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Current therapy of acute bacterial meningitis in children: Part II
Review Article
Cument Therapy of Acute Bacterial Meningitis in Children: Part II William E. Bell, MD and Gail A. McGuinness, MD
Despite many advances in the past decade in the development of new antimicrobials, acute bacterial meningitis continues to have significant morbidity and mortality in infants and children. Regardless of the effectiveness of the antibiotic preparations, future improvement in outcome is most likely to occur because of more rapid diagnosis and initiation of therapy. The standard penicillins, chlommphenicol, and the aminoglycosides continue to hold an important place in treatment. The recent introduction of new extended including piperacillin and spectrum penicillins, mezlocillin, in addition to the development of the third generation cephalosporins, have expanded alternatives for treating bacterial meningitis. The most appropriate and effective antibiotic or combination of antibiotics must first be selected; thereafter, its use must be monitore to identify its beneficial effects as well as possible adverse effects. Bell WE, McGuinness GA. Current therapy of acute bacterial meningitis in children: Parr II. Pediat Neural
there is a clear advantage of a synergistic effect. In this part, we review important characteristics of those antimicrobials which are currently popular for the treatment of meningitis. Some recently released preparations are discussed, even though their precise role has yet to be established. The first and most important consideration is the selection of the best antibiotic(s), at the correct daily dosage (Table 1, 2), and administered at the correct frequency. The next obligation is to be certain that the child is in fact receiving what has been ordered. With certain drugs, such as chloramphenicol and the aminoglycosides, serum levels should be determined and dosage adjustments made accordingly. Regardless of which antimicrobials are utilized, the physician must be familiar with the pharmacokinetics of the drug in different age groups, the potential drug interactions, and, especially, the many possible adverse effects.
Introduction In Part I, the methods of selection of an antibiotic regimen for treatment of acute bacterial meningitis of childhood were reviewed. Emphasis was placed on the importance of choosing antibiotics which are bactericidal against the known or presumed causative organisms. The selected antimicrobials, with doses that can be given safely systemically, must be capable of penetrating into cerebrospinal fluid (CSF) in concentrations well above the mean bactericidal concentration (NBC) for the infective organism. Combinations of drugs are generally to be avoided unless
Third Generation Cephalosporins The fust available cephalosporin antibiotic was cephalothin. Similar compounds appeared later. The initial preparations had little application to the treatment of central nervous system infections because of limited penetrability into CSF. As new variations of cephalosporins became available they were classified by generations, largely on the basis of their antibacterial spectrum. First generation cephalosporins were active against Gram positive organisms but had limited action against Gram negative organisms. Second generation drugs expanded the antimicrobial effects to some Gram but still penetrated the CSF negative pathogens, poorly. Third generation cephalosporins are useful in the treatment of meningitis because many penetrate CSF adequately, are &lactamase resistant, and have a broad spectrum antibacterial effect. Some of the newest
From
Communications
1985;1:201-9.
the Section
and Neurology; and
the
University
of Pediatric University
Division
of
of Iowa College
Neurology;
Departments
of Iowa College of Medicine; Nconatology; of Medicine,
Department Iowa City,
of Pediatrics Iowa City, of
IA.
IA
Pediatrics;
should
Dr. Bell; Division and Neurology;
be addressed
of Pediatric University
to:
Neurology;
Dcpzutments
of Iowa College of Medicine,
of Pediatrics Iowa City, IA
52242. Received
May 20, 1984; accepted June 12.1985
Bell and McGuincss:
Acute BacteriaI
Meningitis
201
Table
1. Antibiotic
dosages for bacterial
meningitis
(birth
Ampicillin
lSO-20Omg/kg/day,
Peni&lIio G Less than one week
150.000
to two months)
IV (q8h)
units/kg/day.
IV (q8h)
One week to two months
150.000-250,000
units/kg/day,
IV(q6h)
Group
250,000-400.000
units/kg/day,
IV(q6h)
MCdliciIIitl
100 mgIkg/day,
IV (q8h)
Naftilh
100 mglkglday,
IV (q8h)
carbenicillin
300 mglkglday,
IV (q8h)
TicatciIIin
200-300mgIkgIday.
PipeGxillin
200 mglkglday.IV
B Streptococcus
IV (q8h) (q8h)
KiltMDy& Less than one week
2Omglkglday,
IM, IV (ql2h)
One week to two months
3OmgIkgIday.
IM, IV (q8h)
Gentamicin Less than one week
5 mglkglday,
One week to two months
7.5 mglkglday,
IM, IV (ql2h) IM, IV (q8h)
Tobtamycio Less than one week
5 mglkglday.
9°C week to two months
7.5 mglkglday,
IM, IV (ql2h) IM, IV (q8h)
Amikacin Less than one week
15 mglkglday.
One week to two months
22.1 mglkglday,
IM, IV (ql2h) IM, IV (q8h)
MoxaIactam
lOO-150mg/kg/day,
IV (q8h)
Cefotaximc
IOO-150mg/kgIday,
IV (q8h)
Vancomycin Birth to one week
3Omglkglday.
IV (ql2h)
One week to two months
45 mglkglday,
IV (q8h)
15 mg/kg/day,
IV (ql2h)
Mctronidazolc Chloramphenicol Premature (birth
25 mglkglday.
IV (ql2h)
Full term (1st 7 days)
fo 1 month)
25 mglkglday,
IV (ql2h)
Full term (7 to 30 days)
50 mglkglday.
IV (q8h)
Full term (1 to 2 months)
50-100 mglkglday,
third generation drugs are highly effective against all of the common causesof acute bacterial meningitis in the neonate, infant, and child. Nonetheless, third generation cephalosporins have as yet not been accepted as drugs of choice for any type of bacterial meningitis, although cefotaxime is used widely for treatment of sensitive Escher&ha co/i meningitis in infants and in adults. Cefotaxime Cefotaxime, the first of the third generation cephalosporins,wasreleasedfor use in 1981. Although some degree of effectiveness against Gram positive organisms had been sacrificed compared to the earlier cephalosporins, the bactericidal action of cefotaxime 202
PEDIATRIC
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IV (q6h)
against Escherichiaco/i and many other Gram negative organisms was quickly recognized. Cefotaxime rivals and may surpassthe advantages of ampicillin and an aminoglycoside in the treatment of Gram negative meningitis in newborns and following head trauma or neurosurgical proceduresin children and adults. It is an important alternative for children with Hemophilus infuenzae or meningococcal meningitis when customary antimicrobials cannot be used, and can be administered as initial therapy, in combination with other antibiotics, in children with focal intracranial infections when Gram negative bacteria might be present. Cefotaxime is well tolerated by most children. Infrequent adverse effects include phlebitis, rash,
Table 2. Antibiotic up to 50 kilograms Ampicillin Peni&
dosages for bacterial
meningitis
300-4OOmgIkgIday. G
(over 2 months
-
body weight IV (q4h)
250,00OUnits/kg/day.
Mcdlicillin
200-300mglkglday.
Nddlill
200mg/kg/day,
CtiniCilIiU
400-600
IV (q4h) IV (q4h) IV (q4h)
mglkglday,
IV (q4h)
Ticahllin
300-4OOmg/kg/day,
IV (q4h)
Pipelacillin
300-400
IV (q4h)
mglkglday,
Cblolampbeoicol
75-100 mglkg/day,PO
Gentamicin
4 mglkglday,
IM (q8h)
Tobtamycin
4 mglkglday.
IM (q8h)
Amikacin
15 mglkglday,
of IV (qbh)
IM (q8h)
Moxalactam
15Omglkglday.
IV (q4h)
Cefotaxime
150mglkgIday.
IV (q4h)
Cefoperazone
300 mglkglday,
IV (q8h)
Cefuiaxone
lOOmg/kg/day,
IV (ql2h)
Rihlpin
20 mg/kg/day,
PO (q8h)
(up to 600 mg) Streptomycin
antimicrobials because such infections are sometimes polymicrobial and may include anaero bes .
20-40 mglkglday,
IM (q12h)
(not over 1 gram) Vancomycin
60 mglkglday.
Sulfadiazine
150mglkglday.
Mecconidatole
40mg/kgIday,
PO (q8h)
3OmgIkgIday.
IV (qbh)
IV (q6h) IV (q8h)
eosinophilia, drug fever, and vertigo [l]. CSF penetration through inflamed meninges is adequate. An adult intravenous dose of 8-12 grams/24 hours results in CSF levels of 5-13 g/ml, levels 40-200 times the MBC for most EscheriGhia cofi and Klebsiella species [2]. Cefotaxime is primarily excreted in the urine, some unchanged, but most in the form of its major metabolite, deacetylcefotaxime. In adults with normal renal function, the half-life is approximately 60 minutes; in neonates, it is 3.4-4.6 hours [3,4]. The role of cefotaxime in the treatment of central nervous system infections in infants and children is still being studied. Although cefotaxime is more effective than combined therapy with ampicillin and an aminoglycoside in the treatment of bacillary meningitis, it is also more toxic. In the neonate, it should be combined with ampicillin prior to identification of the causative organism, because of its questionable efficacy against Group B Streptococcus and its lack of activity against ListerG monocytogenes and enterococcal Group D streptococci. In the treatment of meningitis complicating head trauma, intracranial operative procedures, or brain abscess, cefotaxime is used in combination with other
Cefthxone Ceftriaxone differs from other third generation cephalosporins because of its extended spectrum against Gram positive and Gram negative bacteria and because of its uniquely prolonged serum and CSF half-life. In addition to its superior antibacterial activity against the Entenhctetieae, Hemophihs influenzae, and Neisserih meningitidis, cef&xone reaches serum and CSF concentrations far in excess of that needed for effective treatment for infections caused by Streptococcuspneumoniae and Group B Streptococcus [5,6]. These charateristics indicate that it is effective against all bacterial meningitis in the newborn period and childhood. Like other members of the newer cephalosporins, it is poorly active against Group B streptococci and Listeria monocytogenes; therefore, it would not be acceptable monotherapy in newborns before the etiological agent is identified. Ceftriaxone is eliminated by renal and hepatic mechanisms; impairment of function of either organ does not markedly alter drug excretion. The half-life of ceftriaxone in young children is approximately 6.5 hours [7] and is longer in adults. The prolonged halflife, the dual mechanism of elimination, the low incidence of adverse effects, and the readily achievable serum and CSF levels in infants and children make ceftriaxone a serious consideration for clinical use in infections. While it has not achieved “drug of choice” popularity, ceftriaxone is accepted as an alternative for the treatment of meningitis caused by Hemophilus infruenzae , Streptococcus pneumoniae , and Neissetia meningitidir when other antibiotics cannot be used because of drug intolerance or bacterial resistance. Cefoperazone Cefoperazone, like ceftriaxone, has enhanced activity against Gram positiye bacteria as compared to cefotaxime, as well as excellent activity against a variety of Gram negative organisms. Its popularity is largely due to its effectiveness against many strains of Pseudomonas aeruginosa and indole-positive Proteus species. Cefoperazone is as effective as piperacillin and four times as active as cefotaxime against Pseudomonas aeruginosa [8]. It is at least as effective as chloramphenicol for /3-lactamase positive Hemophhs influenzue. Conuadictory studies concerning the . CSF peneuation of cefoperazone have been reported. Cable BeIl and McGuines:
Acute Bacterial
Meningitis
203
et al. [9] found CSF penetration variable and not entirely reliable. Conversely, Chartrand et al. [lo] studied CSF penetration following a single 100 mg /Kg intravenous dose in children with meningitis and found the concentration to exceed the MIC for Hemophilur infuenzae , Streptococcus pneumonias , and Neissetia meningitidis by 15 to 237-fold. Biliary excretion is the major pathway of elimination of cefoprazone so that dosage adjustments are unnecessary in the presence of renal compromise. Cefoperazone is 70 to 90% protein-bound and the serum half-life id the older child or adult is 1.6-2.6 hours [ll]. In premature and term newborn infants, the mean serum half-life ranges from seven to nine hours [12]. At the present time, there is no specific indication to use cefoperazone in the treatment of central nervous system infections. In combination with other antimicrobials, it is now used for certain Gram negative infections in immunosuppressed or neutropenic patients. Cefoperazone with an aminoglycoside can be considered as an alternative caused by Pseudomonas regimen for meningitis aeruginosa or Proteus species when other more commonly used antimicrobials are ineffective or not tolerated. PenicilJim Following the introduction of penicillin in 1941, there has been a gradual elaboration of related compounds. The penicillins have remained the most widely used class of antimicrobials for the treatment of infections of the central nervous system. Most of the penicillins undergo rapid renal excretion resulting in a adshort serum half-life following intravenous ministration. Exceptions include nafcillin which is largely excreted via the biliary tract [ 131 and mezlocillin which is largely eliminated by the kidneys, but has greater biliary clearance than most other penicillins. This property can be of clinical significance because renal compromise will cause less accumulation in serum, and thus less toxicity. In the presence of normal renal function, except in the neonate, most of the penicillins have a half-life of 30 to 60 minutes after intravenous infusion. The halflife of ampicillin, like other penicillins, is inversely related to post-natal age. The half-life of ampicillin in serum is approximately four hours in term infants from birth to seven days of age, 2.8 hours from eight to 14 days of age, 1.7 hours from 15 to 30 days of age, and still less in older infants [ 141. Because of their short 204
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half-life, the penicillin preparations should be given at four hour intervals to those with mature renal function and at eight hour intervals in the neonate less than one week of age. Most of the penicillins are transported into CSF very poorly when the meninges are not inflamed, but in adequate concentration when meningeal inflammation is present [15]. There is little available information regarding CSF penetration of carbenicillin or ticarcillin. Nafcillin enters CSF better than methicillin (16-181. For this reason, and because of its greater efficacy, it is the preferred drug for penicillinase-producing sensitive staphylococcal infections. The sodium and potassium content of the penicillin preparations can be important as it pertains to possible adverse effects of the drugs. The potassium salt of benzyl penicillin contains 1.7 mEq of potassium per lo6 units and can be cardiotoxic if a large dose is given rapidly. The sodium content of the penicillinaseresistant and extended-spectrum penicillins can be associated with the development of hypokalemia and can also lead to volume overload when large doses are given to patients with cardiorespiratory compromise. Among the extended-spectrum penicillins, the newest members are the acylampicillins, piperacillin, and mezlocillin [19]. The role of these new antimicrobials for treatment of central nervous system infection is still uncertain, although piperacillin may prove useful in certain instances. Similar to the other extended spectrum penicillins, these semi-synthetic preparations are susceptible to P-lactamase and therefore not effective against many strains of StapbyLococcus species, /3-lactamase positive Hemophilus influenzae , and P-lactamase producing members of the Enterobacteriaceae. Piperacillin and mezlocillin are active against several Gram negative and Gram positive organisms, but their greatest asset is their bactericidal effect against Klebsiella pneumoniae, Pseudomonas aeruginosa, and, to a lesser extent, Serratia marcescens. Piperacillin is more effective than metlocillin against Pseudomonas aeruginosa. Most isolates of this organisms are inhibited at concentrations of piperacillin that are considerably lower than those of carbenicillin (20,2 11. In addition, piperacillin is active against many anaerobes, Proteus mirabi/is, and indolepositive Pmteus species. Neither piperacillin or mezlocillin should be used alone. Monotherapy results in the rapid emergence of resistant organisms. These drugs are synergistic with aminoglycosides against Pseudomonas aenrginosa and
certain sensitive Entembacteriaceae [22]. Preliminary studies indicate that piperacillin penetrates inflamed meninges into CSF reasonably well. Using continuous intravenous infusion in doses of 300-400 mg/Kg/day , Dickinson et al. [23] found mean CSF levels of 23 @g/ml, concentrations almost one-third those maintained in the serum. In most instances, the new acylampicillins provide no advantages over the previously available extended-spectrum penicillins. Chloramphenicol Following its introduction in 1949, chloramphenicol became widely used for treatment of many infectious illnesses and was routinely given prophylactically to neonates born after premature rupture of membranes. With the recognition of the toxic effects of the drug in the newborn infant in 1959, its use was sharply curtailed. Chloramphenicol once again enjoyed widespread use with the development of ampicillinresistant Hemophikr infruenzae strains in 1974 and because of its value against anaerobic organisms, especially Bacteroia’esfiagiiis. Chloramphenicol is supplied in the form of crystalline capsules and chloramphenicol palmitate suspension for oral administration, and chloramphenicol succinate for intravenous use. The palmitate and succinate esters have no antimicrobial activity and must be hydrolyzed to the free, biologically active compound. An important and remarkable feature of chloramphenicol is that, except in the neonate, the oral palmitate ester provides greater bioavailability of the active free form of the drug than does the intravenous preparation [24,2 51. The little data available pertaining to the neonate indicates that the bioavailability of chloramphenicol after oral administration is quite variable and significantly lower than after intravenous use [26]. Hydrolysis of the palmitate ester to the free form takes place by action of pancreatic enzymes in the proximal small intestine. The conversion is almost complete as is absorption of the active product. Less than 10% of the palmitate ester is excreted unchanged in the urine. The succinate ester administered intravenously is hydrolyzed mainly within the liver and to a lesser extent in other tissues. This hydrolysis is far more variable than intestinal hydrolysis and over 30% of the ester can be excreted unchanged in the urine [27]. Therefore, higher chloramphenicol blood levels may be achieved with the oral than with intravenous administration at equal doses. A 25 % reduction in the dose of chloramphenicol may be required when the
administration route is changed from intravenous to oral after four or five days of ueatment of Hemopbih infruenzae meningitis. Because serum levels cannot be accurately predicted, periodic monitoring of the free component is recommended. Peak levels occur 30-60 minutes after inuavenous infusion and two to three hours after oral administration [28]. Following intravenous dosing, peak venuicular fluid levels are reached in approximately three hours [29]. Penetration of chloramphenicol into CSF is independent of meningeal inflammation or route of administration. CSF levels are generally 50%‘or greater than the simultaneous serum level [28,30], but can be considerably lower [29]. In children with a ventricular shunt or reservoir, periodic serum and ventricular fluid chloramphenicol levels can provide valuable information which allows adjustment of the dosage for optimal therapy. interactions can be important when Dmg chloramphenicol is used in conjunction with antiepileptic drugs. While the clinical relevance is still speculative, drug interactions can produce inadequate levels of chloramphenicol or toxic concentrations of the antiepileptic drug. Phenobarbital induces hepatic microsomal enzymes leading to acceleration of chloramphenicol conjugation and subsequent decline in its serum level [31-331. This possible interaction requires close monitoring of the chloramphenicol serum level whenever it is given in combination with phenobarbital. Conversely, chloramphenicol can retard hepatic biotransformation of several drugs, including tolbutamide, dicumarol, and phenytoin [34]. Elevation of the phenytoin serum level into the toxic range can result. Drug interactions between chloramphenicol and other antimicrobials must also be considered. Chloramphenicol in combination with certain of the penicillins can be less effective against Streptococcus pneumoniae, Group B Streptococcus, and certain meningococcal isolates than either drug alone [35-371. Simultaneous adminisuation of chloramphenicol and gentamicin may abolish the bactericidal effect of the aminoglycoside against certain Gram negative enteric bacilli [38] while the combination of chloramphenicol and ampicillin has been reported to be either synergistic or less effective in combination when used against Gram negative enteric bacteria [39]. The potential antagonism between chloramphenicol and the penicillins against Streptococcuspneumoniae and some meningococcal species is of considerable concern, because chloramphenicol and ampicillin are the usual Bell and McGuincss: Acute Bacterial Meningitis
205
initial therapy for acute meningitis in children older than eight to ten weeks. With organisms other than Hemophilus infruenzae , the regimen should be changed immediately to avoid compromise of the antimicrobial action. Possible adverse reactions to chloramphenicol are remarkably different from those of most other antibiotics, in part because of its peculiar effect on bone marrow function and also because of the hepatic metabolism of the drug. Unlike most of the penicillins and cephalosporins, rash and drug fever are unusual complications. Renal compromise is less important as a cause of unexpectedly elevated serum levels. Nausea, vomiting, or diarrhea are seen occasionally with chloramphenicol, especially with the oral preparation. . Chloramphenicol can cause bone marrow depression of two types, one toxic, the other idiosyncratic. The frost is a dose-related, predictable form which initially affects erythropoiesis and is characterized by a decrease in hemoglobin and reticulocyte count, increased serum iron concentration, and vacuolization of erythrocyte precursors in bone marrow. This process commonly occurs within a few days after initiation of therapy and especially when serum chloramphenicol levels exceed 2 5 ccg/ml. Depression of erythropoiesis can be followed by thrombocytopenia and neutropenia if the drug is continued. Once the drug is discontinued, the hematologic findings revert to normal within a week to ten days. Toxic depression of the bone marrow has been attributed to inhibition of mitochondrial protein synthesis and thus is similar to the mechanism of the antibacterial effect of chloramphenicol [40]. It should be monitored at three to four day intervals with complete blood counts. Neutropenia or thrombocytopenia rarely occurs in the absence of red blood cell depression. Idiosyncratic aplastic anemia is estimated to occur in one in 40,000 to 60,000 persons who receive the drug [41,42]. This complication is not dose-related, can occur after a single dose of the drug, and usually appears weeks to months after treatment. Although the two types of bone marrow depression from chloramphenicol have been assumed to be unrelated and caused by different mechanisms, Daum et al. [43] have recently described an example in which the doseby the related, ‘ ‘reversible ’ ’ type was followed even though the drug had progressive aplastic state, been discontinued. A dramatic type of acute toxic reaction to
206
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chloramphenicol, directly related to serum levels, is the “gray baby” syndrome. In the past, this condition was seen mainly in young infants intentionally treated with high doses [44,45]. Currently, it is usually the result of calculation error in the drug dosage. While the disorder is primarily one of infancy, it can occur at any age. Neonates, especially those of low birth weight, as well as older persons with advanced liver disease, are unduly susceptible to this shock state because of an immature or limited hepatic glucuronidation mechanism. The syndrome may occur at serum levels greater than 50 e/ml, but in most cases serum levels are greater than 80 g/ml. Clinical manifestations usually begin three to six days after the onset of therapy and consist of lethargy, hypotonia, abdominal distention, hypotension with an ashen-gray appearance from poor tissue perfusion, hypothermia, and metabolic acidosis. Many of these symptoms are attributable to peripheral vascular collapse; however, recent observations suggest a cardiogenic component of shock resulting from direct toxic effects of the drug on the myocardium [46]. Charcoal hemoperfusion is an effective method of rapidly reducing the serum chloramphenicol level and can reverse the process if ischemic tissue damage has not yet occurred [47]. Peritoneal dialysis and hemodialysis are far less efficient in the removal of chloramphenicol from the serum. An acute encephalopathy manifested by delerium, confusion, or lethargy has been described with chloramphenicol, but must be exceedingly unusual [48]. Optic neuritis and visual loss have been reported on several occasions as a complication of long-term chloramphenicol therapy, mainly in children with cystic fibrosis (49,501. Chloramphenicol in concentrations readily achieved in body fluids and tissues is bactericidal against Hemophilus influenzae , Neissen’a meningitidis , and to a lesser extent, Streptococcus pneumoniae, but is only bacteriostatic against most of the Enterobacteriaceae and Staphylococcus species [5 11. Like rifampin and isoniazid, chloramphenicol has the advantage over fllactam antibiotics and aminoglycosides of a high degree of intracellular penetration and, thus, intracellular killing of sensitive organisms [52,53]. The clinical importance of this characteristic of certain antibiotics, however, remains unclear. Although there are standard recommended doses for the initiation of therapy depending on the age of the child, the ultimate dose of chloramphenicol is that amount necessary to bring about peak serum levels of lo-25 @/ml. This is best
achieved by monitoring minations.
periodic
serum level deter-
Vancomycin Vancomycin, the only glycopeptide antibiotic with extensive clinical use, has become more important in recent years because of the increasing occurrence of methicillin-resistant strains of St@7hylOcoct~r alcreicr and Staphy/Ococcus epidermidis. The bactericidal effects of the drug are due to inhibition of cell wall synthesis by a mechanism different from that of the /3lactam antibiotics. Vancomycin is administered by the intravenous route for invasive infections and has a halflife of approximately six hours in patients beyond the newborn period. Elimination is mainly by the kidneys and renal compromise causes a significant rise in serum levels of the drug. A major problem with vancomycin in the treatment of neurologic infections is its limited penetration into CSF at dosages that can be safely administered. With meningeal inflammation, CSF concentrations range from 7 to 21% percent (mean 14%) of the simultaneous serum level [54]. CSF penetration is negligible in patients with shunt infection and little or no meningeal inflammation. In this situation, vancomycin must be injected directly into the ventricle. Vancomycin has had a reputation for greater ototoxicity and nephrotoxicity than most other antibiotics. Recent observations suggest that the drug is now less toxic than in past years, perhaps due to improved removal of impurities from the formulation and greater awareness of the effects of renal compromise on drug elimination. Nephrotoxicity is now considered to be infrequent when vancomycin is used alone, but remains a decided risk when it is combined with an aminoglycoside [55]. Other possible adverse effects of vancomycin are rash, drug fever, systemic hypotension, and neuuopenia. Thrombophlebitis is infrequent with the current formulations. Vancomycin has bactericidal activity against several Gram positive cocci including Staphylococcus species resistant to other antibiotics and Streptococcus pneumoniae. Its primary role is for the treatment of methicillin-resistant staphylococcal shunt infections for which it can be used alone or in combination with r&unpin [56,57]. Combined therapy is indicated for those cases which prove intractable to vancomycin alone or in the absence of meningeal inflammation. Vancomycin alone or in combination with an aminoglycoside has been used successfully for the
treatment of Group D enterococcal meningitis [58]. Vancomycin is also an alternative for the rare case of pneumoccal meningitis in which neither penicillin nor chloramphenicol can be used. The daily intravenuicular dose of vancomycin varies from 5-20 mg depending upon ventricular capacity. In the term newborn infant less than one week of age, the IV dose is 30 mg I kg /day in two divided doses. For the low-birthweight newborn in the first week of life, the IV dose is 20 mglkglday. From one week to two months of age, the dose is 45 mg /kg /day if renal function is adequate. Metconidazole Metronidazole is a nitroimidazole antimicrobial with bactericidal activity against common anaerobic organisms, but with little or no effect upon facultative and aerobic bacteria. Its activity is also poor against microaerophilic streptococci. The mechanism of action of metronidazole against anaerobes is not well understood, although it has been shown to block DNA replication of Bacteroides fragifir [Xl]. It is well absorbed after oral administration with peak serum levels achieved between 1-2 hours after ingestion. With serious invasive infections, the inuavenous preparation is preferred [60]. The serum half-life is approximately eight hours and the drug is minimally protein bound [61]. Meuonidazole diffuses well into tissues; CSF levels are almost equal to those in plasma. Because it is largely metabolized by the liver, plasma concentrations can become markedly elevated in patients with hepatic insufficiency. Drug metabolites are excreted mainly by the kidneys. The risk of toxicity in patients with renal insufficiency is not clear. Meuonidatole is used primarily for the treatment of meningitis or brain abscesses caused by Bactemides fiagiks , Fusobacterium species, or other sensitive anaerobic infections that have not responded adequately to penicillin. It is often used in combination with cefotaxime or penicillin for the initial treatment of brain abscess when the flora is presumed to include anaerobes . Adverse effects of metronidazole are usually mild including a metallic taste, nausea, or vertigo. Continuous infusion of the drug may be complicated by phlebitis and intermittent infusion is recommended. Effects of warfarin can be potentiated resulting in a prolongation of the prothrombin time 1621. Peripheral neuropathy can occur with high dose intravenous meuonidazole therapy as can an acute encephalopathy Bell and McGuincss: Acute Bacterial Meningitis
207
manifested by seizures, stupor, or coma [63]. In children, an oral dose of 40 mglkgiday given in three divided doses results in peak CSF levels greater than 10 #/ml. In the neonate, intravenous metronidazole is given as a single loading dose of 15 mglkg followed by doses of 7.5 mglkg every 12 hours [64]. In older infants and children, the intravenous dose is 30 mglkglday in divided doses every 6 hours infused over one hour.
[16]
autcus meningitis. 1181
[l]
Smith
CR. Ccfotaximc
[2 ]
and ccphalosporins.
Landesman
SH, Corrado
CE. Past and current
in treatment
of meningitis.
meningitis.
[3]
Franckc
into
human
roles for ccphalosporin
Emphasis
on USC in Gram-negative
of serious infections.
organisms.
McCracken
of ccfotaximc
GH.
a B-lactamasc
[I91
indudin
those due
Am J Mcd 1981;71:435-42.
Thrclkcld
in newborn
NE, Thomas
infants.
serious infections. [6]
ML. Parmacokinctics
Antimicrob
Agents
Ccftriaxonc
for the treatment
[20]
nervous
[7]
Schaad
ccftriaxonc
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in
timicrobial
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Stocckcl
infants
and
spectrum,
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Antimicrob
Agents
Scribncr
RK.
meningitis.
function.
Ml.
enzyme
patients
with of Agents
of its an-
meningitis.
Johnston
Rose&Id AJ.
WN,
neonates.
JT,
Frederick
in acute
AU, Craig WA.
DF.
childhood
Pharmacokinctics
and impaired
of
hcpatic
R. Jhavcri
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Antimicrob
Agents
in
with
SG. Yaffc in
of
and renal
in
RC, Vohra full-term
K, and
Chcmothcrap
1983;
failure.
JP,
in children
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Acute Bacterial
Meningitis
M, of
209
Cument Therapy of Acute Bacterial Meningitis in Children: Part II William E. Bell, MD and Gail A. McGuinness, MD
Despite many advances in the past decade in the development of new antimicrobials, acute bacterial meningitis continues to have significant morbidity and mortality in infants and children. Regardless of the effectiveness of the antibiotic preparations, future improvement in outcome is most likely to occur because of more rapid diagnosis and initiation of therapy. The standard penicillins, chlommphenicol, and the aminoglycosides continue to hold an important place in treatment. The recent introduction of new extended including piperacillin and spectrum penicillins, mezlocillin, in addition to the development of the third generation cephalosporins, have expanded alternatives for treating bacterial meningitis. The most appropriate and effective antibiotic or combination of antibiotics must first be selected; thereafter, its use must be monitore to identify its beneficial effects as well as possible adverse effects. Bell WE, McGuinness GA. Current therapy of acute bacterial meningitis in children: Parr II. Pediat Neural
there is a clear advantage of a synergistic effect. In this part, we review important characteristics of those antimicrobials which are currently popular for the treatment of meningitis. Some recently released preparations are discussed, even though their precise role has yet to be established. The first and most important consideration is the selection of the best antibiotic(s), at the correct daily dosage (Table 1, 2), and administered at the correct frequency. The next obligation is to be certain that the child is in fact receiving what has been ordered. With certain drugs, such as chloramphenicol and the aminoglycosides, serum levels should be determined and dosage adjustments made accordingly. Regardless of which antimicrobials are utilized, the physician must be familiar with the pharmacokinetics of the drug in different age groups, the potential drug interactions, and, especially, the many possible adverse effects.
Introduction In Part I, the methods of selection of an antibiotic regimen for treatment of acute bacterial meningitis of childhood were reviewed. Emphasis was placed on the importance of choosing antibiotics which are bactericidal against the known or presumed causative organisms. The selected antimicrobials, with doses that can be given safely systemically, must be capable of penetrating into cerebrospinal fluid (CSF) in concentrations well above the mean bactericidal concentration (NBC) for the infective organism. Combinations of drugs are generally to be avoided unless
Third Generation Cephalosporins The fust available cephalosporin antibiotic was cephalothin. Similar compounds appeared later. The initial preparations had little application to the treatment of central nervous system infections because of limited penetrability into CSF. As new variations of cephalosporins became available they were classified by generations, largely on the basis of their antibacterial spectrum. First generation cephalosporins were active against Gram positive organisms but had limited action against Gram negative organisms. Second generation drugs expanded the antimicrobial effects to some Gram but still penetrated the CSF negative pathogens, poorly. Third generation cephalosporins are useful in the treatment of meningitis because many penetrate CSF adequately, are &lactamase resistant, and have a broad spectrum antibacterial effect. Some of the newest
From
Communications
1985;1:201-9.
the Section
and Neurology; and
the
University
of Pediatric University
Division
of
of Iowa College
Neurology;
Departments
of Iowa College of Medicine; Nconatology; of Medicine,
Department Iowa City,
of Pediatrics Iowa City, of
IA.
IA
Pediatrics;
should
Dr. Bell; Division and Neurology;
be addressed
of Pediatric University
to:
Neurology;
Dcpzutments
of Iowa College of Medicine,
of Pediatrics Iowa City, IA
52242. Received
May 20, 1984; accepted June 12.1985
Bell and McGuincss:
Acute BacteriaI
Meningitis
201
Table
1. Antibiotic
dosages for bacterial
meningitis
(birth
Ampicillin
lSO-20Omg/kg/day,
Peni&lIio G Less than one week
150.000
to two months)
IV (q8h)
units/kg/day.
IV (q8h)
One week to two months
150.000-250,000
units/kg/day,
IV(q6h)
Group
250,000-400.000
units/kg/day,
IV(q6h)
MCdliciIIitl
100 mgIkg/day,
IV (q8h)
Naftilh
100 mglkglday,
IV (q8h)
carbenicillin
300 mglkglday,
IV (q8h)
TicatciIIin
200-300mgIkgIday.
PipeGxillin
200 mglkglday.IV
B Streptococcus
IV (q8h) (q8h)
KiltMDy& Less than one week
2Omglkglday,
IM, IV (ql2h)
One week to two months
3OmgIkgIday.
IM, IV (q8h)
Gentamicin Less than one week
5 mglkglday,
One week to two months
7.5 mglkglday,
IM, IV (ql2h) IM, IV (q8h)
Tobtamycio Less than one week
5 mglkglday.
9°C week to two months
7.5 mglkglday,
IM, IV (ql2h) IM, IV (q8h)
Amikacin Less than one week
15 mglkglday.
One week to two months
22.1 mglkglday,
IM, IV (ql2h) IM, IV (q8h)
MoxaIactam
lOO-150mg/kg/day,
IV (q8h)
Cefotaximc
IOO-150mg/kgIday,
IV (q8h)
Vancomycin Birth to one week
3Omglkglday.
IV (ql2h)
One week to two months
45 mglkglday,
IV (q8h)
15 mg/kg/day,
IV (ql2h)
Mctronidazolc Chloramphenicol Premature (birth
25 mglkglday.
IV (ql2h)
Full term (1st 7 days)
fo 1 month)
25 mglkglday,
IV (ql2h)
Full term (7 to 30 days)
50 mglkglday.
IV (q8h)
Full term (1 to 2 months)
50-100 mglkglday,
third generation drugs are highly effective against all of the common causesof acute bacterial meningitis in the neonate, infant, and child. Nonetheless, third generation cephalosporins have as yet not been accepted as drugs of choice for any type of bacterial meningitis, although cefotaxime is used widely for treatment of sensitive Escher&ha co/i meningitis in infants and in adults. Cefotaxime Cefotaxime, the first of the third generation cephalosporins,wasreleasedfor use in 1981. Although some degree of effectiveness against Gram positive organisms had been sacrificed compared to the earlier cephalosporins, the bactericidal action of cefotaxime 202
PEDIATRIC
NJWROLOGY
Vol. 1 No. 4
IV (q6h)
against Escherichiaco/i and many other Gram negative organisms was quickly recognized. Cefotaxime rivals and may surpassthe advantages of ampicillin and an aminoglycoside in the treatment of Gram negative meningitis in newborns and following head trauma or neurosurgical proceduresin children and adults. It is an important alternative for children with Hemophilus infuenzae or meningococcal meningitis when customary antimicrobials cannot be used, and can be administered as initial therapy, in combination with other antibiotics, in children with focal intracranial infections when Gram negative bacteria might be present. Cefotaxime is well tolerated by most children. Infrequent adverse effects include phlebitis, rash,
Table 2. Antibiotic up to 50 kilograms Ampicillin Peni&
dosages for bacterial
meningitis
300-4OOmgIkgIday. G
(over 2 months
-
body weight IV (q4h)
250,00OUnits/kg/day.
Mcdlicillin
200-300mglkglday.
Nddlill
200mg/kg/day,
CtiniCilIiU
400-600
IV (q4h) IV (q4h) IV (q4h)
mglkglday,
IV (q4h)
Ticahllin
300-4OOmg/kg/day,
IV (q4h)
Pipelacillin
300-400
IV (q4h)
mglkglday,
Cblolampbeoicol
75-100 mglkg/day,PO
Gentamicin
4 mglkglday,
IM (q8h)
Tobtamycin
4 mglkglday.
IM (q8h)
Amikacin
15 mglkglday,
of IV (qbh)
IM (q8h)
Moxalactam
15Omglkglday.
IV (q4h)
Cefotaxime
150mglkgIday.
IV (q4h)
Cefoperazone
300 mglkglday,
IV (q8h)
Cefuiaxone
lOOmg/kg/day,
IV (ql2h)
Rihlpin
20 mg/kg/day,
PO (q8h)
(up to 600 mg) Streptomycin
antimicrobials because such infections are sometimes polymicrobial and may include anaero bes .
20-40 mglkglday,
IM (q12h)
(not over 1 gram) Vancomycin
60 mglkglday.
Sulfadiazine
150mglkglday.
Mecconidatole
40mg/kgIday,
PO (q8h)
3OmgIkgIday.
IV (qbh)
IV (q6h) IV (q8h)
eosinophilia, drug fever, and vertigo [l]. CSF penetration through inflamed meninges is adequate. An adult intravenous dose of 8-12 grams/24 hours results in CSF levels of 5-13 g/ml, levels 40-200 times the MBC for most EscheriGhia cofi and Klebsiella species [2]. Cefotaxime is primarily excreted in the urine, some unchanged, but most in the form of its major metabolite, deacetylcefotaxime. In adults with normal renal function, the half-life is approximately 60 minutes; in neonates, it is 3.4-4.6 hours [3,4]. The role of cefotaxime in the treatment of central nervous system infections in infants and children is still being studied. Although cefotaxime is more effective than combined therapy with ampicillin and an aminoglycoside in the treatment of bacillary meningitis, it is also more toxic. In the neonate, it should be combined with ampicillin prior to identification of the causative organism, because of its questionable efficacy against Group B Streptococcus and its lack of activity against ListerG monocytogenes and enterococcal Group D streptococci. In the treatment of meningitis complicating head trauma, intracranial operative procedures, or brain abscess, cefotaxime is used in combination with other
Cefthxone Ceftriaxone differs from other third generation cephalosporins because of its extended spectrum against Gram positive and Gram negative bacteria and because of its uniquely prolonged serum and CSF half-life. In addition to its superior antibacterial activity against the Entenhctetieae, Hemophihs influenzae, and Neisserih meningitidis, cef&xone reaches serum and CSF concentrations far in excess of that needed for effective treatment for infections caused by Streptococcuspneumoniae and Group B Streptococcus [5,6]. These charateristics indicate that it is effective against all bacterial meningitis in the newborn period and childhood. Like other members of the newer cephalosporins, it is poorly active against Group B streptococci and Listeria monocytogenes; therefore, it would not be acceptable monotherapy in newborns before the etiological agent is identified. Ceftriaxone is eliminated by renal and hepatic mechanisms; impairment of function of either organ does not markedly alter drug excretion. The half-life of ceftriaxone in young children is approximately 6.5 hours [7] and is longer in adults. The prolonged halflife, the dual mechanism of elimination, the low incidence of adverse effects, and the readily achievable serum and CSF levels in infants and children make ceftriaxone a serious consideration for clinical use in infections. While it has not achieved “drug of choice” popularity, ceftriaxone is accepted as an alternative for the treatment of meningitis caused by Hemophilus infruenzae , Streptococcus pneumoniae , and Neissetia meningitidir when other antibiotics cannot be used because of drug intolerance or bacterial resistance. Cefoperazone Cefoperazone, like ceftriaxone, has enhanced activity against Gram positiye bacteria as compared to cefotaxime, as well as excellent activity against a variety of Gram negative organisms. Its popularity is largely due to its effectiveness against many strains of Pseudomonas aeruginosa and indole-positive Proteus species. Cefoperazone is as effective as piperacillin and four times as active as cefotaxime against Pseudomonas aeruginosa [8]. It is at least as effective as chloramphenicol for /3-lactamase positive Hemophhs influenzue. Conuadictory studies concerning the . CSF peneuation of cefoperazone have been reported. Cable BeIl and McGuines:
Acute Bacterial
Meningitis
203
et al. [9] found CSF penetration variable and not entirely reliable. Conversely, Chartrand et al. [lo] studied CSF penetration following a single 100 mg /Kg intravenous dose in children with meningitis and found the concentration to exceed the MIC for Hemophilur infuenzae , Streptococcus pneumonias , and Neissetia meningitidis by 15 to 237-fold. Biliary excretion is the major pathway of elimination of cefoprazone so that dosage adjustments are unnecessary in the presence of renal compromise. Cefoperazone is 70 to 90% protein-bound and the serum half-life id the older child or adult is 1.6-2.6 hours [ll]. In premature and term newborn infants, the mean serum half-life ranges from seven to nine hours [12]. At the present time, there is no specific indication to use cefoperazone in the treatment of central nervous system infections. In combination with other antimicrobials, it is now used for certain Gram negative infections in immunosuppressed or neutropenic patients. Cefoperazone with an aminoglycoside can be considered as an alternative caused by Pseudomonas regimen for meningitis aeruginosa or Proteus species when other more commonly used antimicrobials are ineffective or not tolerated. PenicilJim Following the introduction of penicillin in 1941, there has been a gradual elaboration of related compounds. The penicillins have remained the most widely used class of antimicrobials for the treatment of infections of the central nervous system. Most of the penicillins undergo rapid renal excretion resulting in a adshort serum half-life following intravenous ministration. Exceptions include nafcillin which is largely excreted via the biliary tract [ 131 and mezlocillin which is largely eliminated by the kidneys, but has greater biliary clearance than most other penicillins. This property can be of clinical significance because renal compromise will cause less accumulation in serum, and thus less toxicity. In the presence of normal renal function, except in the neonate, most of the penicillins have a half-life of 30 to 60 minutes after intravenous infusion. The halflife of ampicillin, like other penicillins, is inversely related to post-natal age. The half-life of ampicillin in serum is approximately four hours in term infants from birth to seven days of age, 2.8 hours from eight to 14 days of age, 1.7 hours from 15 to 30 days of age, and still less in older infants [ 141. Because of their short 204
PEDIATRIC
NEUROLOGY
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half-life, the penicillin preparations should be given at four hour intervals to those with mature renal function and at eight hour intervals in the neonate less than one week of age. Most of the penicillins are transported into CSF very poorly when the meninges are not inflamed, but in adequate concentration when meningeal inflammation is present [15]. There is little available information regarding CSF penetration of carbenicillin or ticarcillin. Nafcillin enters CSF better than methicillin (16-181. For this reason, and because of its greater efficacy, it is the preferred drug for penicillinase-producing sensitive staphylococcal infections. The sodium and potassium content of the penicillin preparations can be important as it pertains to possible adverse effects of the drugs. The potassium salt of benzyl penicillin contains 1.7 mEq of potassium per lo6 units and can be cardiotoxic if a large dose is given rapidly. The sodium content of the penicillinaseresistant and extended-spectrum penicillins can be associated with the development of hypokalemia and can also lead to volume overload when large doses are given to patients with cardiorespiratory compromise. Among the extended-spectrum penicillins, the newest members are the acylampicillins, piperacillin, and mezlocillin [19]. The role of these new antimicrobials for treatment of central nervous system infection is still uncertain, although piperacillin may prove useful in certain instances. Similar to the other extended spectrum penicillins, these semi-synthetic preparations are susceptible to P-lactamase and therefore not effective against many strains of StapbyLococcus species, /3-lactamase positive Hemophilus influenzae , and P-lactamase producing members of the Enterobacteriaceae. Piperacillin and mezlocillin are active against several Gram negative and Gram positive organisms, but their greatest asset is their bactericidal effect against Klebsiella pneumoniae, Pseudomonas aeruginosa, and, to a lesser extent, Serratia marcescens. Piperacillin is more effective than metlocillin against Pseudomonas aeruginosa. Most isolates of this organisms are inhibited at concentrations of piperacillin that are considerably lower than those of carbenicillin (20,2 11. In addition, piperacillin is active against many anaerobes, Proteus mirabi/is, and indolepositive Pmteus species. Neither piperacillin or mezlocillin should be used alone. Monotherapy results in the rapid emergence of resistant organisms. These drugs are synergistic with aminoglycosides against Pseudomonas aenrginosa and
certain sensitive Entembacteriaceae [22]. Preliminary studies indicate that piperacillin penetrates inflamed meninges into CSF reasonably well. Using continuous intravenous infusion in doses of 300-400 mg/Kg/day , Dickinson et al. [23] found mean CSF levels of 23 @g/ml, concentrations almost one-third those maintained in the serum. In most instances, the new acylampicillins provide no advantages over the previously available extended-spectrum penicillins. Chloramphenicol Following its introduction in 1949, chloramphenicol became widely used for treatment of many infectious illnesses and was routinely given prophylactically to neonates born after premature rupture of membranes. With the recognition of the toxic effects of the drug in the newborn infant in 1959, its use was sharply curtailed. Chloramphenicol once again enjoyed widespread use with the development of ampicillinresistant Hemophikr infruenzae strains in 1974 and because of its value against anaerobic organisms, especially Bacteroia’esfiagiiis. Chloramphenicol is supplied in the form of crystalline capsules and chloramphenicol palmitate suspension for oral administration, and chloramphenicol succinate for intravenous use. The palmitate and succinate esters have no antimicrobial activity and must be hydrolyzed to the free, biologically active compound. An important and remarkable feature of chloramphenicol is that, except in the neonate, the oral palmitate ester provides greater bioavailability of the active free form of the drug than does the intravenous preparation [24,2 51. The little data available pertaining to the neonate indicates that the bioavailability of chloramphenicol after oral administration is quite variable and significantly lower than after intravenous use [26]. Hydrolysis of the palmitate ester to the free form takes place by action of pancreatic enzymes in the proximal small intestine. The conversion is almost complete as is absorption of the active product. Less than 10% of the palmitate ester is excreted unchanged in the urine. The succinate ester administered intravenously is hydrolyzed mainly within the liver and to a lesser extent in other tissues. This hydrolysis is far more variable than intestinal hydrolysis and over 30% of the ester can be excreted unchanged in the urine [27]. Therefore, higher chloramphenicol blood levels may be achieved with the oral than with intravenous administration at equal doses. A 25 % reduction in the dose of chloramphenicol may be required when the
administration route is changed from intravenous to oral after four or five days of ueatment of Hemopbih infruenzae meningitis. Because serum levels cannot be accurately predicted, periodic monitoring of the free component is recommended. Peak levels occur 30-60 minutes after inuavenous infusion and two to three hours after oral administration [28]. Following intravenous dosing, peak venuicular fluid levels are reached in approximately three hours [29]. Penetration of chloramphenicol into CSF is independent of meningeal inflammation or route of administration. CSF levels are generally 50%‘or greater than the simultaneous serum level [28,30], but can be considerably lower [29]. In children with a ventricular shunt or reservoir, periodic serum and ventricular fluid chloramphenicol levels can provide valuable information which allows adjustment of the dosage for optimal therapy. interactions can be important when Dmg chloramphenicol is used in conjunction with antiepileptic drugs. While the clinical relevance is still speculative, drug interactions can produce inadequate levels of chloramphenicol or toxic concentrations of the antiepileptic drug. Phenobarbital induces hepatic microsomal enzymes leading to acceleration of chloramphenicol conjugation and subsequent decline in its serum level [31-331. This possible interaction requires close monitoring of the chloramphenicol serum level whenever it is given in combination with phenobarbital. Conversely, chloramphenicol can retard hepatic biotransformation of several drugs, including tolbutamide, dicumarol, and phenytoin [34]. Elevation of the phenytoin serum level into the toxic range can result. Drug interactions between chloramphenicol and other antimicrobials must also be considered. Chloramphenicol in combination with certain of the penicillins can be less effective against Streptococcus pneumoniae, Group B Streptococcus, and certain meningococcal isolates than either drug alone [35-371. Simultaneous adminisuation of chloramphenicol and gentamicin may abolish the bactericidal effect of the aminoglycoside against certain Gram negative enteric bacilli [38] while the combination of chloramphenicol and ampicillin has been reported to be either synergistic or less effective in combination when used against Gram negative enteric bacteria [39]. The potential antagonism between chloramphenicol and the penicillins against Streptococcuspneumoniae and some meningococcal species is of considerable concern, because chloramphenicol and ampicillin are the usual Bell and McGuincss: Acute Bacterial Meningitis
205
initial therapy for acute meningitis in children older than eight to ten weeks. With organisms other than Hemophilus infruenzae , the regimen should be changed immediately to avoid compromise of the antimicrobial action. Possible adverse reactions to chloramphenicol are remarkably different from those of most other antibiotics, in part because of its peculiar effect on bone marrow function and also because of the hepatic metabolism of the drug. Unlike most of the penicillins and cephalosporins, rash and drug fever are unusual complications. Renal compromise is less important as a cause of unexpectedly elevated serum levels. Nausea, vomiting, or diarrhea are seen occasionally with chloramphenicol, especially with the oral preparation. . Chloramphenicol can cause bone marrow depression of two types, one toxic, the other idiosyncratic. The frost is a dose-related, predictable form which initially affects erythropoiesis and is characterized by a decrease in hemoglobin and reticulocyte count, increased serum iron concentration, and vacuolization of erythrocyte precursors in bone marrow. This process commonly occurs within a few days after initiation of therapy and especially when serum chloramphenicol levels exceed 2 5 ccg/ml. Depression of erythropoiesis can be followed by thrombocytopenia and neutropenia if the drug is continued. Once the drug is discontinued, the hematologic findings revert to normal within a week to ten days. Toxic depression of the bone marrow has been attributed to inhibition of mitochondrial protein synthesis and thus is similar to the mechanism of the antibacterial effect of chloramphenicol [40]. It should be monitored at three to four day intervals with complete blood counts. Neutropenia or thrombocytopenia rarely occurs in the absence of red blood cell depression. Idiosyncratic aplastic anemia is estimated to occur in one in 40,000 to 60,000 persons who receive the drug [41,42]. This complication is not dose-related, can occur after a single dose of the drug, and usually appears weeks to months after treatment. Although the two types of bone marrow depression from chloramphenicol have been assumed to be unrelated and caused by different mechanisms, Daum et al. [43] have recently described an example in which the doseby the related, ‘ ‘reversible ’ ’ type was followed even though the drug had progressive aplastic state, been discontinued. A dramatic type of acute toxic reaction to
206
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NEUROLOGY
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1 No. 4
chloramphenicol, directly related to serum levels, is the “gray baby” syndrome. In the past, this condition was seen mainly in young infants intentionally treated with high doses [44,45]. Currently, it is usually the result of calculation error in the drug dosage. While the disorder is primarily one of infancy, it can occur at any age. Neonates, especially those of low birth weight, as well as older persons with advanced liver disease, are unduly susceptible to this shock state because of an immature or limited hepatic glucuronidation mechanism. The syndrome may occur at serum levels greater than 50 e/ml, but in most cases serum levels are greater than 80 g/ml. Clinical manifestations usually begin three to six days after the onset of therapy and consist of lethargy, hypotonia, abdominal distention, hypotension with an ashen-gray appearance from poor tissue perfusion, hypothermia, and metabolic acidosis. Many of these symptoms are attributable to peripheral vascular collapse; however, recent observations suggest a cardiogenic component of shock resulting from direct toxic effects of the drug on the myocardium [46]. Charcoal hemoperfusion is an effective method of rapidly reducing the serum chloramphenicol level and can reverse the process if ischemic tissue damage has not yet occurred [47]. Peritoneal dialysis and hemodialysis are far less efficient in the removal of chloramphenicol from the serum. An acute encephalopathy manifested by delerium, confusion, or lethargy has been described with chloramphenicol, but must be exceedingly unusual [48]. Optic neuritis and visual loss have been reported on several occasions as a complication of long-term chloramphenicol therapy, mainly in children with cystic fibrosis (49,501. Chloramphenicol in concentrations readily achieved in body fluids and tissues is bactericidal against Hemophilus influenzae , Neissen’a meningitidis , and to a lesser extent, Streptococcus pneumoniae, but is only bacteriostatic against most of the Enterobacteriaceae and Staphylococcus species [5 11. Like rifampin and isoniazid, chloramphenicol has the advantage over fllactam antibiotics and aminoglycosides of a high degree of intracellular penetration and, thus, intracellular killing of sensitive organisms [52,53]. The clinical importance of this characteristic of certain antibiotics, however, remains unclear. Although there are standard recommended doses for the initiation of therapy depending on the age of the child, the ultimate dose of chloramphenicol is that amount necessary to bring about peak serum levels of lo-25 @/ml. This is best
achieved by monitoring minations.
periodic
serum level deter-
Vancomycin Vancomycin, the only glycopeptide antibiotic with extensive clinical use, has become more important in recent years because of the increasing occurrence of methicillin-resistant strains of St@7hylOcoct~r alcreicr and Staphy/Ococcus epidermidis. The bactericidal effects of the drug are due to inhibition of cell wall synthesis by a mechanism different from that of the /3lactam antibiotics. Vancomycin is administered by the intravenous route for invasive infections and has a halflife of approximately six hours in patients beyond the newborn period. Elimination is mainly by the kidneys and renal compromise causes a significant rise in serum levels of the drug. A major problem with vancomycin in the treatment of neurologic infections is its limited penetration into CSF at dosages that can be safely administered. With meningeal inflammation, CSF concentrations range from 7 to 21% percent (mean 14%) of the simultaneous serum level [54]. CSF penetration is negligible in patients with shunt infection and little or no meningeal inflammation. In this situation, vancomycin must be injected directly into the ventricle. Vancomycin has had a reputation for greater ototoxicity and nephrotoxicity than most other antibiotics. Recent observations suggest that the drug is now less toxic than in past years, perhaps due to improved removal of impurities from the formulation and greater awareness of the effects of renal compromise on drug elimination. Nephrotoxicity is now considered to be infrequent when vancomycin is used alone, but remains a decided risk when it is combined with an aminoglycoside [55]. Other possible adverse effects of vancomycin are rash, drug fever, systemic hypotension, and neuuopenia. Thrombophlebitis is infrequent with the current formulations. Vancomycin has bactericidal activity against several Gram positive cocci including Staphylococcus species resistant to other antibiotics and Streptococcus pneumoniae. Its primary role is for the treatment of methicillin-resistant staphylococcal shunt infections for which it can be used alone or in combination with r&unpin [56,57]. Combined therapy is indicated for those cases which prove intractable to vancomycin alone or in the absence of meningeal inflammation. Vancomycin alone or in combination with an aminoglycoside has been used successfully for the
treatment of Group D enterococcal meningitis [58]. Vancomycin is also an alternative for the rare case of pneumoccal meningitis in which neither penicillin nor chloramphenicol can be used. The daily intravenuicular dose of vancomycin varies from 5-20 mg depending upon ventricular capacity. In the term newborn infant less than one week of age, the IV dose is 30 mg I kg /day in two divided doses. For the low-birthweight newborn in the first week of life, the IV dose is 20 mglkglday. From one week to two months of age, the dose is 45 mg /kg /day if renal function is adequate. Metconidazole Metronidazole is a nitroimidazole antimicrobial with bactericidal activity against common anaerobic organisms, but with little or no effect upon facultative and aerobic bacteria. Its activity is also poor against microaerophilic streptococci. The mechanism of action of metronidazole against anaerobes is not well understood, although it has been shown to block DNA replication of Bacteroides fragifir [Xl]. It is well absorbed after oral administration with peak serum levels achieved between 1-2 hours after ingestion. With serious invasive infections, the inuavenous preparation is preferred [60]. The serum half-life is approximately eight hours and the drug is minimally protein bound [61]. Meuonidazole diffuses well into tissues; CSF levels are almost equal to those in plasma. Because it is largely metabolized by the liver, plasma concentrations can become markedly elevated in patients with hepatic insufficiency. Drug metabolites are excreted mainly by the kidneys. The risk of toxicity in patients with renal insufficiency is not clear. Meuonidatole is used primarily for the treatment of meningitis or brain abscesses caused by Bactemides fiagiks , Fusobacterium species, or other sensitive anaerobic infections that have not responded adequately to penicillin. It is often used in combination with cefotaxime or penicillin for the initial treatment of brain abscess when the flora is presumed to include anaerobes . Adverse effects of metronidazole are usually mild including a metallic taste, nausea, or vertigo. Continuous infusion of the drug may be complicated by phlebitis and intermittent infusion is recommended. Effects of warfarin can be potentiated resulting in a prolongation of the prothrombin time 1621. Peripheral neuropathy can occur with high dose intravenous meuonidazole therapy as can an acute encephalopathy Bell and McGuincss: Acute Bacterial Meningitis
207
manifested by seizures, stupor, or coma [63]. In children, an oral dose of 40 mglkgiday given in three divided doses results in peak CSF levels greater than 10 #/ml. In the neonate, intravenous metronidazole is given as a single loading dose of 15 mglkg followed by doses of 7.5 mglkg every 12 hours [64]. In older infants and children, the intravenous dose is 30 mglkglday in divided doses every 6 hours infused over one hour.
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