- Email: [email protected]
Penicillins, cephalosporins and tetracyclines
T. Midtvedt
26
Penicillins, cephalosporins and tetracyclines
fl-LACTAM ANTIBIOTICS (SEDA-9, 230) Misuse - the most serious side effect of newer/I-lactam antibiotics 'Magicomycin' - the elusive ideal antibiotic with a broad spectrum antimicrobial activity and a complete absence o f toxicity to the host - has been the dream of many infectious disease specialists, chemists, pharmacologists, microbiologists and sales people in the pharmaceutical industry. In the last 10 years there has been an explosion in the fl-lactam group o f antibiotics, and we are now speaking of the 4th generation of penicillins, 3rd generation o f cephalosporins, and such novel members of the family as the imipenem and monobactams, while several others are Just around the corner'. I f we dare to believe the pamphlets from the pharmaceutical industry, many of these new drugs are very close to the definition given for a 'magicomycin ". However, real life is not that easy. In parallel with this so-called evolution o f newer fl-lactams, 2 major obstacles are repeatedly encountered." the evolution of new pathogens in specific clinical settings, and the acquisition of resistance. Streptococcus epidermidis, enterococci, Acinetobacter calcoaceticus, Serratia marcescens, Enterobacter spp., Clostridium difficile and Bacteroides fragilis spp., rarely mentioned in infectious disease journals 20 years ago, are now among the major pathogens in many hospitals. Most of the species encountered are resistant to multiple antibiotics. We can hardly blame the microbes. The situation is created by our use - and misuse - of the antimicrobial agents available. Every time that we introduce a new antibiotic into our therapeutic armamentarium we appear to offer one or several new microbial agents an opportunity to
Side Effects of Drugs Annual 10 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1986
join the bandwagon o f resistance, and they are hardly reluctant to take the Chance. Time and again, colleagues all around the world have given their several warnings. In spite of trying to review the overwhelming flow of well-written and well-documented papers, I would merely point to a cornerstone in the whole situation: 'The newer agents are not able to eradicate any additional pathogens that the older and less expensive antibiotics cannot"
(1R). Accepting that statement, the next question should be: Why are they then brought into use? O f course it is true that the specific therapeutic situation can often be quite critical. The patient is seriously ill, the physician recalls the problems which he encountered earlier with a patient having an infection with a multiresistant organism and so on. The activists among us will in such a situation be only too happy that they have access to the very latest wonderdrug, and several others among us will feel similarly comfortable at being able to initiate therapy, often without serious attempts to make a specific microbiological diagnosis. However, let us never forget that in following this course we alb escaping from the long and often agonizing process of trying to make a correlation between the clinical presentation o f the patient and the most likely microbial pathogen. And, as ever, there will also be a question of money. Most of the newer fl-lactams cannot be called cheap; the cost for I patient can be as high as $100-200 per day. In a life-threatening situation that is of course peanuts, but paying that much for creating future problems of resistance is not so acceptable. Consuming an increasingly high antibiotic budget might well be taken as an indication of a decreasing diagnostic and therapeutic standard in your ward. Let us therefore inflate neither the pharmacy budget nor the microbial troublemakers in our hospital by using these newer fl-lactam antibiotics unnecessarily. 'Magicomycin' is still nothing but a dream.
Penieillins, cephalosporins and tetr
Chapter 26
Host defence mechanisms and/]-Iactam antibiotics: a call for further investigations There is increasing evidence suggesting that many fl-lactam antibiotics might modulate various host defence mechanisms in different ways. Some of these drugs have been shown to influence humoral immune response, the lymphocyte response to mitogens, chemotaxis and phagocytic functions of macrophages or granulocytes (2 g, 3r, 4 R 6R). Recently, the immunomodulating effects of 6 new cephalosporins (cefotaxime, cefoxitin, cefsulodin, cefoperazone, cefotetan, cefmenoxime) were tested in mice using the plaque assay of Jerne, the footpad-swelling test and peritoneal clearance of micro-organisms (7R). The results were compared with the effect in experimental infections with Candida albieans. With none of these antibiotics were the results homogeneous in all test models. In another study it was concluded that a new cephalosporin, CPW 86-363 'owes its good in vivo efficacy to a yet unknown interaction with host defences' (8R). None of these results really seem to permit any conclusions to be drawn concerning the relative ability of the fl-lactam antibiotics to act as immunomodutators. However, the mere fact that they might interfere with the host defence mechanisms should indeed stimulate further investigations.
Seizures and ~-Iactam antibiotics Soon after its introduction to clinical practice, penicillin G was recognized to have direct CNS toxicity (9 c, 10c). Since then, it has repeatedly been shown that high doses of penicillin given intravenously produce neurotoxic reactions similar to those reported after subarachnoid, ventricular space, or direct cortical instillation of penicillin, and that patients with impaired renal function are most predisposed to neurotoxic reactions if no dosage adjustment is made. The clinical picture includes hyperreflexia, myoclonus, and generalized seizures. EECs may show diffuse slowing, hypersynchrony or loss of alpha rhythms (1 lC). The convulsions appear to arise from interference with the inhibitory transmitter function induced by yaminobutyric acid (12s). It has been proposed that decreasing 7-aminobutyric acid inhibition releases intrinsic burst-generating properties in neurons that are triggered by dendritic excitation (13R). Ebersole and Chatt (14g), injecting picoliter volumes of penicillin into the striate
235
cortex of cats, report that both intrinsic neuronal and population interaction abnormalities are responsible for in-vivo neocortical epileptogenesis. However, other factors may also play a role in penicillin-epileptogenesis. At least in rabbits, there appears to be a relation between the neurotoxicity of various penicillins and their hydrophobic character (15R). With an increasing partition coefficient, the neurotoxicity increases in the following order: carbenicillin, ticarcillin, methicillin, penicillin G, oxacillin, phenethicillin, cloxacillin and dicloxacillin. Ampicillin has a partition coefficient similar to that of ticarcillin and methicillin, and there have been few reports of neurotoxicity related to ampicillin therapy. Recently, however, 2 cases of ampicillin-associated seizures were reported (16c). Although they had complex medical problems, the high serum concentrations of ampicillin at the time of seizures without their recurrence after discontinuing the antibiotic allowed the authors to suggest that the seizures were related to the ampicillin therapy. The neurotoxicity of the/~-Iactam antibiotics is certainly not restricted to the penicillin group. The use of cephalosporins in patients with renal insufficiency has also been linked with CNS toxicity (12R). Recently, 2 cases of 'seizure-like activity associated with imipenem' were reported (17c). The important part of the molecule might be the/%lactam ring (18R~, and if so, seizures can be expected in patients receiving all types of new/%lactam antibiotics. High drug dosage, severe renal insufficiency and underlying cerebral dysfunction are then factors which one would then expect to predispose to or potentiate such neurotoxicity.
Hemodynamic reactions in ~-Iactam anaphylaxis Anaphylactic reactions to fl-lactam antibiotics are indeed well known and anaphylaxis due to penicillin has been said to cause 400-800 deaths a year in the United States (19R). Since these acute reactions might progress to death within a matter of minutes, there has been little opportunity to evaluate the hemodynamic and respiratory changes that really occur. It is therefore of interest to focus upon a report describing a patient who experienced an anaphylactic reaction to penicillin (nafcillin i.v.) while being monitored in an intensive-care unit for ischemic heart disease (20c). The anaphylactic shock was characterized by reductions in
236 mean arterial blood pressure, cardiac output, pulmonary capillary wedge pressure, and pulmonary artery pressure, and increases in peak airway pressure and pulmonary vascular resistance. The observations were similar to findings in an animal model of anaphylaxis (21', 22r). All the details given in the report should be of interest for anesthesiologists and other staff on duty in the intensive-care unit. Human anaphylactic reactions are usually unexpected and catastrophic, and all information which can lead to their immediate recognition should be appreciated. Urine glucose test methods and the newer ~-Iactam antibiotics
The copper-reduction method (Clinitest) and the glucose-oxidase method (Diastix, TesTape) are the 2 most commonly used methods for detection of glycosuria. A variety of drugs, including levodopa, salicylates, probenecid, and antimicrobials such as isoniazid, nalidixic acid and fl-lactam antibiotics, are known to be capable - by various mechanisms - of influencing the results of such tests. This fact inspired an investigation to determine the effects on these 2 tests for glycosuria of 10 new fl-lactam antibiotics added in varying concentrations to normal urine samples (23s). Ten fl-lactams were tested: aztreonam, azlocillin, mezlocillin, piperacillin, ticarcillin, cefoperazone, ceftazidime, ceftizoxime, ceftriaxone, cefotaxime and its metabolite deacetylcefotaxime. Clinically obtainable urinary drug concentrations were prepared in vitro, and urine samples from healthy volunteers were used to stimulate diabetic urine by addition of glucose (0.5, 1 and 2%, respectively). All urine samples containing fl-lactams were estimated accurately by the glucose-oxidase method. Employing the copper-reduction method, falsely elevated readings were generally observed at lower glucose concentrations in the urine containing penicillin derivatives. This might mistakenly lead to supplementary administration of insulin. The authors therefore advise against the use of the copperreduction test for glycosuria in diabetic patients receiving fl-lactams, especially penicillin derivatives. MONOBACTAMS Only a few years ago, Syke~s et al (24 R) isolated a new class of antibiotics derived from a strain of Chromobacterium violaceum found in
Chapter 26
T. Midtvedt
the New Jersey marshes. The class has a singlering structure and differs from other fl-lactams in that it has a sulfonic acid salt substituted at the 1-position and has 1 fused thiazolidine ring. 'Monobactam' is the name given to this group of antibiotics, so-called because of their monocyclic ring structure, bacterial origin and /3lactam nucleus. Aztreonam is so far the most potent of this new monobactam family and is the only derivative which has to some extent been evaluated clinically. A world-wide overview of 2117 patients who have received aztreonam shows that the adverse reactions so far described are qualitatively similar to those usually reported for other fl-lactam antibiotics, i.e. rash, eosinophilia, transient increase in hepatic enzyme parameters and phlebitis at the infusion site (25R). There was an apparent lack of adverse effects on the kidney, inner ear and blood coagulation system. The results suggest that aztreonam may be a fairly safe drug. However, this is by no means the first time that a new class of drugs is initially reported to be safe and well tolerated, and several areas need to be further elucidated before a definitive view is taken. One key problem in the introduction of new groups of fl-lactam antibiotics is the use of these compounds in penicillin-allergic patients. In the overview mentioned, a history of allergy to penicillin or cephalosporins was present in 134 of the 2117 patients treated with aztreonam. Of these 134 patients, only 1 developed a possible IgE-mediated urticarial rash, thought to be a hypersensitivity reaction. Aztreonam thus seems to be a safe drug in patients allergic to penicillins or c~9halosporins. Possible drug interactions should always be investigated when new drugs are likely to be introduced. The pharmacokinetic interactions of aztreonam with cefradine (cepharadine), clindamycin, gentamicin, metronidazole, and nafcillin have recently been investigated in a single-dose, 3-way balanced cross-over study in 48 healthy volunteers (26c). Twenty-fourhour cumulative urinary excretion of aztreonam and clindamycin rose by 5.1 and 10.9%, respectively, when they were administered simultaneously. Maximum serum concentrations of aztreonam were reduced by about 12 and 10%, respectively, when it was given with gentamicin and metronidazole. The percentage of aztreonam bound to protein fell by 5% when aztreonam was given in conjunction with nafcillin and rose by about 5% when it was accompanied by cefradine. All these altera-
Penicillins, cephalosporins and tetrao'clines Chapter26 tions were statistically significant, but whether they should give rise to therapeutic concern remains to be seen. The same holds true for multiple-dose regimens. It should also be mentioned that all drugs were administered through separate lines and that they were mixed in single-infusion bottles. Possible pharmaceutical interactions must therefore also be looked for. CARBAPENEMS
Streptomyces cattle), is yet another antibiotic-producing organism which was first isolated from soil in New Jersey. The first compound to be isolated in a group of antibiotics with a carbapenem nucleus obtained from this organism was thienamycin. The carbapenems are characterized by the 4:5 fused ring lactam of the penicillins with the substitution of carbon for sulfur and with unsaturation in the 5-member ring. The first problem to be overcome with thienamycin was its marked instability. This was accomplished through the synthesis of a N-formimidoyl derivative, now given the generic name 'imipenem'. The second problem to be solved was its marked metabolic inactivation in the kidney, owing to the presence of a brush-border dipeptidase, dehydropeptidase-l; that was accomplished by finding a highly selective enzyme inhibitor, now known as 'cilastatin'. This novel combination of a/~lactam antibiotic (imipenem) and an enzyme inhibitor (cilastatin) has now been on clinical trial for some time, and the first review, covering adverse experiences and tolerability in some 2500 patients receiving the combination has now been published (27c). Basically, the safety profile of this antibiotic appears to be similar to that of other/~-lactam antibiotics. Clinical adverse reactions were predominantly related to the gastrointestinal system. Nausea and/or vomiting occurred in approximately 4%, and diarrhea in about 3.3%. Antibiotic-related diarrhea, defined as comprising either positive assay results for Clostridium diffieile toxin or positive culture results for C. difficile, occurred in 0.79%. This is a rather high value among the /~-lactam antibiotics. However, factors such as prior antibiotic courses or prolonged hospital stay may here have been involved. No anaphylactic reactions were reported. However, it has to be added that patients with a history of serious/3-1actam allergy were supposed to be excluded from these trials. In a
237
series of 12 patients with previously known mild to moderate allergic reactions to penicillin, imipenem cilastatin induced allergic manifestations in 2. Although the incidence of seizures during imipenem cilastatin therapy was no higher than in patients treated with other antibiotics (approx. 1.5% in both groups), the authors nevertheless believed that the combination in some patients gave rise to seizures. They cite preliminary, unpublished data from the Mayo Clinic indicating an incidence of seizure of about 5% in severely ill infected patients. Recently, 2 cases of 'seizure-like activity' in patients receiving imipcnem have been reported (17c). Until more definitive data are presented, it might be wise not to use imipenem cilastatin in patients with a history of seizures or receiving anticonvulsant therapy. In patients who developed seizures during imipenem-cilastatin therapy, antibiotic administration should be discontinued and anticonvulsant therapy should be started. The most frequent adverse laboratory experiences were transient elevations of liver Junction test values; however, the abnormalities were usually minor and of little (if any) clinical consequence. Of greater clinical importance may be the observation in a group of 717 severely ill patients from the United States of a 3.2% incidence of colonization with bacteria resistant to imipenem and an 8% incidence of colonization with yeast or moulds. There was an approximately 4% incidence of superinfections, most often caused by resistant Pseudomonas aeruginosa, P. maltophilia or yeast. Hopefully, imipenem cilastatin will prove, as Neu has put it, to be a 'useful addition to our current antimicrobial armamentarium if it is used properly' (28R). OTHER PENICILLINS DicloxacUlin and nephrotoxicity In 1975, K6hler et al (29 c) treated l0 patients with high intravenous doses of dicloxacillin (8 16 g/24 h) and noted a transient increase in serum creatinine. They considered the toxic effect to be dose-related. Recently, Isacson and Collert reported impairment of renal function in patients subjected to joint replacement (30c). This side effect appeared in 35 of 278 patients who received prophylaxis with intravenous dicloxacillin (13 g in the course of approximately
238 3 days). This high rate contrasted with a zero incidence in 72 patients undergoing the same operative procedures without receiving any dicloxacillin. Thirteen of the 35 patients were clinically affected; 2 had to be dialyzed and 1 died. These Swedish data have already being criticized as 'hardly acceptable (...) because a number of biases may lead to wrong conclusions' (31R). Of course, the only way to find out whether dicloxacillin is nephrotoxic or not is to perform a prospective, strictly randomized comparative study. In the meantime, possibly the main thing to remember is that all patients with renal complications were older than 60 years, with a mean age of 76 years. Especially in elderly patients, serum drug concentrations should be performed; it should as always be realized that dosage recommendations are usually based upon findings in young and healthy volunteers. TETRACYCLINES (SED-IO, 467; SEDA-8,
251; SEDA-9, 234) Tetracyelines, cancer and AIDS The ability of tetracyclines, including doxycycline, to inhibit protein synthesis in microbial and mammalian systems is well known. In man, this ability has not been utilized therapeutically. However, recent investigations indicate that tetracyclines might exert antiproliferative effects in various tumor-model systems in vivo. The rational for using tetracyclines was the assumption that intentional inhibition of mitochondrial synthesis would reduce the cell's energy-generating capacity, ultimately leading to an arrest of multiplication. Most active in this field has been a group from the Netherlands, and they have recently demonstrated that doxycycline arrests the proliferation of cells in a tissue culture secondary to inhibition of mitochondrial protein synthesis, and that doxycycline treatment could lead to a complete regression of a transplanted human renal carcinoma in athymic (nude) rats and of a syngenic T-cell tumor of the rat (32R). These authors defend the hypothesis that tetracyclines, especially doxycycline, can be utilized as cytostatic agents in the treatment of cancer. They found that T-cell proliferation was sensitive to treatment with tetracyclines. Recent findings that the duration of survival of heart transplants increased in mice treated with doxycycline might be explained by a similar mechanism (33R).
Chapter 26 T. Midtvedt Whether the tetracyclines can be used as cytostatic adjuvants remains to be seen. However, even the slightest indication that they interfere with the proliferation and functioning of T-cells should be further investigated. If this holds true, they might have to be avoided in the treatment of infections in AIDS patients.
Minocycline and acute hepatic injury (SED10, 474) Tetracyclines are known to produce hepatic injury, and this is now also known to hold good for minocycline (34c): A 57-year-old non-obese, non-diabetic, non-alcoholic woman was admitted to hospital because of a suicide attempt. After 24 hours in hospital an aspiration pneumonia developed, and initially she was given ampicillin sodium. The culture disclosed Staphylococcus aureus and Streptococcus salivarius and ampicillin was replaced by minocycline hydrochloride (400 mg/d i.v.) and penicillin G (10,000,000 IU/d i.v.). Four days later, the patient complained of anorexia, nausea and diffuse abdominal pain. Results of liver function tests were abnormal whereas the results of specific serological tests for hepatitis A and B virus, Epstein-Barr virus, cytomegalovirus and toxoplasmosis all were negative. After some days, a mild jaundice developed, and ultrasonography and endoscopic retrograde cholangiopancreatography excluded common bile duct obstruction. The cliniciansjudged minocyclineto be the offending agent, and therapy with minocyclinewas discontinued after approximately 1 week. Additionally, penicillinG was replaced with penicillinV (3,000,000 IU/d p.o. for 7 days). Laparoscopy 8 days after discontinuation of minocycline therapy showed a greenish, smooth, slightly enlarged liver. Light microscopy disclosed diffuse steatosis thdt displaced the nuclei of the hepatocytes. However, some hepatocytes evidenced microvesicular fat without displaced nucleus. There was no foamy fatty vacuolization but some fatty cysts, ballooning degeneration and a mild periportal inflammation. The clinical outcome was favorable with a complete normalization of all liver function tests within 3 weeks after minocycline therapy was discontinued. Previously, most cases of tetracyclineinduced hepatotoxic effects have been observed in women, and the susceptibility seems to be enhanced by pregnancy and renal disease (35R, 36c, 37c). As in the present case, clinical signs and biochemical disorders reflecting a hepatic disturbance usually appear within a week on tetracycline therapy. A reduced hepatic concentration of choline has recently been claimed to increase the risk of tetracycline-induced hepatic injuries (SEDA-8, p. 253). Whilst the
Penicillins, cephalosporins and tetracyclines
Chapter 26
239
mechanisms are still largely unknown, it seems wise to keep in mind that all tetracyclines, including minocycline, may now be regarded as potential causes of hepatic injury.
All systemic medications, including minocycline, were immediately discontinued. The galactorrhea ceased within a week, and the skin pigmentation slowly resolved during the subsequent 6 months.
Minocycline and pigmentation (SED.4-9, 235)
Most probably, the galactorrhea in this patient was due to the use of perphenazine. Drugs blocking the dopaminc receptors in the hypothalamus, such as phenothiazine, are known to be able to influence the level of serum prolactin (41c). It seems reasonable to assume that the iron-containing particles in the milk were related to her use of minocycline. However, the possibility that the onset can have been triggered by a concomitant use of amitriptyline is supported by another report in which minocycline and amitriptyline were being concurrently administered and a dramatic, rapidly progressive pigmentation occurred after only 2 months (42c). The patient, a 30-year-old white woman, had been taking amitriptyline 200 mg/d for several months prior to being placed on minocycline 100 mg/d. The authors postulated that 'amitriptyline may possibly have a synergistic effect with minocycline, potentiating the functional disruption in cellular activity that leads to hyperpigmentation and thereby enhancing the clinical demonstration of this effect.' Obviously, there is a need for more investigations about the mechanisms by which minocycline causes functional disruptions in cellular activity. The dark deeds caused by minocycline should be elucidated before more patients are turned black!
The ability of minocycline to induce pigmentation in various organs is well established (SEDA-8, 252; SEDA-9, 235), and new reports continue to come. However, in many cases there is a history of unsupervised usage of high doses for rather long periods of time, e.g. 400 mg/d for 2 years (38 c) or 200 mg/d for 18 years (39c). In a recent report, the authors focus upon black galactorrhea as a consequence of minocycline and phenothiazine therapy (40c): A 24-year-old woman had received minocycline hydrochloride 100 mg twice daily for almost 4 years to control her pustulocystic acne. During this time, irregular, darkly pigmented macules developed in areas of acne scarring. Periodically, she was also receiving perphenazine, amitriptyline hydrochloride and diphenhydramine hydrochloride for an unrelated psychiatric problem. One day the patient phoned her doctor to tell him that a black fluid was emerging from her nipples. She was investigated later the same day, and palpation of the breasts resulted in the expression of small droplets of milk containing a tinge of pigmented liquid. Microscopic examination showed nurr/,erous macrophages, containing aggregates of particles staining positive for iron and assumed to be hemosiderin. Laboratory screening tests for hepatic, renal and adrenal function yielded normal results.
REFERENCES 1. Eng RHK (1984) Review: new antibiotics - new hopes and new problems. Int. J. Dermatol., 23, 153. 2. Eickenberg H-U, Hahn H, Opferkuch W (Eds) (1982) The Influence o f Antibiotics on the HostParasite Relationship. Springer-Verlag, BerlinHeidelberg-New York, pp 1 268. 3. Kosuzume H, Inaba H, Tajima H et al (1982) The effect of AC-1370, a new semisynthetic cephalosporin on phagocyte function. In: Abstracts, 22ndlnterscience Conference on Antimicrobial Agents and Chemotherapy, Miami Beach, 1982. Abstract No. 758. American Society for Microbiology, Washington, DC. 4. Mandell LA (1982) Effect of antimicrobial and antineoplastic drugs on the phagocytic and microbicidal function of the polymorphonuclear leucocyte. Rev. Infect. Dis., 4, 683. 5. Lingaas E, Midtvedt T (1983) Effects of some new beta-lactam antibiotics on phagocyte function. In: Bergan T, Hahn H, Lorian V (Eds), Proceedings, 13th International Congress of Chemotherapy, Vienna, 1983. SE 3.2/1-9, Part 53.
6. Voss R, Lang J, Ditter H et al (1984) Antibiotika-induzierte Hemmung der Granulozytenaggregation. Med. Welt, 35, 1518. 7. Gillissen G, Pusztai-Markos ZS (1984) Influence of antibiotics on immunological parameters: significance in experimental infections. Drugs Exp. Clin. Res., 10, 813. 8. Lain C, Laber G, Hildebrandt J e t al (1984) Therapeutic relevance of antibiotic-induced augmentation of host defences in experimental infections. Drugs Exp. Clin. Res., 10, 703. 9. Rammelkamp CH, Keefer CS (1943) The absorption, excretion and toxicity of penicillin administered by intrathecal injection. Am. J. Med. Sci., 205, 342. 10. Pilcher C, Meacham WF (1943) The chemotherapy of intracranial infections. Ill. The treatment of experimental staphylococci meningitis with intrathecal administration of penicillin. J. Am. Med. Assoc., 123, 330. 11. Oldstone MBA, Nelson E (1966) Central ner-
240 vous system manifestations of penicillin toxicity in man. Neurology, 16, 693. 12. Snavely SR, Hodges GR (1984) The neurotoxicity of antibacterial agents. Ann. Intern. Med., 101, 92. 13. Schwartzkroin PA, Wyler AR (1980) Mechanisms underlying epileptiform burst discharge. Ann. Neurol., 7, 95. 14. Ebersole JS, Chatt AB (1981) Toward a unified theory of focal penicillin epileptogenesis: an intracortical evoked potential investigation. Epilepsia, 22, 347. 15. Weihrauch TR, K6hler H, H6ffler D et al (1975) Cerebral toxicity of penicillins in relation to their hydrophobic character. Naunyn-Schmied. Arch. Pharmacol., 289, 55. 16. Hodgman T, Dasta JF, Armstrong DK (1984) Ampicillin-associated seizures. South Med. J., 77, 1323. 17. Brotherton TJ, Kelber RL (1984) Seizure-like activity associated with imipenem. Clin. Pharm., 3, 536. 18. Sobotka P, Safanda J (1976) The epileptogenic action of penicillins: structure-activity relationship. J. MoL Med., 1, 151. 19. Erffmeyer JE (1981) Adverse reactions to penicillin. Ann. Allergy, 47, 288. 20. Silverman H J, Smith PL, Lichtenstein L e t al (I 982) Effects of anti-histamine agents on immunologic and physiologic alterations during canine anaphylaxis (Abstract). Fed. Proc., 41, 1134. 21, Beeley L (1984) Allergy to penicillin. Br. Med. J., 288, 511. 22. Bleecker ER, Smith PL, Enjeti S et al (1979) Immunologic and physiologic alterations during anaphylaxis in dogs (Abstract). J. Allergy Clin. lmmunoL, 63, 177. 23. LeBel M, Paone RP, Lewis GP (1984) Effect of ten new fl-lactam antibiotics on urine test methods. Drug Intell. Clin. Pharm., 18, 617. 24. Sykes RB, Bonner DP, Bush K et al (1981) Monobactams: monocyclic beta-lactam antibiotics produced by bacteria. J. Antimicrob. Chemother., 8, Suppl. E, 1. 25. Sharon HA, Bendush CB (1985) Aztreonam: worldwide overview of the treatment of patients with gram-negative infections. Am. J. Med., 78, 57. 26. Creasey WA, Adamovics J, Dhruv R et al (1984) Pharmacokinetic interaction of aztreonam with other antibiotics. J. Clin. Pharmacol., 24, 174.
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T. Midtvedt
27. Calandra GB, Brown KR, Grad LC et al (1985) Review of adverse experiences and tolerability in the first 2516 patients treated with imipenem/cilastatin. Am. J. Med., 78, Suppl. 6A, 73. 28. Neu HC (1985) Summary of imipenem/cilastatin symposium. Am. J. Med., 78, Suppl. 6A, 165. 29. K6hler H, Weihrauch TR, Prellwitz W et al (1975) Side-effects of high-dose dicloxacillin therapy. In: Proceedings, 9th International Congress of Chemotherapy, p 333. Cited in Ref. 31. 30. lsacson J, Collert S (1984) Renal impairment after high doses of dicloxacillin-prophylaxis in joint replacement surgery. Acta Orthop. Scand., 55, 407. 31. Nordbring F (1984) Is dicloxacillin nephrotoxic? Acta Orthop. Scand., 55, 405. 32. Kroon AM, Dontje BHJ, Holtrop M et al (1984) The antitumor action of doxycycline. Drugs Exp. Clin. Res., 10, 759. 33. Bellahsene A, Forsgren A (1985) Effect ofdoxycycline on immune response in mice. Infect. Immun., 48, 556. 34. Burette A, Finet C, Prigogine T et al (1984) Acute hepatic injury associated with minocycline. Arch. Intern. Med., 144, 1491. 35. Davis JS (1968) Liver damage due to tetracycline and its relationship to pregnancy. In: Meyler L, Peck MH (Eds), Drug-Induced Diseases, p 103. Excerpta Medica, Amsterdam. 36. Schultz J, Adamson JS, Workman WN et al (1968) Fatal liver disease after intravenous administration of tetracycline in high dosage. N. Engl. J. Med., 269, 999. 37. Dowling HF, Lepper MH (1964) Hepatic reactions to tetracycline. J. Am. Med, Assoc., 188, 235. 38. Wolfe ID, Reichmister J (1984) Minocycline hyperpigmentation: skin, tooth, nail, and bone involvement. Cutis, 33, 457. 39. Tsu Tung Liu T, May N (1985) Pigmentary changes due to long-term minocycline therapy. Cutis, 35, 254. 40. Basler RSW, Lynch PJ (1985) Black galactorrhea as a consequence of minocycline and phenothiazine therapy. Arch. DermatoL, 121, 417. 41. Gelenburg AJ, Cooper DS, Doller JC et al (1979) Galactorrhea and hyperprolactinemia associated with amoxapine therapy. J. Am. Med. Assoc., 242, 1900. 42. Basler RSW, Goetz CS (1985) Synergism of minocycline and amitriptyline in cutaneous hyperpigmentation. J. Am. Acad. Dermatol., 12, 577.
26
Penicillins, cephalosporins and tetracyclines
fl-LACTAM ANTIBIOTICS (SEDA-9, 230) Misuse - the most serious side effect of newer/I-lactam antibiotics 'Magicomycin' - the elusive ideal antibiotic with a broad spectrum antimicrobial activity and a complete absence o f toxicity to the host - has been the dream of many infectious disease specialists, chemists, pharmacologists, microbiologists and sales people in the pharmaceutical industry. In the last 10 years there has been an explosion in the fl-lactam group o f antibiotics, and we are now speaking of the 4th generation of penicillins, 3rd generation o f cephalosporins, and such novel members of the family as the imipenem and monobactams, while several others are Just around the corner'. I f we dare to believe the pamphlets from the pharmaceutical industry, many of these new drugs are very close to the definition given for a 'magicomycin ". However, real life is not that easy. In parallel with this so-called evolution o f newer fl-lactams, 2 major obstacles are repeatedly encountered." the evolution of new pathogens in specific clinical settings, and the acquisition of resistance. Streptococcus epidermidis, enterococci, Acinetobacter calcoaceticus, Serratia marcescens, Enterobacter spp., Clostridium difficile and Bacteroides fragilis spp., rarely mentioned in infectious disease journals 20 years ago, are now among the major pathogens in many hospitals. Most of the species encountered are resistant to multiple antibiotics. We can hardly blame the microbes. The situation is created by our use - and misuse - of the antimicrobial agents available. Every time that we introduce a new antibiotic into our therapeutic armamentarium we appear to offer one or several new microbial agents an opportunity to
Side Effects of Drugs Annual 10 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1986
join the bandwagon o f resistance, and they are hardly reluctant to take the Chance. Time and again, colleagues all around the world have given their several warnings. In spite of trying to review the overwhelming flow of well-written and well-documented papers, I would merely point to a cornerstone in the whole situation: 'The newer agents are not able to eradicate any additional pathogens that the older and less expensive antibiotics cannot"
(1R). Accepting that statement, the next question should be: Why are they then brought into use? O f course it is true that the specific therapeutic situation can often be quite critical. The patient is seriously ill, the physician recalls the problems which he encountered earlier with a patient having an infection with a multiresistant organism and so on. The activists among us will in such a situation be only too happy that they have access to the very latest wonderdrug, and several others among us will feel similarly comfortable at being able to initiate therapy, often without serious attempts to make a specific microbiological diagnosis. However, let us never forget that in following this course we alb escaping from the long and often agonizing process of trying to make a correlation between the clinical presentation o f the patient and the most likely microbial pathogen. And, as ever, there will also be a question of money. Most of the newer fl-lactams cannot be called cheap; the cost for I patient can be as high as $100-200 per day. In a life-threatening situation that is of course peanuts, but paying that much for creating future problems of resistance is not so acceptable. Consuming an increasingly high antibiotic budget might well be taken as an indication of a decreasing diagnostic and therapeutic standard in your ward. Let us therefore inflate neither the pharmacy budget nor the microbial troublemakers in our hospital by using these newer fl-lactam antibiotics unnecessarily. 'Magicomycin' is still nothing but a dream.
Penieillins, cephalosporins and tetr
Chapter 26
Host defence mechanisms and/]-Iactam antibiotics: a call for further investigations There is increasing evidence suggesting that many fl-lactam antibiotics might modulate various host defence mechanisms in different ways. Some of these drugs have been shown to influence humoral immune response, the lymphocyte response to mitogens, chemotaxis and phagocytic functions of macrophages or granulocytes (2 g, 3r, 4 R 6R). Recently, the immunomodulating effects of 6 new cephalosporins (cefotaxime, cefoxitin, cefsulodin, cefoperazone, cefotetan, cefmenoxime) were tested in mice using the plaque assay of Jerne, the footpad-swelling test and peritoneal clearance of micro-organisms (7R). The results were compared with the effect in experimental infections with Candida albieans. With none of these antibiotics were the results homogeneous in all test models. In another study it was concluded that a new cephalosporin, CPW 86-363 'owes its good in vivo efficacy to a yet unknown interaction with host defences' (8R). None of these results really seem to permit any conclusions to be drawn concerning the relative ability of the fl-lactam antibiotics to act as immunomodutators. However, the mere fact that they might interfere with the host defence mechanisms should indeed stimulate further investigations.
Seizures and ~-Iactam antibiotics Soon after its introduction to clinical practice, penicillin G was recognized to have direct CNS toxicity (9 c, 10c). Since then, it has repeatedly been shown that high doses of penicillin given intravenously produce neurotoxic reactions similar to those reported after subarachnoid, ventricular space, or direct cortical instillation of penicillin, and that patients with impaired renal function are most predisposed to neurotoxic reactions if no dosage adjustment is made. The clinical picture includes hyperreflexia, myoclonus, and generalized seizures. EECs may show diffuse slowing, hypersynchrony or loss of alpha rhythms (1 lC). The convulsions appear to arise from interference with the inhibitory transmitter function induced by yaminobutyric acid (12s). It has been proposed that decreasing 7-aminobutyric acid inhibition releases intrinsic burst-generating properties in neurons that are triggered by dendritic excitation (13R). Ebersole and Chatt (14g), injecting picoliter volumes of penicillin into the striate
235
cortex of cats, report that both intrinsic neuronal and population interaction abnormalities are responsible for in-vivo neocortical epileptogenesis. However, other factors may also play a role in penicillin-epileptogenesis. At least in rabbits, there appears to be a relation between the neurotoxicity of various penicillins and their hydrophobic character (15R). With an increasing partition coefficient, the neurotoxicity increases in the following order: carbenicillin, ticarcillin, methicillin, penicillin G, oxacillin, phenethicillin, cloxacillin and dicloxacillin. Ampicillin has a partition coefficient similar to that of ticarcillin and methicillin, and there have been few reports of neurotoxicity related to ampicillin therapy. Recently, however, 2 cases of ampicillin-associated seizures were reported (16c). Although they had complex medical problems, the high serum concentrations of ampicillin at the time of seizures without their recurrence after discontinuing the antibiotic allowed the authors to suggest that the seizures were related to the ampicillin therapy. The neurotoxicity of the/~-Iactam antibiotics is certainly not restricted to the penicillin group. The use of cephalosporins in patients with renal insufficiency has also been linked with CNS toxicity (12R). Recently, 2 cases of 'seizure-like activity associated with imipenem' were reported (17c). The important part of the molecule might be the/%lactam ring (18R~, and if so, seizures can be expected in patients receiving all types of new/%lactam antibiotics. High drug dosage, severe renal insufficiency and underlying cerebral dysfunction are then factors which one would then expect to predispose to or potentiate such neurotoxicity.
Hemodynamic reactions in ~-Iactam anaphylaxis Anaphylactic reactions to fl-lactam antibiotics are indeed well known and anaphylaxis due to penicillin has been said to cause 400-800 deaths a year in the United States (19R). Since these acute reactions might progress to death within a matter of minutes, there has been little opportunity to evaluate the hemodynamic and respiratory changes that really occur. It is therefore of interest to focus upon a report describing a patient who experienced an anaphylactic reaction to penicillin (nafcillin i.v.) while being monitored in an intensive-care unit for ischemic heart disease (20c). The anaphylactic shock was characterized by reductions in
236 mean arterial blood pressure, cardiac output, pulmonary capillary wedge pressure, and pulmonary artery pressure, and increases in peak airway pressure and pulmonary vascular resistance. The observations were similar to findings in an animal model of anaphylaxis (21', 22r). All the details given in the report should be of interest for anesthesiologists and other staff on duty in the intensive-care unit. Human anaphylactic reactions are usually unexpected and catastrophic, and all information which can lead to their immediate recognition should be appreciated. Urine glucose test methods and the newer ~-Iactam antibiotics
The copper-reduction method (Clinitest) and the glucose-oxidase method (Diastix, TesTape) are the 2 most commonly used methods for detection of glycosuria. A variety of drugs, including levodopa, salicylates, probenecid, and antimicrobials such as isoniazid, nalidixic acid and fl-lactam antibiotics, are known to be capable - by various mechanisms - of influencing the results of such tests. This fact inspired an investigation to determine the effects on these 2 tests for glycosuria of 10 new fl-lactam antibiotics added in varying concentrations to normal urine samples (23s). Ten fl-lactams were tested: aztreonam, azlocillin, mezlocillin, piperacillin, ticarcillin, cefoperazone, ceftazidime, ceftizoxime, ceftriaxone, cefotaxime and its metabolite deacetylcefotaxime. Clinically obtainable urinary drug concentrations were prepared in vitro, and urine samples from healthy volunteers were used to stimulate diabetic urine by addition of glucose (0.5, 1 and 2%, respectively). All urine samples containing fl-lactams were estimated accurately by the glucose-oxidase method. Employing the copper-reduction method, falsely elevated readings were generally observed at lower glucose concentrations in the urine containing penicillin derivatives. This might mistakenly lead to supplementary administration of insulin. The authors therefore advise against the use of the copperreduction test for glycosuria in diabetic patients receiving fl-lactams, especially penicillin derivatives. MONOBACTAMS Only a few years ago, Syke~s et al (24 R) isolated a new class of antibiotics derived from a strain of Chromobacterium violaceum found in
Chapter 26
T. Midtvedt
the New Jersey marshes. The class has a singlering structure and differs from other fl-lactams in that it has a sulfonic acid salt substituted at the 1-position and has 1 fused thiazolidine ring. 'Monobactam' is the name given to this group of antibiotics, so-called because of their monocyclic ring structure, bacterial origin and /3lactam nucleus. Aztreonam is so far the most potent of this new monobactam family and is the only derivative which has to some extent been evaluated clinically. A world-wide overview of 2117 patients who have received aztreonam shows that the adverse reactions so far described are qualitatively similar to those usually reported for other fl-lactam antibiotics, i.e. rash, eosinophilia, transient increase in hepatic enzyme parameters and phlebitis at the infusion site (25R). There was an apparent lack of adverse effects on the kidney, inner ear and blood coagulation system. The results suggest that aztreonam may be a fairly safe drug. However, this is by no means the first time that a new class of drugs is initially reported to be safe and well tolerated, and several areas need to be further elucidated before a definitive view is taken. One key problem in the introduction of new groups of fl-lactam antibiotics is the use of these compounds in penicillin-allergic patients. In the overview mentioned, a history of allergy to penicillin or cephalosporins was present in 134 of the 2117 patients treated with aztreonam. Of these 134 patients, only 1 developed a possible IgE-mediated urticarial rash, thought to be a hypersensitivity reaction. Aztreonam thus seems to be a safe drug in patients allergic to penicillins or c~9halosporins. Possible drug interactions should always be investigated when new drugs are likely to be introduced. The pharmacokinetic interactions of aztreonam with cefradine (cepharadine), clindamycin, gentamicin, metronidazole, and nafcillin have recently been investigated in a single-dose, 3-way balanced cross-over study in 48 healthy volunteers (26c). Twenty-fourhour cumulative urinary excretion of aztreonam and clindamycin rose by 5.1 and 10.9%, respectively, when they were administered simultaneously. Maximum serum concentrations of aztreonam were reduced by about 12 and 10%, respectively, when it was given with gentamicin and metronidazole. The percentage of aztreonam bound to protein fell by 5% when aztreonam was given in conjunction with nafcillin and rose by about 5% when it was accompanied by cefradine. All these altera-
Penicillins, cephalosporins and tetrao'clines Chapter26 tions were statistically significant, but whether they should give rise to therapeutic concern remains to be seen. The same holds true for multiple-dose regimens. It should also be mentioned that all drugs were administered through separate lines and that they were mixed in single-infusion bottles. Possible pharmaceutical interactions must therefore also be looked for. CARBAPENEMS
Streptomyces cattle), is yet another antibiotic-producing organism which was first isolated from soil in New Jersey. The first compound to be isolated in a group of antibiotics with a carbapenem nucleus obtained from this organism was thienamycin. The carbapenems are characterized by the 4:5 fused ring lactam of the penicillins with the substitution of carbon for sulfur and with unsaturation in the 5-member ring. The first problem to be overcome with thienamycin was its marked instability. This was accomplished through the synthesis of a N-formimidoyl derivative, now given the generic name 'imipenem'. The second problem to be solved was its marked metabolic inactivation in the kidney, owing to the presence of a brush-border dipeptidase, dehydropeptidase-l; that was accomplished by finding a highly selective enzyme inhibitor, now known as 'cilastatin'. This novel combination of a/~lactam antibiotic (imipenem) and an enzyme inhibitor (cilastatin) has now been on clinical trial for some time, and the first review, covering adverse experiences and tolerability in some 2500 patients receiving the combination has now been published (27c). Basically, the safety profile of this antibiotic appears to be similar to that of other/~-lactam antibiotics. Clinical adverse reactions were predominantly related to the gastrointestinal system. Nausea and/or vomiting occurred in approximately 4%, and diarrhea in about 3.3%. Antibiotic-related diarrhea, defined as comprising either positive assay results for Clostridium diffieile toxin or positive culture results for C. difficile, occurred in 0.79%. This is a rather high value among the /~-lactam antibiotics. However, factors such as prior antibiotic courses or prolonged hospital stay may here have been involved. No anaphylactic reactions were reported. However, it has to be added that patients with a history of serious/3-1actam allergy were supposed to be excluded from these trials. In a
237
series of 12 patients with previously known mild to moderate allergic reactions to penicillin, imipenem cilastatin induced allergic manifestations in 2. Although the incidence of seizures during imipenem cilastatin therapy was no higher than in patients treated with other antibiotics (approx. 1.5% in both groups), the authors nevertheless believed that the combination in some patients gave rise to seizures. They cite preliminary, unpublished data from the Mayo Clinic indicating an incidence of seizure of about 5% in severely ill infected patients. Recently, 2 cases of 'seizure-like activity' in patients receiving imipcnem have been reported (17c). Until more definitive data are presented, it might be wise not to use imipenem cilastatin in patients with a history of seizures or receiving anticonvulsant therapy. In patients who developed seizures during imipenem-cilastatin therapy, antibiotic administration should be discontinued and anticonvulsant therapy should be started. The most frequent adverse laboratory experiences were transient elevations of liver Junction test values; however, the abnormalities were usually minor and of little (if any) clinical consequence. Of greater clinical importance may be the observation in a group of 717 severely ill patients from the United States of a 3.2% incidence of colonization with bacteria resistant to imipenem and an 8% incidence of colonization with yeast or moulds. There was an approximately 4% incidence of superinfections, most often caused by resistant Pseudomonas aeruginosa, P. maltophilia or yeast. Hopefully, imipenem cilastatin will prove, as Neu has put it, to be a 'useful addition to our current antimicrobial armamentarium if it is used properly' (28R). OTHER PENICILLINS DicloxacUlin and nephrotoxicity In 1975, K6hler et al (29 c) treated l0 patients with high intravenous doses of dicloxacillin (8 16 g/24 h) and noted a transient increase in serum creatinine. They considered the toxic effect to be dose-related. Recently, Isacson and Collert reported impairment of renal function in patients subjected to joint replacement (30c). This side effect appeared in 35 of 278 patients who received prophylaxis with intravenous dicloxacillin (13 g in the course of approximately
238 3 days). This high rate contrasted with a zero incidence in 72 patients undergoing the same operative procedures without receiving any dicloxacillin. Thirteen of the 35 patients were clinically affected; 2 had to be dialyzed and 1 died. These Swedish data have already being criticized as 'hardly acceptable (...) because a number of biases may lead to wrong conclusions' (31R). Of course, the only way to find out whether dicloxacillin is nephrotoxic or not is to perform a prospective, strictly randomized comparative study. In the meantime, possibly the main thing to remember is that all patients with renal complications were older than 60 years, with a mean age of 76 years. Especially in elderly patients, serum drug concentrations should be performed; it should as always be realized that dosage recommendations are usually based upon findings in young and healthy volunteers. TETRACYCLINES (SED-IO, 467; SEDA-8,
251; SEDA-9, 234) Tetracyelines, cancer and AIDS The ability of tetracyclines, including doxycycline, to inhibit protein synthesis in microbial and mammalian systems is well known. In man, this ability has not been utilized therapeutically. However, recent investigations indicate that tetracyclines might exert antiproliferative effects in various tumor-model systems in vivo. The rational for using tetracyclines was the assumption that intentional inhibition of mitochondrial synthesis would reduce the cell's energy-generating capacity, ultimately leading to an arrest of multiplication. Most active in this field has been a group from the Netherlands, and they have recently demonstrated that doxycycline arrests the proliferation of cells in a tissue culture secondary to inhibition of mitochondrial protein synthesis, and that doxycycline treatment could lead to a complete regression of a transplanted human renal carcinoma in athymic (nude) rats and of a syngenic T-cell tumor of the rat (32R). These authors defend the hypothesis that tetracyclines, especially doxycycline, can be utilized as cytostatic agents in the treatment of cancer. They found that T-cell proliferation was sensitive to treatment with tetracyclines. Recent findings that the duration of survival of heart transplants increased in mice treated with doxycycline might be explained by a similar mechanism (33R).
Chapter 26 T. Midtvedt Whether the tetracyclines can be used as cytostatic adjuvants remains to be seen. However, even the slightest indication that they interfere with the proliferation and functioning of T-cells should be further investigated. If this holds true, they might have to be avoided in the treatment of infections in AIDS patients.
Minocycline and acute hepatic injury (SED10, 474) Tetracyclines are known to produce hepatic injury, and this is now also known to hold good for minocycline (34c): A 57-year-old non-obese, non-diabetic, non-alcoholic woman was admitted to hospital because of a suicide attempt. After 24 hours in hospital an aspiration pneumonia developed, and initially she was given ampicillin sodium. The culture disclosed Staphylococcus aureus and Streptococcus salivarius and ampicillin was replaced by minocycline hydrochloride (400 mg/d i.v.) and penicillin G (10,000,000 IU/d i.v.). Four days later, the patient complained of anorexia, nausea and diffuse abdominal pain. Results of liver function tests were abnormal whereas the results of specific serological tests for hepatitis A and B virus, Epstein-Barr virus, cytomegalovirus and toxoplasmosis all were negative. After some days, a mild jaundice developed, and ultrasonography and endoscopic retrograde cholangiopancreatography excluded common bile duct obstruction. The cliniciansjudged minocyclineto be the offending agent, and therapy with minocyclinewas discontinued after approximately 1 week. Additionally, penicillinG was replaced with penicillinV (3,000,000 IU/d p.o. for 7 days). Laparoscopy 8 days after discontinuation of minocycline therapy showed a greenish, smooth, slightly enlarged liver. Light microscopy disclosed diffuse steatosis thdt displaced the nuclei of the hepatocytes. However, some hepatocytes evidenced microvesicular fat without displaced nucleus. There was no foamy fatty vacuolization but some fatty cysts, ballooning degeneration and a mild periportal inflammation. The clinical outcome was favorable with a complete normalization of all liver function tests within 3 weeks after minocycline therapy was discontinued. Previously, most cases of tetracyclineinduced hepatotoxic effects have been observed in women, and the susceptibility seems to be enhanced by pregnancy and renal disease (35R, 36c, 37c). As in the present case, clinical signs and biochemical disorders reflecting a hepatic disturbance usually appear within a week on tetracycline therapy. A reduced hepatic concentration of choline has recently been claimed to increase the risk of tetracycline-induced hepatic injuries (SEDA-8, p. 253). Whilst the
Penicillins, cephalosporins and tetracyclines
Chapter 26
239
mechanisms are still largely unknown, it seems wise to keep in mind that all tetracyclines, including minocycline, may now be regarded as potential causes of hepatic injury.
All systemic medications, including minocycline, were immediately discontinued. The galactorrhea ceased within a week, and the skin pigmentation slowly resolved during the subsequent 6 months.
Minocycline and pigmentation (SED.4-9, 235)
Most probably, the galactorrhea in this patient was due to the use of perphenazine. Drugs blocking the dopaminc receptors in the hypothalamus, such as phenothiazine, are known to be able to influence the level of serum prolactin (41c). It seems reasonable to assume that the iron-containing particles in the milk were related to her use of minocycline. However, the possibility that the onset can have been triggered by a concomitant use of amitriptyline is supported by another report in which minocycline and amitriptyline were being concurrently administered and a dramatic, rapidly progressive pigmentation occurred after only 2 months (42c). The patient, a 30-year-old white woman, had been taking amitriptyline 200 mg/d for several months prior to being placed on minocycline 100 mg/d. The authors postulated that 'amitriptyline may possibly have a synergistic effect with minocycline, potentiating the functional disruption in cellular activity that leads to hyperpigmentation and thereby enhancing the clinical demonstration of this effect.' Obviously, there is a need for more investigations about the mechanisms by which minocycline causes functional disruptions in cellular activity. The dark deeds caused by minocycline should be elucidated before more patients are turned black!
The ability of minocycline to induce pigmentation in various organs is well established (SEDA-8, 252; SEDA-9, 235), and new reports continue to come. However, in many cases there is a history of unsupervised usage of high doses for rather long periods of time, e.g. 400 mg/d for 2 years (38 c) or 200 mg/d for 18 years (39c). In a recent report, the authors focus upon black galactorrhea as a consequence of minocycline and phenothiazine therapy (40c): A 24-year-old woman had received minocycline hydrochloride 100 mg twice daily for almost 4 years to control her pustulocystic acne. During this time, irregular, darkly pigmented macules developed in areas of acne scarring. Periodically, she was also receiving perphenazine, amitriptyline hydrochloride and diphenhydramine hydrochloride for an unrelated psychiatric problem. One day the patient phoned her doctor to tell him that a black fluid was emerging from her nipples. She was investigated later the same day, and palpation of the breasts resulted in the expression of small droplets of milk containing a tinge of pigmented liquid. Microscopic examination showed nurr/,erous macrophages, containing aggregates of particles staining positive for iron and assumed to be hemosiderin. Laboratory screening tests for hepatic, renal and adrenal function yielded normal results.
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6. Voss R, Lang J, Ditter H et al (1984) Antibiotika-induzierte Hemmung der Granulozytenaggregation. Med. Welt, 35, 1518. 7. Gillissen G, Pusztai-Markos ZS (1984) Influence of antibiotics on immunological parameters: significance in experimental infections. Drugs Exp. Clin. Res., 10, 813. 8. Lain C, Laber G, Hildebrandt J e t al (1984) Therapeutic relevance of antibiotic-induced augmentation of host defences in experimental infections. Drugs Exp. Clin. Res., 10, 703. 9. Rammelkamp CH, Keefer CS (1943) The absorption, excretion and toxicity of penicillin administered by intrathecal injection. Am. J. Med. Sci., 205, 342. 10. Pilcher C, Meacham WF (1943) The chemotherapy of intracranial infections. Ill. The treatment of experimental staphylococci meningitis with intrathecal administration of penicillin. J. Am. Med. Assoc., 123, 330. 11. Oldstone MBA, Nelson E (1966) Central ner-
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27. Calandra GB, Brown KR, Grad LC et al (1985) Review of adverse experiences and tolerability in the first 2516 patients treated with imipenem/cilastatin. Am. J. Med., 78, Suppl. 6A, 73. 28. Neu HC (1985) Summary of imipenem/cilastatin symposium. Am. J. Med., 78, Suppl. 6A, 165. 29. K6hler H, Weihrauch TR, Prellwitz W et al (1975) Side-effects of high-dose dicloxacillin therapy. In: Proceedings, 9th International Congress of Chemotherapy, p 333. Cited in Ref. 31. 30. lsacson J, Collert S (1984) Renal impairment after high doses of dicloxacillin-prophylaxis in joint replacement surgery. Acta Orthop. Scand., 55, 407. 31. Nordbring F (1984) Is dicloxacillin nephrotoxic? Acta Orthop. Scand., 55, 405. 32. Kroon AM, Dontje BHJ, Holtrop M et al (1984) The antitumor action of doxycycline. Drugs Exp. Clin. Res., 10, 759. 33. Bellahsene A, Forsgren A (1985) Effect ofdoxycycline on immune response in mice. Infect. Immun., 48, 556. 34. Burette A, Finet C, Prigogine T et al (1984) Acute hepatic injury associated with minocycline. Arch. Intern. Med., 144, 1491. 35. Davis JS (1968) Liver damage due to tetracycline and its relationship to pregnancy. In: Meyler L, Peck MH (Eds), Drug-Induced Diseases, p 103. Excerpta Medica, Amsterdam. 36. Schultz J, Adamson JS, Workman WN et al (1968) Fatal liver disease after intravenous administration of tetracycline in high dosage. N. Engl. J. Med., 269, 999. 37. Dowling HF, Lepper MH (1964) Hepatic reactions to tetracycline. J. Am. Med, Assoc., 188, 235. 38. Wolfe ID, Reichmister J (1984) Minocycline hyperpigmentation: skin, tooth, nail, and bone involvement. Cutis, 33, 457. 39. Tsu Tung Liu T, May N (1985) Pigmentary changes due to long-term minocycline therapy. Cutis, 35, 254. 40. Basler RSW, Lynch PJ (1985) Black galactorrhea as a consequence of minocycline and phenothiazine therapy. Arch. DermatoL, 121, 417. 41. Gelenburg AJ, Cooper DS, Doller JC et al (1979) Galactorrhea and hyperprolactinemia associated with amoxapine therapy. J. Am. Med. Assoc., 242, 1900. 42. Basler RSW, Goetz CS (1985) Synergism of minocycline and amitriptyline in cutaneous hyperpigmentation. J. Am. Acad. Dermatol., 12, 577.