Aminoglycoside Antibiotics in Infectious Diseases. An Overview

 

Arhnoglycoside Antibiotics in Infectious Diseases An Overvi Overview ew

WALTER

E. SIEGENTHALER,

ANTONIO RUEDI Zurich,

BONETTI,

LUTHY,

This article presents an overview of the aminoglycoside antibiotics used in clinic al practice. Facts concerning concerning the discovery and properties of the aminog lycos lycosides ides are followed by information about spectrums of activity and mechanisms of action and resistance. Individu al ccompounds ompounds are compared and proposal proposalss on the poss ibilibil ities for their cli nical use, bboth oth as single drugs and in combination combination with beta-lactam antibio tics, are made. The importance placed on measuring the serum concentrat concentrations ions of aminoglycoside antibiotics should serve as a reminder that this procedure is important, on one hand, to increase clinical efficacy and, on the other, to reduce the

M.D.

M.D.

M.D.

Switzerland

side effects of these antibiotics. Finally, tthe he aminoglycosides are compared brief ly with other antibacte rial compounds, some of which are very new. There is no doubt that in the future future the aminoglycosides will continue continue to occupy an important important place in the treatment of severe infection s, although newly developed agents appear to be effective complements. Since the the discovery and clinical clinical use of streptomycin by Waksm an and co-workers [l] more than 40 years ago, various aminoglycosides have been developed and introduced in clinical me dicine. This article provides an overview disease.

of the actual

significance significance

of aminoglycosides

in infectious

The discovery of streptothricin streptothricin in 1942 and the isolation isolation of streptomycin from Streptomyces griseus by Waksm an’s research group in 1943 ushered in an explorator exploratoryy era for a new chemical class of antibiotics, the aminoglycosidic aminocyclitols, i.e., the aminoglycosides (Table I). The clinical application of strepto mycin began in 1944, followed in 1949 by neomycin, isolated isolated from Streptomyces fradiae; in 1957 by kanamycin, isolated isolat ed from Streptomyces kanam yceticus; in 1963 by gentamicin, isolated from Micromonospora purpurea; in 1967 by tobramycin, isolated isolated from Streptomyces tenebrarius; tenebrarius; and in 1970 by sisomicin, isolat isolated ed from Micromonospora inyoensis. Amikacin, introduced introduced in 1972, is a semisynthetic derivative derivative of kanamycin A, and netilmicin, netilmicin, introduced introduced in 1975, is a semisynthetic analog of sisomicin. Kanamycin is composed of three fractions, 98 percent A and 2 percent 6 and C. Gentamicin is also composed of three fractions, 40 percent gentamicin Cl, 20 percent gentamicin Cl a,

From pital, should

the Department of Medicine, University University HosZurich, Switzerland. Requests for reprints be addressed

Department Ramistrasse

2

June

to Dr. Walter

of Medicine, 100, CH 8091

30, 1988

The

and 40 percent gentamicin C2. The newer aminoglycosides, however, are singl singlee substances. As shown in Table II, all amino glycoside s are obtained from microorganisms of the genus Streptomyces (e.g., streptomycin,

E. Siegentha ler,

University University Hospital, Zurich, Switzerland.

American

Journal

neomycin,

kanamycin,

tobramycin,

and

amikacin)

or from

the

genus Micromonospora (e.g., gentamicin, sisomicin, and netilmici netilmicin). n). Structurally, all representatives of the kanamycin and gentamicin fami-

of Medicine

Volum e

80

(suppl 8B)

 

SYMPOSIUM

lies possess

two amino

sugars,

whereas

neomycin

and

paromomycin possess three. The amino sugars are glycosidicallyy cosidicall linked with a central he xose, aminocyclitol, a 2-deoxystreptamine. In streptomycin, this aminocyclitol is streptidine, streptidine, and is not located in the center of the molecule. Various structural arrangements for these compounds are depicted The aminoglycosides

in Figure 1. are strongly

polar cations,

stabl stablee

in the pH range of 6 to 8, and basic in character. Being water soluble, th ey are distributed throughout the extra-

TABLE

ON AMINOGLYCOSIDE

I

Year

Discovery

THERAPY-SIEGENTHALER

ET AL

of the Aminoglycosides

Antibiotic

Species

1949

Streptomycin Neomycin

From From

Streptomyces Streptomyces

griseus fradiae

1957

Kanamycin

From

Streptomyces

kanamyceticcus us

1963

Gentamicin

From

Micromonospora

purpurea

1967 1970

Tobramycin Sisomicin

From From

Streptomyces Micromonospora

tenebrarius inyoensis

1972

Amikacin

Semisynthetic

derivative derivative

of kanamycin

1975

Netilmic in

Semisynthetic

derivative

of sisomicin

TABLE

II

1944

A

cellular cellular space, i.e., about 25 percent of the lean body mass . Metabolicall Metabolically, y, they are highly stable; about 95 percent is excreted via the kidneys. Aminoglycosides are poorly absorbed from the intest intestinal inal tract, and because of their polarity, they inadequately penetrate the intracellular space and cerebrospinal fluid. SPECTRUM

have a very broad antimicrobial antimicrobial from gram-positive gram-positive cocci to gram-

negative

are ineffective

bacilli. They

organisms, inadequatee inadequat

against

and their activity against when used as monotherapy

used successfully against [3], but their activity against limited. action

the enterococci is [2]. Listeri Listeriaa mon -

Streptomycin

Gentamicin

Neomycin Kanamycin

Netilmicin

Sisomicin

tuberculosis aeruginos aeruginosaa is

acetyltransferases, phosphotransferases, and adenyltransferases, all of which have numerous subtypes (Figure 1). Due to chemical differences, not al alll aminoglyco-

share similar antibacterial aerobic pathogens, al-

sides are suitabl suitablee substrates for all enzym es, and the binding bindi ng sites for these enzym es even differ within the mol-

Mycobacterium Pseudomonas

All amino glycoside s against gram-negative

though their intrinsic activities and sens itivity patterns fer. In addition, individual difference s betwee n a gents

difare

ecule. Amikacin, the agent m ost resistant resistant to inactivati inactivation, on, is inactivated inactivated princi principally pally by an acetyltransferase from

reported from hospital to hospital due to time- and iindicandication-related induction of resistan ce.

gram-negative gram-negative from certain

M EC H AN I SM

from various enterococci [4-71. This also explains

OF AC T I ON

Although the mechan isms only partially partially understood,

Micromonospora Group

Tobramycin Amikacin

all anaerobic

ocytogenes and Nocardia species are generally generally resistant to the aminoglycosides; however, amikacin is effective against Nocardia Nocardia [3]. Streptomycin and kanamycin are

of Aminoglycosides

Streptomyces Group

OF ACTIVITY

The aminoglycosides spectrum, extending

Groups

AN D

R ESI ESIST ST AN C E

of aminoglycoside action are it is now known that the drugs

bind to the surface of the bacteria and are transport transported ed through the cell wall. Once within the cell, they bi bind nd to the 30s ribosomal ribosomal subunit, causing a misreading of messenger RNA during n g the translat translation ion process and produci producing ng “nonsense proteins.” proteins.” The sum of the events from drug entry into the cell to interf interference erence with protein protein synthesis disturbs membrane function and causes dium, amino acids, and and other ,essential leak out, resulting in bacterial death.

potassium, constituents

soto

Almost all pathogens that are sensitive sides can develop resistance. Resistance

to aminoglycodevelops most

commo nly in response to plasmid-mediat plasmid-mediated ed enzyme s that can modify the aminoglycoside molecule in three differ different ent ways: by acetylation acetylation at an amino group, by phosphorylation, or by adenylation on at a hydroxyl group. The molecule becomes changed in such a way that it can no longer bind to the ribosome subunits. The enzyme s involved include include

June

30,1988

organisms, staphylococci

whereas an adenyltransferase adenyltransferase and a phosphotransferase are not important quantitati quantitatively vely w hy cross-resistance does not

necessarily exist between aminoglycosides. A second possibility possibility for development of resistance

is

that the complex and energy-depende energy-dependent nt transport sy stem across the cytoplasmic membrane to the ribosomes becomes changed in such a way that the target canno t be reached. P. aeruginosa, Serrati Serratiaa species, and Streptococcus faecalis can become resistant to aminoglycosides in this way, whereas the group resistance of the anaerobes results from from the absence of an oxygen-dependent transport system across the cytoplasmic membrane [8]. A third possibility appears to be of importan ce only for streptomycin. In contrast to the other am inoglycosides, streptomycin binds only to a subgroup of the 30s ribo ribo-somes [6]. These proteins can mutate in such a way that no binding binding takes place place between streptomycin and the ribosome s. This phenomenon can be clinically clinically important in combination therapy of enterococcal endocarditis, a situation in which streptomycin resistance necessitates the use of gentamicin

The

American

along with penici penicilli llinn

Journal

of Medicine

for adequate

Volum e

80

treatment.

(suppl

86)

3

 

SYMPOSIUM

ON AMINOGLYCOSIDE

THERAPY-SIEGENTHALER

ET AL

CH,NH, ZGip

Kanamycin A

j-0. Gentamlcin C,a

b

Tobramycin

Slsomicin

Amlkacin

Netllmicln

0

OH

OH

gure 1. C hemical structure of aminnoglycosides. AAC = site of action of acetylati acetylation on ion enzym es; APH = site of action of phosphoryiation phosphoryiation enzyme s.

CdM~ARATlVE

REVIEW

OF THE AMINOGLYCOSIDES

Streptomycin. Although streptomycin. has been replaced by newer aminoglycosides, it is still used today for special indications in tubercu losis therapy [9] and in enterococc al endo carditis. In the latter condition, it should be used only when the minimal inhibi inhibitory tory concentrati concentration on is

enzym es;

AAD = site of action of adeny-

tis. In Francisella tularensis infection, i.e., in tularemia, streptomycin ranks as the drug of first choice, as it does against Yersinia pes tis, i.e., in bubonic plague. Streptomycin is princi principally pally vestibulotoxic, but in 4 to 15 percent of treated patients, cochleotoxic side effects also also

less than 2,000 m g/liter, and it should be combined with penicillin G or, in the case of penicillin allergy, with vanco-

appear after one week o f therapy. They begin primarily primarily in the high-tone range and are demo nstrable only on the audiogram; the entir entiree hearing hearing range becomes affected in

mycin

[IO]. The same

later

ditions

to treat other

4

June

30,1988

regimen streptoco cci

The

American

is used under certain implicated

Journal

con-

in endocardi-

of Medicine

Volume

never

80 (supp (suppll

stage s

[ll].

observed

8B)

Certain

side

with the other

effe cts

that

aminoglycosides

are virtually can de-

 

SYMPOSIUM

velop

with

streptomycin

use,

including including

these

neuromuscular

ON AMINOGLYCOSIDE

technical technical

THERAPY-SIEGENTHALER

difficult difficulties. ies.

In a retrospective

ET AL

analysis,

block, peripheral neuritis, ing, exfoliati exfoliative ve dermatitis,

perioral paresthesia with flushscotoma , and eosinophilia. eosinophilia. In

Lance and co-workers [24] found ototoxicity with amikacin in 2 to 4 percent of cases, whereas Black and associates

contrast, low [ll].

potency

[25], in prospective studies, found an ototoxicity incidence of 24 to 25 percent with amikacin. The comprehensive

the nephrotoxic

Neomycin.

For years,

of streptomycin

neomycin

is very

has not been used par-

enterally because of its marked ototoxicity and nephrotoxenterally icity. In combination with bacitracin, which is bacteric bactericidal idal

results of investigat investigations ions by Kahlmeter and Dahlager [23], who reviewed comparative aminoglycoside toxicity studies publis published hed between 1975 and 1982, showed that gen-

against gram-positive gram-positive organisms, neomycin is an effective and safe topical agent. Occasionally, neomycin is administered orally for preoperative sterilization of the gut and in in

tamicin, tobramycin, and amikacin were about equal equally ly vestibulotoxic, that amikacin was more cochleotoxic than gentamicin and tobramycin, and that netilmic netilmicin in showed

portal encephalopathy. Despite the the minimal intest intestinal inal sorption (between 1 and 6 percent of the total dose),

the lowest potency directly comparative

abse-

for cochlear and vestibul vestibular ar studies between indivi individual dual

vere side side effects such as tubular necrosis and deafness have occurred [12]. Malabsorption Malabsorption syndrome can also

cosides, these investigators results, due to the technical

develop

In seven comparative micin, the incidence

locally

Kanamycin.

[I 31. Kanamycin

is another

is rarely used today b ecause ity. Against P. aeruginosa,

aminoglycoside aminoglycoside

of its considerable considerable ototoxickanamycin is almost com -

pletely inactive, and the Enterobacteriaceae Enterobacteriaceae idly resistant due to numerous modifying two acetyltransferases, two adenyltransferases multiple multiple amycin

mycobacterial still be used

Gentamicin. worldw ide,

become enzyme s,

rapi.e.,

two phosphotransferases, and [4,14]. Only in the presence of resistance to other drugs can kanas a reserve tuberculostati tuberculostaticc agent.

Since 1963, gentamicin has been used and during its years of clinical application, re-

sistance and sensitivity edly in in Staphylococcus

changes aureus

and other Enterobacter Enterobacteriaceae iaceae important cause o f resistance tion of posons, riaceae,

that

have appeared repeat[I %171, P. aeruginosa,

[18,19]. Here, too, the mos t lies in the bacterial bacterial produc-

modifying enzyme s coded b y plasmids, transepisomes, and phages. In sensitive Enterobactetobram ycin and gentam icin are identical in effi-

cac y, according to double-blind studies

the findings [20]. Against

Serratia species, ge ntamicin Serratia cacy [21]. Gentamicin can

of controlled E scherichia

clinical coli and

appears to have greater effi effi-be modified primarily primarily by four

somewh at divergent already mentioned.

trials trials between gentamicin and netil netil-of cochleotoxicity for gentamicin

amounted to 2.1 percent; trials trials between gentamicin with gentamicin

obtai obtained ned problems

toxicity. In aminogly-

was

in contrast, in 10 comparative and amikacin, cochlear toxicity

11.4 percent.

Tobramycin.

Tobramycin closely resembles in terms of antimicr antimicrobial obial and pharmacokinetic One recognized difference difference is that tobramycin

gentamicin properties. has greater

activity agains P. aerugi aeruginosa nosa [26,27]. H owever, be noted that, depending on each individual gentamicin-resistant gentamicin-resistant sensitive [28,29].

it should situation,

strains are not always ttobramycinobramycinTobramycin-resistant Pseudomonas

strains are are generall generallyy cross-resistant kanamycin, gentamicin, and netilmicin netilmicin tamicin- resistant Klebsiella, Serratia, species, tobramycin Enterobacteriaceae, Enterobacteri aceae,

with streptomycin, [30]. Against genand Enteroba cter

is also usually inactive. Sensitive with the exception of Serratia Serratia and E.

coli, are killed killed by tobramycin just as they would be by gentamicin [31]. Tobramycin is mainly modified by five enzyme s: two acetyltransferases, and one phosphotransferase. a second acetyltransferase Tobramycin ototoxicity

two adenyltransferases, Resistance associated with

is inconsistent [4]. appears to develop

as

com-

enzym es: two acetyltransferases, one adenyltransferase, and one phosphotransferase [4]. Cross-resistance with other aminoglycosides is commo n and, with netilmicin, netilmicin,

monly as does gentamicin ototoxicity, whereas tobramytin is less nephrot nephrotoxic oxic than gentamicin 1231. A large-scale, large-scale, double-bli double -blind nd study in the United States showed that ele-

almost complete [22]. In contrast, amikacin is still effective against gentamicin-resistant gentamicin-resistant Enterobacter Enterobacteriaceae iaceae and

vations of the serum cre atinine level were recorded significantly less frequently with tobramycin than with gentami-

P. aerugin aeruginosa osa strains, because vated by gentamicin-modifying gentamicin-modifying Gentamicin appears to have

tin [32]. In the comparative assessm ent of ototoxicity, the investigators found no significant significant differences. Other stud-

amikacin is rarely inacti inacti-enzyme s. the the most definit definitee nephro-

toxic potency compared with tobramycin, netilmicin, netilmicin, amikacin [23]. With regard to cochleotoxicity and tibuloto xicity, the findings need to be interpreted

and veswith

some caution. Audiogr Audiograms ams and vestibul vestibular ar investigati investigations ons are harder to perform and assess in a standardized standardized manner than are creatinine creatinine clearance measurem ents or an excretion crepancies

analysis

of tubular

in results

from

enzym es. various

In part, the dis-

investigators

June

reflect

30,1988

ies have also also establis established hed a lower nephrotoxici nephrotoxicity ty rate for tobramycin when compared with gentamicin [33,34]. Sisomicin. Introduced in 1970, sisomicin is chemically related to gentamicin related and is described as 4,5 dehydrogentamicin Cl a. It appears to be superior superior in efficacy to the other aminoglycosides, especially against Serratia Serratia and Proteus species, including some resistant strains [35-371. Sisomicin is more active than gent gentamicin amicin against P. aeruginosa, and comparable comparable in this respect to tobramycin, to

The

American

Journal

of

Medicine

Volum e

80

(suppl 6B)

5

 

SYMPOSIUM

TABLE

ON AMINOGLYCOSIDE

III

THERAPY-SIEGENTHALER

Broad

Disadvantages

stability

Nephrotoxicity

antibacterial

spectrum

Rapid bactericidal Experience over Rare- allergic

Gerding and Larson [45] and Bet% and co-w orkers [46] reported the interesting and important observations that the resist ance of gram-negative organism s to gentamicin and tobramycin declined s ignificantly in numero numerous us hospitals when amikacin was used alone, while amikacin resistance itself did not increase significantly. Although there are centers that regard amikacin as a reserve aminoglycoside, other centers employ it as first-line aminoglyco-

Aminoglycosides

Advantages Chemical

ET AL

action many years years

side

Synergism with antibiotics

effects effects

Low

and

ototoxicity

against

concentration

fluid

beta-lactam

and

Lack of activity activity organisms

anaerobic

in cerebrospinal

bile

side therap therapyy and find no substantial substantial increase in resistance [47-491. Netilmicin. A semisynthetic derivative of sisomicin, netilmicin was introduce introducedd in 1975. 1975. This am inoglycoside is primarily mari ly modified by three acetyltra nsferase s, but not by adenyltransferases adenyltrans ferases or phosphotransferases [4]. Therefore, sisomicin -, gentamicin-, gentamicin-, and tobramycin-resistant E. coli, Klebsiella species, Serratia species, and even P. aerugin aeruginosa osa are ofte oftenn stil l eradicated eradicated by netilmicin. Nevertheless, cross-resistan ce with gent gentamicin amicin is not uncommon in P. aeruginosa strain s [50-521. In animal studies, s tudies, netilmicin shows a lower nephrotoxicity than gentamicin and amikacin amikaci n [53,54], and cli clinic nical al tria ls indicate that the the fewest cochlear and vestibular side effects occur with netilmicin [23].

Variable pharmacokinetics Lack of correlation between administered dose and measured serum

concentration

Inactivation

of aminoglycosides

the extent that tobramycin-resis tobramy cin-resis tant strain s of P. aeruginosa are are usually also resistant to sisomici n [3 [30,38 0,38]. ]. This agent, which seem s to penetrate bacteria l cells better tha thann other aminoglycosides, is primarily modified by five enzymes:: three acetyltra nsferase s, one adenyltransferenzymes adenyltrans ferase, and one phosphotransferase [4]. The factor limiting broad clinical application of sisomicin is its well-do well-documented cumented renal toxicity in animal studies. studies. A comparison of so-called tubulotoxic threshold doses revealed that the dose of sisomicin that first leads to excretion of renal epithelial cel ls is one-fifth and one-tenth lower than the doses of tobramycin and gentamicin, respectively, that produce this effect [39]. Amikacin. A semisynthetic analog of kanamycin A, amikac kacin in was introduced in 11972. 972. The main advantage of this aminoglycoside lies in its extensive resistance to inactivating enzymes. Only an acetyltransferase acetyltransferase from gr gramamnegative pathogens, prin cipa lly P. aeruginosa, is of quantitative relevance, whereas both an adenyltransferase from certain staph yloco cci and a phosphotransferase from certain enterococci and staphylococci are ooff mino minorr importance [4-71. Amikacin can, therefore, be used against gentamicin-resista nt pathogens, for which it offers the greatest ce rtainty of therapeutic response. It continues

INDICATIONS

to be active against o rganisms resista nt to tobramycin and netilmicin, including such resistant strains as P. aeruginosa [40]. Cross -resis tance between gentamicin and amikac kacin in is observed les lesss often than between gentam icin and tobramycin or sisomicin [41]. Certain “non-fermenters” such as Acinetobacter species, Flavobacter species, and P. aerugin aeruginosa osa show cross-resistanc e against amikacin, tobramycin, and gentamicin, caused by failure of aminoglyco side uptake into the cel l [42,43]. Like the other other aminoglycosides, amikacin also has a nephrotoxic potential, which, adjusted for the higher doses given , approximates that of netilm icin and must be be judged more favorable than that of gentamicin [23,44]. The vestibulotoxic potency appears to equal that of gentamicin and and tobramycin; tobramycin; however, coc hleotoxicity is somewhat greater [23].

toxicity and ototoxicity and the associated narrow therapeutic range between suboptimal serum concentrations and toxic toxic values. Other disadvantages disadvantages are the lack of activity against anaerobi anaerobicc organisms; the relatively low concentrations centrati ons in cerebrospinal fluid and bile; the markedly variable pharmacokinetics influenced influenced by age, renal function, fever, ascites, and obesity; the lack of correlation between the administered dose and the measured serum concentration; and, finally, final ly, the inactivation of aminoglycoaminogly cosides by reversible binding to lysed granulocytes, granulocytes, low pH, anaerobic environment, high concentration s of calcium calc ium and magnesium ions, and beta-lactam antibiotics. antibioti cs. The last factor, however, probably plays a role only in vitro, and is rarely of clinical import importance ance except during concomitant adminis administrations trations and when renal function is seve rely impaired [55,56].

6

June

30,1966

The

American

Journal

of Medicine

Volum e

FOR AMINOGLYCOSIDES

Before discussing specific indications for aminoglycoside therapy, we should consid er some of the advantages and disadvantages of these antib iotics (Table IlIll). l). The advantages include chemical stability withou withoutt metabolic changes, broad antibacterial spectrum, rapid bactericidal action, and comprehensive experience over many years. This experience experience has shown that the the efficacy and success rate can be improved by the use of controlled , optim al serum concentrations. Two othe otherr advantages are the very rare occurrences of allergic side effects, and the synergism demonstrated when used along with beta-lactam antibiotics. Some disadvantages include the potential for nephro-

60

(suppl

6B)

 

SYMPOSIUM

Clinic ally, aminoglycosides are used in infections caused by pathogens pathogens resistant to othe otherr less toxic antibiotits (Table IV). When used empirically or as specific therapy in severe gram-negative, hospital-a cquired infections infections,, especially in neutrop neutropenic enic patient patients, s, aminoglycosides are often combined with beta-lactam antibi antibiotics otics because of the possible synergy. This article briefly discusses some infections in which aminoglycosides are frequent frequently ly used

TABLE

(Table

TABLE

V).

Among the important infections of the upper respiratory tract is malignant malignant otitis ext externa erna caused by P. aerugin aeruginosa. osa. It can lead to severe complications, such as osteomyelit osteomyelitis, is, basal meningitis with cranial nerve involvement, cerebritis, and venous sinu s thromboses, and ttherefore herefore requires combined therapy with aann antipseudomonal peni cilli n or a third-generation cephalos cephalosporin porin w ith an aminogly aminoglycoside. coside. Hospital-acquired Hospitalacquired bronchopneumonias are generally caused by Pseudomon Pseudomonas, as, E. coli, Klebsiella, Enterobacter, Serratia, Proteus, Providencia, and Acinetobacter species, speci es, and, rare ly, S. aureus. Depending on the bacterial resistan ce pattern of the partic particular ular hospital and th thee status of host-defense mechanism s, an aminogly coside must be added to an antipseudomonal penicill peni cillin in or a third-

ON AMINOGLYCOSIDE

IV

Infections

Principal Principal Indicati Indications ons Aminoglycosides caused

by pathogens

antibiotics Severe gram-negative, neutropenic

V

THERAPY-SIEGENTHALER

ET AL

for

resistant

hospital-acquired

to other

less less

infections,

toxic

especially

in

patients

Infections Malign ant otitis hospital-acquired Urogenital

Treated

with Aminoglycosides

externa pneumonias

infections

Endocarditis Intra-abdominal Gram-negative Infectious Nosocomial Infections

infections meningitis

arthritis

or osteomyelitis

septicemia in immunocom promised

patients

5 percent and appears to be increasin g [64-701. Endoca rditis exhibits special anatomic and functional features, such as an impaired lo cal host-defense response with few

generation cephalosporin. The pathogenic pathogenic spectrum of bacteri bacterial al pneumonias acquired o utside the hospital has clear ly changed in recent years. The pneumoco cci that were predominant until about 1970 have been less commonly isolated in recent years. Acco rding to a study in Connecticut, the frequency of pneumoco cci isolated during 1980 to 1981 was 30 to 40 percent, while Legionella pneumophila, Hemophilus influi nfluenzae, P. aeruginosa, and other aerobic/anaero bic organism s were isolated more frequently [57-601. Severe pyelonephritis with septicemia that is due ttoo P. aeruginosa aeruginosa or Ente Enterobacteri robacteriaceae aceae can devel develop op in hospitalized patients, especially those undergoing urologic intervention or those with urogenital anomalies, includi including ng obstruction, malformation, or neurogenic bladder. In these

phagocytes. In addition, large bacteria l populations of IO* to 10” colonycolony-forming forming units per gram of tissue , with reduced metabolic activity, are protected from the antibiotics by a fibrin network. For these reasons reasons,, corroborated by animal studies, endocarditis endocar ditis is generall generallyy treated with combined drugs: penicillin G plus streptomycin against enterococci, provided that the minima l inhibitory conc concentration entration for streptomycin is less than than 2,00 2,0000 mg/liter. If the minimal inhibitory concentration concentra tion is great greater, er, penicillin G plus gentamicin is used. Pen icillin G is ccombined ombined with streptomycin against viridans streptococci when the minimal inhibitory concentration for penicillin exceeds 0.2 mgiliter, or when the streptococci are fully sensitive (i.e., the minimal inhibitory concentration concentra tion for penicillin is belo below w 0.2 mg/liter) and a

case s, the newer and less toxic third-generation cephalosporins offer a valuable alternative to the aminoglycosides [61,62]. However, combination therapy with an aminoglycoside is advised when multiply resistant organisms are isolated. It should be remembered that aminog lycos lycosides ides can be be inact inactivated ivated by high urine concentrati concentrations ons of calcium and magnesium ions and by a low urinar urinaryy pH [63]. Endocarditis requires some special considerations. Approximately 80 to SO SOpercent percent of the endocar endocarditis ditis case s are caused by gr gram-positive am-positive cocci, i.e., the ent enterococci, erococci, viridans streptococci, other streptococci, and coagulasepositive or coagulasecoagulase-negative negative staphylococci. Although aminoglycosides are not intrinsic ally very active against these organisms, they are indicated in this situation because of the severit y of the infection. The frequency of

short, 14-day course of therapy i s plann planned. ed. Gentamicin is combined with a penicillinase-stable penicillin for treattreatment of S. aureus endocarditis. Bacteremia is cleared more rapidly by drug drug combinations, but the clinica l course is not substantially influen influenced. ced. Gentamicin plus vancomytin plus rifampicin is used in patients with Staphylococcus epidermidis endocarditis involving prosthetic heart valves. Finally, an aminoglycoside is generally used with a bet betaalactam antibioti antibioticc against gram-negative endocar endocarditis ditis pathogens. In these cases, the best possible combination with regard to synergism should be sought in vitro [lo,71 -741. Empiric therapy therapy of intr intra-abdominal a-abdominal infections should be effective against a mixed flora, including enterococci, Enterobacteriaceae terobact eriaceae,, P. aerugin aeruginosa, osa, and strictly anaerobi anaerobicc organisms. An aminoglycoside in combinat combination ion with clinda-

endocarditis endocar ditis caused by gram-negative pathogens is about

mycin, a 5nitroimidazole 5nitroimidazole,,

June

30, 1988

The

American

Journal

or cefoxitin has be been en eff effective ective

o f Medicine

Volum e

80

(suppl 86)

7

 

SYMPOSIUM

TABLE

ON AMINOGLYCOSIDE

VI

THERAPY-SIEGENTHALER

Combination Therapy Aminoglycosides

Aminoglycosides

ET AL

with

are combined

to broaden

the

to enhance

antibacterial

antimicrobia l

spectrum

especially in situations in which other or in combinatio n are not as effective, in life-threatening

infections

or

activit activityy

with

antibiotic i.e.,

unknown

groups

alone

pathogens

cocc i and also sh show ow inadeq inadequate uate activity against Bacteroides fragilis. Most penicillins are inactive against Klebsiella species. In addition, clinical trials have shown that during monotherapy with third-generation cephalos cephalosporins porins and antip antipseudomo seudomonal nal penicillins, Pseud Pseudomonas omonas strains often become re sistant, causin g ttherapeutic herapeutic failure s [86911. Furthermore, the choice of substances has ttoo be adapted based on the pathogens in an individua l hospital.

in these situatio ns. Among drugs used as monot monotherapy, herapy, piperacillin and imipenem have the broadest spectrums of activity. According to a review by Kager and Nord [75], imipenem has already been proved very successful as monotherapy. The third-generation cephalos cephalosporins porins are strong competitors of the amin oglyco sides in the tre treatment atment of gramnegative men ingitis in patients of all ages [76[76-781. 781. However, when combination therapy is needed to treat special

In general, a combination of a beta-lactam antibioti antibioticc with an aminoglycoside is used initially, then then chang changed ed to monotherapy only after identificati identification on of the patho pathogen gen in a patient with normal host-defense mechanism s. As mentionedd previous ly, th tione thee aminoglycosides have new co compempetition in the monobactams (e.g., aztreonam), the carbapenems (e.g., imipenem), and the the 5-quinolones (e.g., ciprofloxacin, ofloxacin, and norfloxacin). Some of these agents possess even broader activity than the aminoglycosides, primarily beca because use they attack anaerob anaerobes. es. It may eventually be possible to use them with sufficient safety as monotherapy in immunocompetent patients with septicemia. A review of the many studies in which aminoglycosides have been used as monotherapy in septicem ia rrevea evea ls

pathogens, such as P. aeruginosa or Enterobacter species, or when when ventric ulitis i s present present,, additional routes of administration administrat ion may be necessary. For example, injection of the aminoglycoside directly into th thee ventricle via an Ommaya or Rickham re servoir may improve its efficacy [79-811. McCrac McCracken ken and co-w orkers [82] reported that intrave ntricul ntricular ar administration of gentamicin does not improve prognosis in newborns. Therefore, this for form m of therapy should not be used as routine treatment for neonatal meningitis caused by gram-neg gram-negative ative enteric bacilli. If infectious arthritis or acute or chronic osteomyelitis develops in infants under one month of age or in patients more than 50 years of age, the differential diagnosis should consider Enterobacteriaceae and P. aeruginosa in addition to staph yloco cci as poss possible ible pathogens [83-851.

succes suc cesss rates of 24 to 10 1000 percent. In neutropenic patients with septicemia, failures of often ten occur. However, consistently pos itive results can be attai attained ned in patien patients ts with normal host defenses [92-981. Pathogens for which an aminoglycoside is the drug of choice are discussed later in this article, as are those compounds that are equally effective [99]. In infection s with Acinetob acter anitratus o r Iwoffi, an aminogly aminoglycoside, coside, an antipseudomonal peni penicilli cillin, n, or one of the new 5-quinolone preparations can all probably be considered considered equally effective as altern alternative ative therap therapy. y. Cefotaxime, c eftizoxim e, ceftazidime, or imipenem (plus cilastatin) are the alternatives to an aminoglycoside in infections with Enterobacter Enterobacter species. In infections with Hafnia alvei, an aminoglycoside is the drug of first choice, and chloramphenicol is only tthe he drug of second choice.

Emp iric therapy should, therefore, cons ist of combining an aminoglycoside with a beta-lac beta-lactamase-stab tamase-stable le penicillin. After causative organisms are identified, therapy should be modified. It is important to consid er the spectrum s of action of all available antibiotics-especially those of beta-l beta-lactam actam antibiotics and aminoglycosides-when choosing therap therapyy for nosocomial septicemia. For nnewly ewly ddevelope evelopedd substances such as monobactams, carbapenems, and 5-quinolones, 5-quinol ones, there is stil l insufficient experience in this respect. Moreover, the therapeutic gaps with individual substances are important to know. For example, the aminoglyc osides are inact ive against anaerobes; the new beta-lactam beta-l actam antibiotics exhibit only limited activity against penicillinase-producing strains of S. aureus; and the third-

Against Morganella species, imipenem (plus cilastatin) will most likely be as effecti effective ve as an aminogl aminoglycoside. ycoside. Amikacin is the drug of first choice against Providencia species, with the possible alternatives being cefotaxime, moxalactam, moxalact am, ceftizoxime, or imipen imipenem em (plus cilastatin). Streptomycin is tthe he drug of choice against F. tularensis, with chloram phenicol the alternative. Amikacin is the drug of choice against Serratia marcestens, but the new 5-quinolone preparations are, in all lik likeelihood, equally effective. Yersinia enterocolitica is most succe ssfully treat treated ed with aann aminogl aminoglycoside, ycoside, but ceftizoxime, ceftriaxone, and moxalactam are also effective. Streptomy cin continues to bbee the first-lin e drug ffor or treatment of Y. pestis infection, with no equally effective alternative. Only prolonged prolonged clinic al experience and controlled

generation cephalosporins are inactive against entero-

comparative studies will establish the relative reliability

in mixed aerobic/anaerobic in bacterial endoctirditis in systemic in neutropenic

8

Pseudomonas

infections infections

or immuno deficient

June 30, 1986

patients

The American Journal of Medicine

Volume 80 (suppl 6B)

 

SYMPOSIUM

and value of a given drug against a specific pathogen. Combination Combina tion Therapy with Aminoglycosides (Table VI). The need to broaden the spectrum of antibio tic therapy has led to th thee administration of antibioti antibioticc co mbinations. The rationale for combination therapy als o includ es the enhancement of antibacter antibacterial ial a ctiv ity due due to syn ergis tic or addit additive ive interactions. Increased activ ity reduces the ris k of therapeutic f&lure that might iesult when bacter bacterial ial subpopulations develop resista nce to one or both antibiotics. In In additi addition, on, these syn ergistic or iddiiive effects often often allow a reduction in dosage and in consequent tbxic side effects. The value of combining aminoglycosides with beta-lactam betalactam antibiotics i s recognized worldwide. However, drug combinations may also hatie antagonistic interacinterac tions, increased side effects caused by both drugs, possipie provocation of multiply resistant organisms, misinterpretation of therapeutic safety, and finall finally, y, higher costs. Regardlesss of the potential disadvantages Regardles disadvantages,, in mavy clinic al situations, the comb combinatio inationn of an aminoglycoside with a beta-lactam antibio tic continue s to be the optimal therapy. thera py. This is true in life life-threate -threatening ning infections with unknown pathogens, pathogens, in mixed aerobic/anaerobic infections, infections , in infection s in neutropenic or immunodeficient patients, in bactbrial endocarditis, and in systemic Pseudomonas infections. Above all, clinical trials have shown that patients with cjranulocytopenia appear to benefit from combined antibiotic ttierapy. Young and and co-w orkers orker s [loo] and Love et al [IO11 reported a succes suc cesss rate of 8800 p&cent in granulocytopenic patients with septicemia when both antibiotics us&d in the combination, a beta-lactam, plus an aminogl aminoglyycoside, were individually active against the causative organisms. The success rate declined to about 60 percent when one of the antibiotics in the combination proved inactive icvhen ested alone. alone. If both antibiotics were inactive in vitro, the su cce ss rate dropped below 20 percent. Th ere are now numerous numerous animal and clinic al trials that confirm the supe riority of combined antibiotic therapy in appropriate indicatio ns [102-l 071, a fact tthat hat had be been en re cognized

TABLE

ON AMINOGLYCOSIDE

VII

THERAPY-SIEGENTHALER

Suggested Peak and Trough Aminoglycosides

ET AL

Levels

for

mg/liter Gentamicin, Tobramycin, Netilmicin

Levels Peak

(end

of 60-minute

Pseudomonas Trough (before

TABLE

infusion)

7 (6-8)

infections, pneum onia next infusion)

VIII

25 (20-30) PO-35

8-12 ?0.5-

Recomme nded Aminoglycosides

< 2

Dosages

Amikacin

z2-

bf

Gentamicin, Tobramycin, Netilmicin Loading

dose

Maintenance Infusion

(mg/kg) dose

period

< 10

Amikacin

2

(mg/kg

per day)

(minutes)

8

3-6

15-25

60

60

Dosage interval - 3 x t1/2 tlj2 = In 2 x At / In (C,&)

TABLE

IX

Monitorihg of Serum Concentrations Aminoglycosides

Relationsh ip

between

aminoglycoside

serum

concentration

of and

clinical ~efficacy Lack

of reproducible

correlation

administered dose Correlation of serum

doncentrations

between with

serum

level

nephrotoxicity

and and

ototoxicity

to four doses and administered over a period of one hour (Table VIII). Results of clinical and microbiologic studies indi,cate that during am inoglyco ide therapy, drug serum concentrations should be monitored (Table IX). IX) . In vitro and in viv o studies show that there i s a quantitative rela-

as early as 1971 by Schimpff Schimpff and co-workers [108 [108]. ]. Today, however, in various infections, new antibioti antibioticc groups alone or in combinat combination ion show simila r results, a fact that has to to be considere d when evaluating a therapeutic regimen. Monitoring Monitori ng Serum Concentratiok Concentratiok of Aknoglycosides . Suggested peak lgvel lgvelss to be achieved at the end of a 60-minute infusion for gentamicin, tobram ycin, and netilm icin are 6 to 8 mg/liter; trough leve ls befor beforee the next infusion should be between 0.5 and 2 mg/liter. Fo r amikacin, kaci n, the the corresponding peak and trough values are 20 to 30 mg/liter and between 2 and 10 mg/liter, resp ectiv ely (Table VII). These val values ues can be obtained with a maintenance d ose of 3 to 6 mg/kg per day for gentamicin, tobramycin, and netilmicin. For amikacin, they can be achieved

tionship between aminoglycoside serum concentrations and clinical efficacy. In 68 patients with gram-negative infection s, Noone and colleague s [log] showed thtit 46 (84 percent) of 55 patients had cures with adequate gentamicin therapy, compared with only three (23 percent) of 13 patients who received inadequate inadequate therapy. If gram-negative Septicem ia was assessed alone, 10 (91 percent) of 11 treatments were succ essf ul with adequate adequate gentamicin therapy, whereas no success was recorded ih any of the four patients with suboptimal gentam icin concentrations. From case reports of 530 patients, Moore and co-workers [l IO,1 IO,1 1 ] also showed signific ailtly higher clir e rates in patients with adequate adequate serum lev els of gentamicin, tobramycin, myci n, and amikacin than in patients with suboptimal drug

by administration of 15 to 25 mg/kg per day, divided in i n two

concentrations.. concentrations

June 30, 1986

The American

Fina lly, Anderson et al [112] demon-

Journal of Medicine

Volume 60 (suppl 66)

9

 

SYMPOSIUM

TABLE

ON AMINOGLYCOSIDE

X

THERAPY-SIEGENTHALER

ET AL

Lack of Reproducibl Reproduciblee Correlation Correlation between Serum Level and Administered Dose

Infusionwith Amikacin9 Amikacin9 mg/kgbodyweight) mg/kgbodyweight)

Concentrations in the serum (mgiliter)

After 30 Minutes

After 60 Minutes

30.8-50.8

17.6-30.8

After 120 Minutes 10.9-18.9

(the difference differencess among among individual aminoglycosides discussed earlier should be considered here). Cochleotoxic side effects are even less frequent, and the the occurrence of vestibulotoxic side effects are rare. Moore et al [119] analyzed the course of gram-negative infection and treatment iri ir i 214 patients who had received either gentamicin o r tobramycin in randomized prospec prospec-tive clinic al st studies. udies. In tthe he contrql contrql group without without aminogly-

strated “breakthrough bacteremia” in 52 (22 percent) of 237 patients undergoing antibiotic antibioti c ttherapy herapy for gramnegative bacteremia; of 42 samples evaiuated, 20 showed subinhibitory drug concentrations when the positive blood cultures were takeri. Instead of measuring aminoglycoside concentrations in serum, some some investigators have correlated correlated c linica l outc outcome ome with serum serum bactericidal titers [113,114]. [113,114]. Klas ters ky and co-w orkers orker s [114] reported a succes suc cesss rate of more than 80 percent among 317 patients with tumors when the bacteriostatic bacter iostatic acti activity vity in the serum equaled or exceeded 1:8. Another reason for measuring serum concentrations is

coside therapy, a 50 percent percent reduction in creatinine clearance (the criterion of nephrotoxicity) w as observed observed only once; however, this side effect occur occurred red in 30 (14.1 (14.1 percent) patients receiving gentamicin or tobramycin. After investigation and statistical evaluation of various cofactors, the following circumstances were found to be significantly nific antly associa ted with nephrotoxicity. nephrotoxic ity. In the group that showed toxicity, the peak serum level of 7.2 -t 0.4 mgiliter was higher than in the group group without toxic ity, which had a leve l of 5. 5.33 +- 0.1 mgiliter. The trough leve l of 3. 3.44 -t 0.3 mg/liter in the group with toxicity was also higher than the trough leve l of 2.6 + 0.1 mgilite r iinn the group without side effects. Patients who experienced toxicity had a higher creatinine clearanc clearancee before therapy. It is possible poss ible tliat the higher initial drug drug “flooding” to the the tubular c ells contrib-

the lac lackk of a reproducible reproduc ible correlati correlation on between the serum leve l and the administered dose. Barza Barz a and colleagu es [I 151 measured peak serum concentration s in 23 patients after intravenous or intramus intramuscular cular administratio n of gentamic micin in at 1.2 to 1.7 mgikg bo dyweight, and found that lev lev-eis ranged from 1.7 to 7.4 mg/liter. Kaye and co-workers [116] studied 23 patients in whom whom a gentamicin serum concehtration of 5 mg/liter w as attained one hour after intramus cular injection injecti on of doses ranging from 0. 0.99 to 2. 2.35 35 mg/kg bodyweight. A dose of 2.35 mg/kg bodyweight given to two different patients yielded extremely different peak concentrations of 5.2 mg/liter and 14 mg/liter. Goodman et al [117 [117]] m easured trough and peak concentrations and found, in agreement with other authors, a high degree of variabi var iability lity among patients. Moreover, pa tients given

uted to to the development of nephroto xicity. Some of the affected patients also had hepatic disorders, suggesting a connection between hepatic insufficiency, reduced renal blood flow, and activatio n of the renin-angiotensin renin-angiotens in mechanism. Shock states occu rred m ore commonly in the group group with toxicity and led to reduced organ perfusion. Finally, women were affected more often than men. The data from 135 patients receiving gentamicin and tobramycin were also analyzed by Moore and co-workers [120] with reference to ototoxicity. The total dose of aminoglycoside received was higher in, the group in which inipaired hearing developed. This group had received 3.06 ? 0.37 grams of aminoglycoside, aminogly coside, compared with 2.01 -C0.15 -C0.15 grams in i n the group without side effects. The duration of therapy also differed. The group with side ef-

identic al doses showed different serum concentrations at different times. In our institu tion, a, study b y Ltithy (Table X) confirmed this variabi var iability lity [118]: 30, 60, and 1120 20 minutes after starting an infusion of amikacin at 9 mg/kg bodyweight, the corresponding serum concentrations were 30.8 to 50.8 50.8 mg/liter, 17.6 to 30.8 mg/liter mg/liter,, and 10.9 ttoo 18.9 mg/liter, respectively. Nephrotoxicity and ototoxicity associated with the aminoglycosides appear to be correlated with the area under the serum concentration-time curve, but there are also reports suggesting that ototoxi ototoxicity city depends more on peak concentrations. concentrat ions. According to a major study by Kahlme Kahlmeter ter and Dahlager [23], who reviewed data on about 10,000 patients over the period from 1975 to 1982, nephrotoxic side effect effectss associated with gen gentamicin, tamicin, tobramycin, netil-

fects received aminoglycosides for 9.1 -I 0.8 days, compared with 6.6 + 0.1 days for the group without side effects. Patients with ototoxicity also had higher fever initially. It was suspected in these c ases that th thee cytoprotective prostaglandins prostaglandins of class E are produced produced in smaller quantities under the influence of fever and aminoglycosides. More patients with ototoxicity had an initial bacteremia that could lead to direct cochlear injury by bacterial endotoxins and/or changes in the endolymph caused by these toxin s. The peak and trough leve ls of aminoglycoaminogly coside were, in contrast to the situation with nephrotoxicity, not sign ifica ntly associated with the the development of ototoxicity. This observation is in disagreement disagreement to some extent with the studies of Wil son and and Ramsden [12lj, who described a reversible cochlear damage with peak peak tob tobraramycin myc in concentrations above 8 to 10 mgilite r.

micin, and amikacin occurred at a rate of about 10 percent

10

June

30,

1986

The

American

Journal

of Medicine

Volum e

80

(suppl

66)

 

SYMPOSIUM

It is clear ment mize

from

all these

studies

of aminoglycoside serum therapy in many wa ys. therapy

AMINOGLYCOSIDES Results

of numerous

that regular regular

concentrations concentrations

measure-

regardless

can

apeu tic

opti-

of which

failures

THERAPY-SIEGENTHALER

ET AL

new agent was used, resulti resulting ng

[I 22-l

in ther-

241.

C OM M EN T S

AND THE FUTURE clinical clinical

ON AMINOGLYCOSIDE

studies

Amino glycoside s

with similar

retained

their

place

in the treat-

tions for amino glycoside therapy are already available on new antibiotics antibiotics such as carbapenems, monob actams, and

ment of various infectious diseases, particul particularly arly those acquired in the hospital. Newly develop developed ed agents from other classes of antibioti antibiotics cs undoubtedly represent an en-

5-quinolones. Although the results regarding effica cy in most types of bacteri bacterial al infecti infections ons are consistently positive,

richment of the clinic clinician’s ian’s therapeuti therapeuticc and, at present, appear to be effective

it is also true that resistance

different

to P. aerugino aeruginosa sa

indica-

have

developed

situations

armamentarium compleme nts

in

to the aminoglycosides.

REFERENCES

2.

3.

4.

5.

6. 7.

8. 9.

10. 11.

12.

13. 14. 15.

16.

Waksman SA, Bugie E, Schatz A: Isolation of antibiotic substancess stance from soil microorganisms, with special reference to streptothricin and strepiomycin. Proc Staff Meet Mayo Clin 1944; 19: 537-548. Moelleri ng RC Jr, Weinberg AN: Studies on antibiotic syne synerrgism against enterococci. II. Effect of various antibiotics on

17.

18.

the uptake of C-labeled streptomycin by enterococci. J Clin Invest 1971; 50: 2580-2584. Moelleri ng RC Jr: In vitro antibacterial activity activity of the aminoglycoside antibiotics. Rev Infect Dis 1983; 5 (suppl 2): 212231. Davies JE: Resistance to aminoglycosides: mechanisms and frequency. Rev Infect Dis 1983; 5 (suppl 2): 261-266. Krogstad DJ, Korfhagen TR, Moeller ing RC Jr, Wennersten C, Swartz MN, Per Perzynski zynski S, Davies J: Aminoglycoside-inactivating enzymes in clinical isolates of Streptococcus Streptococcus faecalis. J Clin Invest 1978; 62: 480-486. Davies J, Courvalin P: Mechanisms of resist resistance ance to aminogly-

19. 20.

21. 22.

cosides. Am J Med 1977; 62 : 868-872. Santana m P, Kayser FH: Tobramycin adenylyltransferase: adenylyltransferase: a new aminoglycoside-inactivating enzyme from Staphylococcus epidermidis. J Infect Dis 1976; 1 34 (suppl): 33-39. Verklin RM, Mand ell GL: Alteration of effectiveness v eness of antibiotics by anaerobiosis. J Lab Clin Med 1977; 89 : 65-71. VanScoy RE : Antituberculosis agents isoniazid, rifampin, streptomycin,, streptomycin ethambu tol. Mayo Clin Proc 1977; 52: 694-

23.

24. 25.

700. Sande M A, Scheld WM: Combi nation antibiotic therapy of bacterial endocarditis. Ann Intern Med 1980; 92: 390-395. Sande MA , Mand ell GL: Antimicro bial agents: the aminoglycosides. In: Goodman and Gilman, eds. The pharmacological basis of therapeutics, ed 6. New York: MacMillan Publishi ng Co., Inc., 1980; 1171-1173. Greenberg LH, Momary H: Audiotoxicity and nephrotoxicity due to orally administered neomycin. JAMA 1965; 194: 827828. Achord JL: Neomycin-induced malabsorption in fasting patients (abstr). (abstr). Gastroenterology 1969; 56: 1244. Murray BE, Moeller ing RC Jr: Patterns and mechanisms of antibiotic resistance. resistance. Med Clin North Am 1978; 62: 899-923. Speller DCE, Step hens M, Reeves DS, et al: Epidem ic infection by a gentamicin-resistant Staphylococcus Staphylococcus aureus in three hospitals. Lancet 1976; I: 464-466. Mayhall GG, Medeff G, Marr JJ: Variation in the susceptibility of strain strainss of Staphylococcus Staphylococcus aureus to oxacillin, cephalothin, and

gentamicin.

Antimicrob

Agents

Chemother

1976;

June

26.

27.

28. 29. 30.

31.

32.

10:

30, 1988

The

707-712. Dowding JE: Mechanisms of gentamicin lococcus lococc us aureus. Antimicrob Agents 47-50.

resistance resistance Chemother

in Staphy1977; 12:

Kauffma nn CA, Ramund o NC, Williams SG, Dev CR, Phair JP, Watanakunakorn C: Surveillance of gentamicin-resistant gram-negative bacilli in a general hospital. Antimicrob Agents Chem other 1978; 13: 918-923. Keys TF, Washington JA: Gentamicin-resistant Pseudomonas aeruginosa. Mayo Clin Proc 1977; 52: 797-8Oi. Walker BD, Gentry LO: A randomized, comparative study of tobramycin and gentamicin in treatment of acute urinnary ary tract infections. J Infect Dis 1976; 134 ((suppl): suppl): S146-S148 . Appel GB, Neu HC: Gentamicin in 1978. Ann Intern Intern Med 1978; 89: 528-538. Briedis DJ, Robson HG: Comparative activit activityy of netilmicin , gentamicin, amikacin and tobramycin against Pseudomonas aeruginosa and Enterobacteriaceae. Antimicrob Agents Chemother 1976; 10: 592-597. Kahlme ter G, Dahlager JI JI:: Aminoglycoside toxicity-a toxicity-a review of clinical studies published between 1975 and 1982. J Antimicrob Chemother 1984; 13 (suppl A): 9-22. Lance AZ, Wrigth GE, Blair DC: Ototoxicittyy and nephrotoxicity of amikacin. Am J Med 1977 ; 62 : 911-918. Black RE, Lau WK, Weinstein RJ, Young LS, Hewitt WL: OtoOtotoxicityy toxicit of amikacin. Antimicrob Agents Chemother 1976; 9: 956-961. Brogden RN, Pinder RM, Sawyer PR, Speigh t FM, Avery GS: Tobramycin: a review o f its antibacterial and pharmacokinetic properties and therapeutic use. Drugs 1976 ; 12: 166200. Marks MI, Mammerberg S, Greenstone G, Silver B: Activity of newer aminoglycosides and carbenicillin, alone and in combination, against gentamicin-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1976; 10: 399-401. Neu HC: Tobramycin: an overview. J Infect Dis 1976; 134 (suppl): s3-s19. Liithy R: Aminoglykos idantibiotika aus klinischer Sicht. Int J Clin Pharmacol 1975; 11: 112-l 25. Yu PKW, Washington JA: Antimicrob ial susceptibility of gentamicin-resistant Pseudomonas aeruginosa. Mayo Clin Proc 1977; 52: 802-805. Moellerin g RC Jr, Wennersten C, Kunz LJ, Poitras JW: Resist: Resist: ante to gentamicin, tobramycin and amikacin among clinical isolates of bacteria. Am J Med 1977; 62: 873-881. Smith CR, Lippsky sky JJ, Laskin OL, et al: Double-b lind compari-

American

Journal

of Medicine

Volum e

80 (suppl

8B)

11

 

SYMPOSIUM

33. 34.

35.

36. 37.

38.

39.

40.

41.

42. 43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

ON AMINOGLYCOSIDE

ET AL

son of the nephrotoxicity and auditory toxicity toxicity of gentamicin .and tobramycinn.. N Engl J Med 1980 ; 302: 1106-1109. Kumi n GD: Clinical nephrotoxicity of tobramycin ‘and gentami-

55.

tin: a prospective ve study. JAMA 1980; 244: 1808-1810. Schentag JJ, Cerra FB, Plaut ME: Clinical and pharmacokinetic characterist characteristics ics of aminoglycoside hephrotoxicity in 201 ill patients: Antimicrob Agents Chemother 1982; 5: 721-726. Mauff G, Schaal K P, Pulverer G: Vergleichehde Untersuchung zur in vitro Aktivit$t von Sisomicih, Gentamicin und Tobramycin. Infection 1976; 4 (sup@): S30 0-5304. Knothe H: Die antibakterielle Aktivitat von Gentamicin, Sisbmitin und Tobramycih. Infection i976; 4 (suppl): S294-S299 . Shadomy s, Jutz C, Wagner.G: In vitro studies with sisomicin, gentamicin and tobramycin. Infection 1976; 4 (suppl): S3055308. Sanders CC, Sanders, WE, Goering RV: In vitro studies studies with Sch.21420 and Sch 22591: activity in comparison with six other aminoglycdsides and syner synergy gy w ith penici llin against enterococci. Antimicrob Agents Chemother 1978; 14: 178184. Sack K, Kayser FH, Zullich B, Beck H, Schulz E: Nebenwirkungen von Aminoglykosiden: Nephrotoxizitat. Infection 1976; 4 (suppl): 231-238. ’

56.

ther 1976: 10.: 845-849. Riff, LJ, Jack Jackson son GG: Laboratory and clinical conditions for gentamicin inactivation by carbenicillin. Arch Intern Med 1972; 130: 887-891.; Laughl in JE, Reeves DS: Clinical and laboratory evidence for inactivation of gentamicin by carbenicillin: Lancet 1971; I: 261-264. :

57.

Karnad A, Alvarez negative baciili.

58.

Tillotson

59. 66. 61.

Lerner

M : Pneumon ias

caused

by gram-negative

bacilli. Medicine (Baltimore) 1966; 45: 65-76. Neu HC: Optimal antib iotic therapy in bronchopulmonary infections Infection 1980; 8 (suppl 1): 62-69. Donowitz GR, Mand ell GL: Empiric therapy for pneumo nia. Rev Infect Dis 1983; 5 (suppl): 46-51. Preheim LC: Complicated urinary tract infections. Am J Med i985; 79 (SUPPI 2A): 62-66.

64.

Amikacin im Med Klin 1978;

65.

1985; 7 8 (Suppl 68): 157-162. Wilson WR, Giulian i ER, Danielson

Schiffmann DO: Evaluation of amikacin sulfate. JAMA 1977; 238,: 1547-1550. Price KE, DeFuria MD, Pursiano TA: pmikacin, an aminoglycoside with marked activity activity against antibiotic-resistant clinical isolates. J Infect Dis 1976; 134 (suppl 1): 249-261. Holm SE, Hill B, Ldwestad A, Maller R, Vikerfors Vikerfors I: A prospecprospective, randomized study of amikacin and gentamicin in seri011s infections with focus on efficacy, efficacy, toxicity toxicity and duration of serum levels above the MIC. J Antimicrob Chemother 1983;

66.

Meyer apy

RD, Lewis for serious

R, CarmaltED, gram-negative

Finegold bacillaty

SM: Amikacin therinfections. Ann In-

tern Med 1975; 83: 790-800. Jotzoff M: Zur antimikrob iellen Aktivitat Vergleich mit drei anderen Aminoglykosiden. 73: 914-917.

von

12: 393-402. Gerding DN, Larson TA: Aminoglycoside resistance resistance in gramnegative bacilli during increased amikacin use. Am J Med 1985; 79 (suppl.lA): l-7. Betts RF, Valen ti WM,, Chapma n SW, et al: Five-year Five-year surveillance of aminoglycoside usage in a university university hospital. Ann Intern Me d 1984; 100: 219-222. Lee JT: Three-year Three-year experience with amikacin sulfate as an exclusive ve surgical aminoglycoside in a large acute-care acute-care hospital. A m J Med. 1985; 79 (suppl 1A): 37-42. Shulm ann ST, Yogev R: Treatment of pediatric infections with amikacin as first-line aminoglycoside. Am J Med 1985; 79 (suppl 1A): 43-50. Carson CC, Paulson DF; Rudd C: Overvieew w of first-line amikacin therapy therapy for urologic infections. Am J Med 1985; 79 (suppl 1A): 51-54. Panwalker Al?, Malow JB, Zimelis VM, Jackson Jackson GG: Netilmicin: clinical efficacy efficacy,, tolerance and toxicity. toxicity. Antimicrob Agents Cherriother 1978; 13: 170-176. Chadwick P, Salmo n G, Taylor B: Activity of netilmtcin compared with those of gentamicin and tobramycin against Enterobacteria and Pseudomonas aeruginosa. Antimicrob Agents Chemo ther 1977; 12: 301-307. Fu KP, Neu HC: In vitro study o f netilmicin compared with other aminoglycosides. Antimicrob Agents Chemother 1976; 10: 526-534. Chiu P JS, Mille r GH, Brown pFiarmacology of netilmicin. 1977; 11: 821-825. Luft FC, Yum MN, Kleit SA:

June

and gentamicin

30, 1986

ihe

ADi Long Antimicrob

62.

JR,

S, Berk SL: Pneum onia caused by gramA m J Med 1985; 70 (suppl 1A): 61-67.

Horowitz EA, Preheim LC, Safranek TJ,.Pugsley MP, Sanders C, Bittner MJ: Randomized , double-blkrd comparison of ceftazidime and moxalactam in complicated urinary ttract ract infections. Antimicrob Agents Chem othe? 1985; 28: 299-301. Minuth JN, Musher DM, Thorstein Thorsteinsson sson SR: Inhibition of the antibacterial activity activity of gentamicin by urine. J Infect Dis 1976; 133: 14-21. Kaye D: Changin g pattern of infective endocarditis. Am J Med

netilmicin

12

THERAPY-SIEGENTCiALER

63.

considerations endocarditis.

67.

68.

69.

70. 71.

72.

73. 74.

75.

76. 77.

JF, Waitz JA: Renal Agents Chemother 78.

Comparative in rats. Antimicrob

American

Journal

nephrotoxicities Agents

of Medicine

of

Chemo-

Volum e

Geraci

JE:

General

of infective

Griffin MR, Wilson WR, Edwards O’Fallon Minnesota, WM, Kurland 1950 LT: Infective endocarditis. Olmsted D, County, through 1981. JAMA 1985; 254: 1199-1202. Pelletier LL Jr, Petersdorf RG: infective endocarditis: a review of 125 case casess from the Universittyy of Washington hospitals, 1963-1972. Medicine (Baltimore) 1977; 56: 287-313. Geraci JE, Wilson WR: Endocarditis due to gram-negative bacteria, report of 56 cases. cases. Mayo Clin Proc 1982; 57: 145148. Finland M, Barnes MW: Changin g etiology.of bacterial endocarditis in the antibacterial era. Ann Intern Med 1970; 72: 341-348. Nastro LJ, Finegold SM: .Endocarditis due to anaerobic gramnegative bacilli. Am J Med 1973; 54 : 482-496. Reyes MP, El-Khatib MR, Brown WJ, Smith F, Lerner AM:.Synergy between ca rbenicillin and an aminoglycqside (gentamitin or tobramycin) against Pseudomonas aeruginosa isolated from patients with endocarditis and sensitivittyy of isolates to normal human serum. J Infect Dis 1979; 146: 19% 202. Drake TA, Bande MA: Studies of carditis: correlation of in vitro, studies. Rev Infect Dis 1983; 5 Wilson WR, Geraci JE: Treatment endocarditis. Am J Med 1985;

the chemotherapy of endoanimal model, and clinical (suppl 2): 345-354. of streptococcal streptococcal infective 78 (suppl 6B): i28-137.

Karch,mer AW: Staphylococcal endocarditis: laboratory and clinical basis for antibiotic therapy. Am J Med 1985; 78 (suppl 6B): 116-l 27. Kager L, Nord CE: Imipenem/cilas tatin in the treatment of intraabdom inal infections: a review of worldwide experience. Rev Infect Dis 1985; 7 (suppl 3): 518-521. Nelson JD: Emergin g role of cephalosporins in bacterial meningitis. Am J Med 198 5; 79 (suppl 2A): 47-51. Cherubin CE, Corrado ML, Nair SR, Gombert ME, Landesman S, Humberg G: Treatment of gram-negative bacillary meningitis: role of the new cephalosporin antibiotics. Rev Infect Dis 1982; 4 (suppl): 453-464. Landesman SH, Corrado Corrado ML, Shah PM, Armengaud M, Barza M, Cherubin CE: Past and current current roles for cephalosporin antibiotics

80 (suppl

GK,

in the diagnosis and treatment Mayo Clin Proc 1982; 57: ,81-85.

6B)

in treatment

of meningitis.

Emphasis

on

use

in

 

SYMPOSIUM

gram-negative 79.

80.

81.

82.

83.

84.

693-703. Eigler JOC,

Wellman

1985; 7 8 (suppl Gribble MJ, Chow

90.

91.

92.

93.

94.

95.

96.

97.

ED , Keith

J Med HM:

1981;

Bacterial

71: 98.

men-

99.

100.

101.

102.

103.

J: Diagnostic

strategies

in osteomyelitis.

Am

6B): 218-224. AW, Naima n SC, et al: Prospective

J Med

THERAPY-SIEGENTHALER

ET AL

infections involving gentamicin-resistant organisms. J Infect Dis 1976; 134 (suppl): 428-432. Yap BS, Bodey GP: Netilmicin in the treatment of infections in patients with cancer. cancer. 1262. Sanford JP: Antimicrob ial organisms, In: Sanford

Arch

apy, 1985; 34-36. Young LS, Meyer-Dudnik cosides in the treatment

Intern

agents JP, ed.

Med

1979;

139:

LV, Hindler J, Martin WJ: of bacteremic infections

for granulocytopenic Am J Med 1980 ;

1259-

of choice aga inst selected Guide to antimicrobial ther-

munocomprom ised host. J Antimicrob Chemother (suppl A): 121-132. Love LJ, Schimpff SC, Schiffer CA, Wiernik PH: prognosis bacteremia.

104.

86.

89.

Rooke

Am

glycoside administered into the cerebral ventricleess in neonates: implications for further evaluation of this route of therapy in meningitis . J Infect D is 1981; 143: 141-147. McCracken McCracken GH Jr, Mize SG, Threlkeld N: lntraventricular gentamicin therapy in gram-negative bacillary meningitis of infancy. Lancet 1980; I: 787-791. Pichichero ME, Friesen HA: Polymicrobial osteomyelitis: report of three cases and revieew w of the literature. Rev Infect Dis 1982; 4: 86-96. Goldenberg DL, Cohen AS: Actue infectious arthritis: a review of patients with nongonococcal joint infections (with emphasis on therapy and progn prognosis). osis). Am J Med 197 6; 60: 369377. Wheat

88.

WE,

meningitis .

ingitis. General review (294 cases) cases).. Mayo Clin Proc 1961; 36: 357-365. Kaiser AB, McGee ZA: Aminoglycoside therapy of gram-negative bacillary meningitis . N Engl J Med 1975; 293: 12151220. Wright PF, Kaiser AB, Bowma n CM, McKee KT Jr, Trujillo H , McGee ZA: The pharmacokinetics and efficac efficacyy of an amino-

85.

87.

bacillary

ON AMINOGLYCOSIDE

patients with 68: 643-648.

Aminoglyin the im1981;

8

Improved

gram-negative

Klastersky Klastersky J, Meunier-Carpentier F, Prevost JM: Significance of antimicrobia l synergism for the outcome of gram-negative sepsis. Am J Med Sci 1977; 273: 157-167. Scott RE, Robson HG: Synergistic activity activity of carbenicillin and gentamicin in experimental Pseudomonas bacteremia in neutropenic rats. Antimicrob Agents Chemother 1976; 10: 646-651. Baltch AL, Smith RP: Combination s of antibiotics against Pseudomonas aeruginosa. Am J Med 1985; 79 (suppl 1A): 8-l 6. Levin S: Antibiotics of choice in suspected serious sepsis. Antimicrob Chemother 1981; 8 (suppl A): 133-142.

random-

105.

ized trial of piperacillin monotherapy versus versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections. Antimicrob Agents

106.

Young L: Aminoglycosides terapia 1984; 3 (suppl):

107.

Zinner SH: Review of amikacin usage in the EORTC trials. Am J Med 1985 ; 7 9 (suppl IA): 17-20. Schimpff S, Satterlee W, Young VM, Serpick A: Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med 1971; 284: 1061-1065. Noone P, Parsons TMC, Pattison JR, Slack RCB, GarfieldDavies D, Hughes K: Experience in monitoring gentamicin therapy during treatment of serious gram-negative sepsis. Br Med J 1974; I: 477-481.

Chemother 1983; 24: 388-393. Platt R, Ehrlich SL, Afarian J, O’Brien TF, Penning ton JE, Kass EH: Moxalactam therapy of infections caused by cephalothin-resistant thin-resist ant bacteria: influ ence of serum inhibitory activity on clinical response and acquisition of antibiotic resist resistance ance during therapy. Antimicrob Agents Chemother 1981; 20: 351-355. Neu HC: Mechanisms of bacterial resistance resistance to antimicrobia l agents, with particular reference to cefotaxime and other

108.

109.

beta-lactam compounds. Rev Infect Dis 1982; 4 (suppl 1): 288-299. Sanders CC, Sanders WE Jr, Goering RV, Werner V: Selection of multip le antibiotic resista resistance nce by quinolones, beta-lactams, and aminoglycosides with special reference to cross-r cross-resis esisttance between unrelated drug classes. classes. Antimicrob Agents Chemother 1984; 26: 797-801. Sanders CC, Sanders WE Jr: Microbial resistance resistance to newer

110.

111.

112.

generation beta-lactam antibiotics: clinical and laboratory implications. J Infect Dis 1985; 15 1: 399-405. Hoogkamp-Korstanje JAA, Erpecum KJ, van Kamp H: Ceftazidime in serious hospital-acquired infections. J Antimicrob Chemother 1985; 15: 743-749. Feld R, Valdivieso M, Bodey GP, Rodriguez V: Comparison of amikacin and tobramycin in the treatment of infections in patients with ca cancer. ncer. J Infect Dis 1977; 135: 61-66. Jackson Jackson GG, Riff LJ: Pseudomonas bacteremia: pharmacologic and other bases for failure of treatment with gentamitin. J Infect Dis 1971; 124 (suppl): 185-191. Jaffe G G,, Ravreby W, Meyers BR, Hirschman SZ: Clinical study of the use of the new aminoglycoside tobramycin for therapy of infections due to gram-negative bacteria. Antimicrob Agents Chemother 1974; 5: 75-81. Bock BV, Edelstein PH, Meyer RD: Prospective comparative study of efficac efficacyy and toxicity toxicity of netilmicin and amikacin. Antimicrob Agents Chemother 1980; 17: 217-225. Valdivieso M, Feld R, Rodriguez V, Bodey GP: Amikacin therapy of infections in neutropenic patients. Am J Med Sci 1975; 270: 453-463. Tally FP, Louie TJ TJ,, O’Keefe P, Gorbach SL, Bartlett JG: Amikacin

therapy

for

severe

gram-negative

sepsis:

efficacy efficacy

June

113.

114.

115.

116.

117.

118. 119.

Che mio-

Klastersky Klastersky J, Daneau D, Swings G, Weerts D: Antibacterial activityy in serum and urine as a therapeutic activit guide in bacterial infections. J Infect Dis 1974; 129: 187-193. Barza M, Brown RB, Shen D, Gibaldi M, Weinstein L: Predictability of blood levels of gentamicin in man. J Infect Dis 1975; 132: 165-i 74. Kaye D, Levison ME, Labovitz ED: The unpredictability of serum concentrations of gentamicin. J Infect Dis 1974; 130: 150-154. Goodman EL, van Gelder J, Holmes R, Hull AR: Prospectiv Prospectivee comparative study of variable dosage and variable frequency regimens for administration of gentamicin. Antimicrob Agen ts Chem other 1975; 4: 434-438. Liithy R: Basis for an adequate dosage of aminoglycoside antibiotics Infection 1980; 8 (suppl 1): 58-61. Moore RD, Smith CR: Lipsky JJ, Mellits ED, Lietman PS: Risk facto factors rs

The

therapy.

Moore RD, Smith CR, Lietman PS: Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 1984; 77: 657-662. 657-662. Moore RD, Smith CR, Lietma n PS: The association of aminoglycoside plasma levels with mortality in patients with gramnegative bacteremia. J Infect Dis 1984; 149: 443-448. Anderson ET, Young LS, Hewitt WL: Simultane ous antibiotic levels in “breakthrough” “breakthrough” gram-negative rod bacteremia. Am J Med 1 976; 61: 493-497. Sculier JP, Klastersky Klastersky J: Significance of the serum ba ctericidal test in gram-negative bacillary bacteremia in patients with and without granulocytopenia. Am J Med 1984; 76: 429435.

in

30, 1988

in combination 38-41.

J

American

for nephrotoxicity

Journal

of Medicine

in patients

Volum e

treated

80 (suppl

with

aminogly-

8B)

13

 

SYMPOSIUM

120.

121.

122.

14

ON AMINOGLYCOSIDE ON

THERAPY-SIEGENTHALER

ET AL

cosides. Ann IIntern ntern Med 1984; 100: 352-357. Moore RD, Smith CR, Lietman PS: Risk factors factors for the development of auditory toxicit toxicityy in patients receiving aminoglycosides. J Infect Dis 1984; 149: 23-30. Wilson P, Ramsden RD: Immedia te effects of tobramycin on human cochlea and correlation with serum tobramycin levels. Br Med J 1977; I: 259-261. Vivas JR, Creixems MR, Bouza E, et al: Evaluation of aztreonam in the treatment of sever severee bacterial infections. Antimicrob Agents Chemother 1985; 28: 222-226.

June

30,

1988

The

American

Journal

of Medicine

Volum e

123.

124.

80 (suppl

Chalkley LJ, Koornhof HJ: Antimicrob ial activit activityy of ciprofloxacin against Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus Staphylococcus aureus determined by the killing curve curve method: antibiotic comparisons comparisons and synergisstic tic interactions. Antimicrob Agents Chemother 1985; 28: 331342. Eron W, Harvey L, Hixon DL, Poretz DM : Ciprofloxacin therapy of infections caused by Pseudomonas aeruginosa and other resistant bacteria. bacteria. Antimicrob Agents Chemother 1985; 27: 308-310.

66)