucocytes may be present in the cerebrospinal fluid, but organisms are seldom found. Whenever a patient presents with these features and without localising signs, the presence of endocarditis should be assumed-even if no heart murmur is heard. In these cases the organisms rapidly destroy the heart valves and, if this is to be prevented, early treatment is essential. When the infection develops in drug addicts, the disease is usually less severe and the prognosis better. These patients often present with "pneumonia" and without cardiac murmurs, since the infection characteristically affects the tricuspid valve (in contrast to non-addicts in whom the disease is usually left-sided). Staph aureus may also infect prosthetic valves, usually as a result of postoperative sternal sepsis, within one to two months of valve replacement. Occasionally it may cause late-onset prosthetic endocarditis. As with infection of natural heart valves it causes a severe septicaemic illness and usually necessitates urgent valve

replacement. We recommend the same antibiotic regimen-flucloxacillin plus fusidic acid or gentamicin-whatever the presentation of the disease and whether the infected valve is natural or prosthetic. The recommended dose of flucloxacillin is 12 g daily in six divided doses by intravenous bolus injection. The dose offusidic acid is 500 mg 8-hourlyby mouth. The initial dose of gentamicin should be 120 mg; the subsequent gentamicin regimen will vary from about 80 to 120 mg iv 8-hourly depending upon the weight of the patient and the antibiotic blood levels. These should be determined at least three times a week and initially more frequently. The objective is to produce peak blood levels of 5-10 mg/1 and trough levels of less than 2 mg/l. Because of the relatively high blood levels required and because renal function maybe impaired, gentamicin should seldom be continued for more than fourteen days. As with streptococcal endocarditis, netilmicin should be considered as an alternative to gentamicin for the elderly and those with impaired renal function. The total duration of antibiotic treatment for Staph aureus endocarditis should be at least four weeks. Back titrations of serum bactericidal activity against the infecting organism should be used to monitor antibiotic treatment. Serum collected 20 to 30 min after the administration of both antibiotics should usually kill the staphylococci at a dilution of 1 in 8 or more. Allergy and resistance.-Vancomycin alone is recommended for patients who are allergic to the penicillins, or when the organism is methicillin/flucloxacillin resistant. The dose of vancomycin should be adjusted to achieve peak blood levels of 30 mg/1 and trough blood levels of 5- 10 mg/1. This can be

817 a dose of 1 g once or twice a day by slow intravenous infusion over 60 min. The duration of treatment should normally be at least four weeks.

achieved with

Staphylococcus epidermidis Unlike Staph aureus, Staph epidermidis tends to infect prosthetic valves rather than natural valves. Its sensitivity is also much less predictable. When the organism is shown to be sensitive to the antibiotics recommended for the treatment of Staph aureus endocarditis, then the same regimens can be used. Unfortunately, despite treatment with antibiotics to

Occasional

Survey

which the organism is sensitive in vitro, eradication of the infection is frequently impossible and valve replacement will be necessary.

REFERENCES 1. 2.

Oakley CM. Infective endocarditis. Br J Hosp Med 1980; 24: 232-43. Bayliss R, Clarke C, Oakley CM, Somerville W, Whitfield AGW, Young SEJ. The microbiology and pathogenesis of infective endocarditis. Br Heart J 1983; 50:

3.

Bayliss R,

513-19. Clarke C, Oakley CM, Somerville W, Whitfield AGW, Young SEJ. The bowel, the genitourinary tract and infective endocarditis. Br Heart J 1984; 51: 339-45.

desirable for several

London SE1 9RT

THERE is uncertainty about what constitutes a biosensor. It either be defined as a small, probe-type device, which, without the addition of a reagent, gives a rapid and specific signal in response to an analyte (organic or inorganic) of biological interest, or it is a term confined to such a device only when a biological component, such as an enzyme or antibody, is needed for its action. These devices will probably make an important contribution to medical science and clinical practice in the next few years. Chemical sensors have received most attention, but some probes detect physical changes in vivo, such as alterations in pressure and temperature.’ The general principle of a chemical biosensor is that a transducing element is coated or impregnated so that it recognises the analyte of interest through relatively specific reactions such as that of antigen with antibody or sugar with lectin. A signal of the reaction is generated by the transducer and it may be an electrical current, charge, heat, light, and so can

on.

WHY DO WE NEED BIOSENSORS?

Many laboratory tests are expensive, tedious and timeconsuming, and some carry a degree of risk (eg, radioisotopes). Biosensors can, in theory, be quick, simple to operate, inexpensive, and safe. They are thus attractive at a time when some clinical biochemistry is moving out of the central laboratory and back to the ward, side-room, and specialist department. They may ease the difficulty of providing a 24-h pathology service and of coping with multisite hospitals and transportation of specimens. One may envisage, also, situations in the operating theatre in which rapid analysis of a blood sample (or direct recording in a vessel draining an organ) could give immediate information on tumour location or type, or adequacy of excision. Another application for biosensors is for the continuous in-vivo monitoring of metabolites, electrolytes, hormones, and drugs. Most effort has been placed in this direction towards the development of an implantable glucose sensor, 2,3 for use in a miniature artificial endocrine pancreas with automatic feedback control of insulin delivery. There is also growing interest in the importance of drug-delivery rates in general for the modulation of pharmacological effects.4,5 The controlled infusion of desferrioxamine, cytotoxic drugs, analgesics, and heparin are examples. Continuous in-vivo monitoring of drug levels with feedback control of delivery rates may be

narrow

therapeutic ranges.

BIOSENSORS: A CLINICAL PERSPECTIVE

J. C. PICKUP Division of Chemical Pathology, United Medical and Dental Schools of Guy’s and St Thomas’ Hospitals, Guy’s Campus,

drugs, particularly those with

ELECTROCHEMICAL SENSORS

Classification Electrochemical

devices

fall

into

categories: amperometric systems. With potentiometric sensors interaction of an analyte with an electrode changes the electrical charge on the electrode and thus the voltage between this "working" electrode and a neutral "reference" electrode, which might be saturated calomel or silver/silver chloride. The voltage (E) in potentiometric sensors is governed by the Nernst equation, which in a simplified form is:

potentiometric

two

or

E=E°+

+ RT In (analyte) zF

where E° is a constant for the system, R the gas constant, T the absolute temperature, z the charge number, and F the Faraday constant. Since the potential difference, is proportional to the logarithm of the analyte concentration (in fact, the activity, rather than the concentration), a major disadvantage of potentiometry is insensitivity since changes in analyte concentration produce very small alterations in voltage. This also means that the reference electrode must be very stable. With amperometry, a fixed voltage is applied (by means ofaa potentiostat) to a working electrode which encourages electrons to move to or from the electrode to the analyte in solution (ie, oxidation and reduction is occurring) and enables a current to be measured. This current is directly proportional to analyte concentration and so the system is inherently more sensitive than potentiometry.

Ion-selective Electrodes

(ISE) This is a potentiometric sensor in which selective concentration of ions from the medium (plasma, say) alters the charge on the sensors The glass pH electrode was the first and is still the most widely-used ISE. Here protons are attracted to negatively-charged oxides such as silicates in the special glass membrane. Other electrodes use, for example, the antibiotic valinomycin (K), crystals of silver halide (Cl-), various negatively-charged phosphate carriers (Ca), or another glass (Na+) as selective binding materials. Valinomycin is a naturally occurring, neutralionophore which, in electrodes, is usually incorporated inpolyvinyl chloride (PVC) membrane. It is a large, 36-membered cyclic molecule made up of repeating units of aminoacids and a-hydroxyacids. The central core has a polar environment (because of carbonyl groups) and an alkali metal ion can form a stable complex by fitting into the cavity and chelating with six oxygen atoms from carbonyl groups. 10